CN1874993A

CN1874993A - Modafinil compositionsc

Info

Publication number: CN1874993A
Application number: CNA2004800319825A
Authority: CN
Inventors: 马加利·布戈尔·希基; 马修·彼得森; 厄恩·奥尔马松; 马克·奥利韦拉
Original assignee: Cephalon LLC
Current assignee: Cephalon LLC
Priority date: 2003-09-04
Filing date: 2004-09-04
Publication date: 2006-12-06
Anticipated expiration: 2024-09-04
Also published as: BRPI0413777A; CN1874993B

Abstract

Co-crystals and solvates of racemic, enantiomerically pure, and enantiomerically mixed modafinil are formed and several important physical properties are modulated. The solubility, dissolution, bioavailability, dose response, and stability of modafinil can be modulated to improve efficacy in pharmaceutical compositions.

Description

Modafinil compositions

The cross reference of related application

The application is the part continuation application of the application PCT/US03/27772 of submission on September 4th, 2003, application PCT/US03/27772 has required the U. S. application 10/378 of submission on March 3rd, 2003,956, the U.S. Provisional Application of submitting on April 18th, 2,003 60/463,962, the U.S. Provisional Application of submitting on February 28th, 2,003 60/451, the right of priority of the U.S. Provisional Application 60/487,064 that on July 11st, 213 and 2003 submitted to.The U. S. application of submitting on March 3rd, 1 10/378,956 has required the right of priority of the U.S. Provisional Application 60/360,768 of submission on March 1st, 2002.

The application still is the part continuation application of the U. S. application 10/660,202 submitted on September 11st, 2003, and U. S. application 10/660,202 has required the right of priority of the PCT/US03/27772 that submitted on September 4th, 2003.The U. S. application 10/660 that on September 11st, 1 submitted to, 202 also require the U. S. application 10/637 of submission on August 8th, 2003,829 right of priority, U. S. application 10/637,829 is the U. S. application of submitting on November 18th, 2,002 10/295,995 divide an application, U. S. application 10/295,995 is the continuation application of the U. S. application 10/232,589 of submission on September 3rd, 2002, U. S. application 10/232,589 have required the U.S. Provisional Application 60/406 of submission on August 30th, 2002,974, the right of priority of the U.S. Provisional Application 60/356,764 that the U.S. Provisional Application 60/380,288 that on May 15th, 2002 submitted to and on February 15th, 2002 submit to.The U. S. application 10/660 that on September 11st, 1 submitted to, 202 still is the U. S. application of submitting on May 30th, 2,003 10/449,307 part continuation application, U. S. application 10/449, the U.S. Provisional Application 60/439 that the U.S. Provisional Application that 307 U.S. Provisional Applications that require to submit on April 18th, 2003 were submitted at January 31 in 60/463,962,2003 was submitted on January 10, in 60/444,315,2003, the right of priority of the U.S. Provisional Application 60/384,152 that on May 31st, 282 and 2002 submitted to.The U. S. application of submitting on September 11st, 1 10/660,202 still be the part continuation application of U. S. application 10/601,092 of submission on June 20th, 2003.The U. S. application 10/660 that on September 11st, 1 submitted to, 202 also require the U.S. Provisional Application 60/451 of submission on February 28th, 2003,213, the U.S. Provisional Application of submitting on April 18th, 2,003 60/463, the right of priority of the U.S. Provisional Application 60/487,064 that on July 11st, 962 and 2003 submitted to.

The application still is the part continuation application of the application PCT/US04/06288 that submitted on February 26th, 2004, application PCT/US04/06288 has required the U.S. Provisional Application 60/451 of submission on February 28th, 2003,213, the U.S. Provisional Application 60/487 that on July 11st, 2003 submitted to, 064, the application PCT/US03/27772 that on September 4th, 2003 submitted to, the U. S. application 10/660 that on September 11st, 2003 submitted to, 202, the application PCT/US03/06662 that on March 3rd, 2003 submitted to, the U.S. Provisional Application 60/508 that on October 2nd, 2003 submitted to, 208, the U.S. Provisional Application 60/542 that on February 6th, 2004 submitted to, 752, the U.S. Provisional Application 60/463 that on April 18th, 2003 submitted to, 962, the U. S. application 10/449 that on May 30th, 2003 submitted to, 307, the U.S. Provisional Application 60/456 that on March 18th, 2003 submitted to, 027, the U. S. application 10/601,092 that on June 20th, 2003 submitted to, the right of priority of the application PCT/US03/41273 that the application PCT/US03/19574 that on June 20th, 2003 submitted to and on December 24th, 2003 submit to.

The application also requires the U.S. Provisional Application 60/508 of submission on October 2nd, 2003,208, the U.S. Provisional Application 60/542 that on February 6th, 2004 submitted to, 752, the U.S. Provisional Application 60/560 that on April 6th, 2004 submitted to, 411, the U.S. Provisional Application 60/573 that on May 21st, 2004 submitted to, 412, the U.S. Provisional Application 60/579 that on June 12nd, 2004 submitted to, 176, the U.S. Provisional Application 60/581 that on June 22nd, 2004 submitted to, 992, the U.S. Provisional Application 60/586 that on July 9th, 2004 submitted to, the right of priority of the U.S. Provisional Application 60/588,236 that on July 15th, 752 and 2004 submitted to.

Above-mentioned all applications that are required right of priority are all incorporated into this paper as a reference in full.

Technical field

The present invention relates to contain API composition, comprise this API pharmaceutical composition, and preparation method thereof.

Background technology

Active pharmaceutical component (API) in the pharmaceutical composition can be prepared as multiple different form.Can prepare this API makes it have multiple different chemical species to comprise chemical derivative, solvate, hydrate, cocrystallization or salt.This API can also be prepared as has different profiles.For example, API can be unbodied, can have different crystalline polymorphs or solvation that can be different or hydration status and exist.By changing the form of API, might change its physical properties.For example, crystalline polymorph typically has the solubleness that differs from one another, and makes that the more stable polymorphic form of thermodynamics is poorer than the solubility of the more unsettled polymorphic form of thermodynamics.Medicinal polymorphic form can also be in many properties differences, as storage life, bioavailability, morphology, vapour pressure, density, color and compressibility.Therefore, the variation of the crystalline state of API is wherein to regulate one of many aspects of its physical properties.

It is favourable that these API have the new form of improving character, particularly as oral preparations.Particularly, expectation is identified and is shown the remarkable improved form that improves the API of character (comprising the water-soluble and stable of increase).In addition, expectation improves the workability or the preparation of medicinal preparations.For example, needle-like crystal form or the crystal habit of API can cause gathering, even therein in API and other material blended composition, obtain uneven mixture.Acicular form can also cause filtration problem (referring to for example, people such as Mirmehrabi, J.Pharm.Sci.Vol.93, No.7,1692-1700 page or leaf, 2004).Also expectation increases the dissolution rate of pharmaceutical composition in water that contains API, increases the bioavailability and the faster onset that the therapeutics effect is provided of liquid preparations for oral administration.Also expect to have a kind of API of form, with it during to the object administration, its API than the present form known of equivalent reaches peak serum concentration sooner, has the comprehensive engagement of more persistent therapeutics plasma concentration and Geng Gao.

Provigil is used for the treatment of the API that suffers from narcoleptic object, and it is water-soluble hardly.Provigil (CAS registration number: 68693-11-8) represent by structural formula (I):

Provigil is owing to the S=O group of chirality becomes chiral molecules.Therefore, Provigil exists as two isomer, is R-(-)-Provigil and S-(+)-Provigil.It is favourable that Provigil has the new form of improving character, particularly as oral preparations.Particularly, the expectation evaluation shows the water solubility of remarkable increase and the improved form of the Provigil of chemistry and shape stability.Also expectation increases the dissolution rate of pharmaceutical composition in water that contains API, increases the bioavailability and the faster onset that the therapeutics effect is provided of liquid preparations for oral administration.Also expect to have a kind of API of form, with it during to the object administration, the comprehensive engagement that it reaches peak serum concentration sooner and/or have more persistent therapeutics plasma concentration and Geng Gao than the API of the present form known of equivalent when high dosage.

Summary of the invention

Have been found that the cocrystallization and the solvate that can obtain Provigil now, wherein have many have with the API of free form compare different character.

Therefore, in first aspect, the invention provides the cocrystallization of Provigil, wherein cocrystallization formation thing (former) is ether, thioether, alcohol, mercaptan, aldehyde, ketone, thioketones, nitric ether, phosphoric acid ester, thiophosphatephosphorothioate, ester, thioesters, sulfuric ester, carboxylic acid, phosphonic acids, phospho acid, sulfonic acid, acid amides, primary amine, secondary amine, ammonia, tertiary amine, sp2 amine, thiocyanic ester, cyanamide, oxime, nitrile, diazonium, Organohalogen compounds, nitro, S-heterocycle, thiophene, N-heterocycle, pyrroles, O-heterocycle, furans, epoxide, hydroxamic acid, imidazoles or pyridine.

The present invention provides the pharmaceutical composition that comprises the Provigil cocrystallization in addition.Typically, pharmaceutical composition comprises one or more pharmaceutically useful carriers, thinner or vehicle in addition.Pharmaceutical composition of the present invention is described in further detail following.

In one aspect of the method, the invention provides the method for the cocrystallization of preparation Provigil, it comprises:

(a) provide Provigil;

(b) provide the cocrystallization compatible to form thing, make cocrystallization formation thing and Provigil can form cocrystallization with the functional group of Provigil;

(c) under crystallization condition, Provigil and cocrystallization formation thing ground, heat, be total to distillation, congruent melting is melted or in solution, contact the feasible solid phase that forms; With

(d) separate the cocrystallization that comprises Provigil and cocrystallization formation thing.

In one embodiment, cocrystallization formation thing has at least a functional group that is selected from ether, thioether, alcohol, mercaptan, aldehyde, ketone, thioketones, nitric ether, phosphoric acid ester, thiophosphatephosphorothioate, ester, thioesters, sulfuric ester, carboxylic acid, phosphonic acids, phospho acid, sulfonic acid, acid amides, primary amine, secondary amine, ammonia, tertiary amine, sp2 amine, thiocyanic ester, cyanamide, oxime, nitrile, diazonium, Organohalogen compounds, nitro, S-heterocycle, thiophene, N-heterocycle, pyrroles, O-heterocycle, furans, epoxide, hydroxamic acid, imidazoles or pyridine.

The Provigil that the embodiment of the present invention that include but not limited to cocrystallization, polymorphic form and solvate can comprise racemize Provigil, enantiomeric pure (promptly, R-(-)-Provigil or S-(+)-Provigil), or the Provigil of enrichment (55 arriving about 90%ee according to appointment).Similarly, cocrystallization form thing and solvent molecule (as, in solvate) form that also can be used as racemic, enantiomeric pure or enrichment is present in embodiment of the present invention.

In one aspect of the method, the invention provides the method that increases the solubleness of Provigil in the water that is used for pharmaceutical composition or medicine, simulated gastric fluid (SGF) or simulated intestinal fluid (SIF), this method comprises:

(a) provide Provigil;

In one aspect of the method, the invention provides the method for the dissolution rate of regulating Provigil, thereby increase it at simulated gastric fluid or simulated intestinal fluid or the water-based dissolution rate in solvent or multiple solvent, this method comprises:

(a) provide Provigil;

In one aspect of the method, the invention provides the method for the bioavailability of regulating Provigil, thereby increase AUC, shorten time of reaching Tmax, prolong concentration in time length of _ Provigil more than the Tmax or increase Cmax, this method comprises:

(a) provide Provigil;

In yet another aspect, the invention provides the method for the dose response of regulating the Provigil that is used for pharmaceutical composition or medicine, this method comprises:

(a) provide Provigil;

In another aspect of the present invention, the invention provides the method for the stability (comparing with reference form such as its free form) of improving Provigil, this method comprises:

(a) provide Provigil;

In one aspect of the method, the invention provides the morphology methods that changes Provigil, this method comprises:

(a) provide Provigil;

In one aspect of the method, therefore the present invention provides the method for screening co-crystallization compound, and it comprises

(a) provide (i) Provigil and (ii) compatible cocrystallization to form thing, make cocrystallization formation thing and Provigil can form cocrystallization with the functional group of Provigil; With

(b) process that may further comprise the steps by the every kind of combination experience that makes Provigil and cocrystallization form thing is screened the cocrystallization of Provigil and cocrystallization formation thing:

(i) under crystallization condition, Provigil and cocrystallization formation thing ground, heat, be total to distillation, congruent melting is melted or in solution, contact the feasible solid phase that forms; With

(ii) separate and comprise that Provigil and cocrystallization form the cocrystallization of thing.

Optionally embodiment relates to the method for screening co-crystallization compound, and it comprises:

(a) provide (i) Provigil to form thing, make various cocrystallization formation things and Provigil can form cocrystallization with (ii) compatible multiple different cocrystallization with the functional group of Provigil; With

In one aspect of the method, the invention provides the cocrystallization composition that comprises cocrystallization, wherein said cocrystallization comprises that Provigil and cocrystallization form thing.In another embodiment, cocrystallization has the character of comparing (it comprises hydrate and solvate) improvement with free form.In another embodiment, the character of improvement is selected from: the bioavailability of the solubleness of increase, the dissolution rate of increase, increase, the dose response of increase or described herein other character.

In another embodiment, the invention provides and comprise that Provigil and cocrystallization form the cocrystallization of thing, cocrystallization forms thing and is selected from: propanedioic acid, oxyacetic acid, fumaric acid, tartrate, citric acid, succsinic acid, 2,5-resorcylic acid, oxalic acid, 1-hydroxyl-2-naphthoic acid, vitamin B13, pentanedioic acid, L-tartrate, palmitinic acid, L-proline(Pro), Whitfield's ointment, lauric acid, L MALIC ACID and toxilic acid.

In another embodiment, the invention provides following cocrystallization: Provigil: propanedioic acid, Provigil: oxyacetic acid, Provigil: toxilic acid, Provigil: L-tartrate, Provigil: citric acid, Provigil: succsinic acid, Provigil: DL-tartrate, Provigil: fumaric acid (I type), Provigil: fumaric acid (II type), Provigil: 2, the 5-resorcylic acid, Provigil: oxalic acid, Provigil: 1-hydroxyl-2-naphthoic acid, R-(-)-Provigil: propanedioic acid, R-(-)-Provigil: succsinic acid, R-(-)-Provigil: citric acid, R-(-)-Provigil: DL-tartrate, R-(-)-Provigil: 1-hydroxyl-2-naphthoic acid, R-(-)-Provigil: vitamin B13, R-(-)-Provigil: pentanedioic acid, R-(-)-Provigil: L-tartrate, R-(-)-Provigil: palmitinic acid, R-(-)-Provigil: L-proline(Pro), R-(-)-Provigil: Whitfield's ointment, R-(-)-Provigil: lauric acid, R-(-)-Provigil: L MALIC ACID and R-(-)-Provigil: 2, the 5-resorcylic acid.

In another embodiment, the invention provides new polymorphic form or the cocrystallization of racemize Provigil (form VII).

In another embodiment, the invention provides following Provigil solvate: acetate, tetrahydrofuran (THF), 1,4-two _ alkane, methyl alcohol, Nitromethane 99Min., acetone, o-Xylol, benzene, ethanol, phenylcarbinol, Virahol, acetonitrile and toluene.

Method of the present invention can comprise separately that the other Provigil cocrystallization that wherein will produce thus is mixed into the one or more steps in the pharmaceutical composition.

In another embodiment, pharmaceutical composition comprises the release profiles of one or more change in racemize Provigil, R-(-)-Provigil and S-(+)-Provigil.The release profiles that changes can comprise for example two or more maximal plasma concentration, as two-fold (dual) release profiles.

The present invention further provides the medicine and the production method thereof of the cocrystallization that comprises Provigil.Typically, medicine comprises one or more pharmaceutically useful carriers, thinner or vehicle in addition.Medicine of the present invention is described in further detail following.

Method of the present invention can comprise separately that the other Provigil cocrystallization that wherein will produce thus is mixed into the one or more steps in the medicine.

In another aspect of the present invention, provide treatment to suffer from wherein Provigil to the method for the object (preferably human subjects) of described illness is the excessive daytime sleepiness effective active medicine, relevant with hypnolepsy, multiple sclerosis is relevant fatigue, Infertility, eating disorder, notes attention-deficit hyperactivity disease (ADHD), Parkinson's disease, incontinence, sleep apnea or myopathy.This method comprises the cocrystallization that comprises Provigil of object drug treatment significant quantity or the polymorphic form of solvate or Provigil.

Description of drawings

Fig. 1-comprise PXRD diffractogram of the cocrystallization of Provigil and propanedioic acid.

Fig. 2-comprise DSC differential thermogram of the cocrystallization of Provigil and propanedioic acid.

Fig. 3-comprise TGA differential thermogram of the cocrystallization of Provigil and propanedioic acid.

Fig. 4 A and 4B-comprise the Raman spectrum (Fig. 4 A) of the cocrystallization of Provigil and propanedioic acid, and Provigil (following spectrum), propanedioic acid (intermediary spectrum) and comprise three Raman spectrums (Fig. 4 B) of the cocrystallization (top spectrum) of Provigil and propanedioic acid.

Fig. 5 A and 5B-comprise the infrared spectra (Fig. 5 A) of the cocrystallization of Provigil and propanedioic acid, and Provigil (top spectrum), propanedioic acid (intermediary spectrum) and comprise three infrared spectras (Fig. 5 B) of the cocrystallization (top spectrum) of Provigil and propanedioic acid.

Fig. 6 A-comprises the PXRD diffractogram of the cocrystallization of Provigil and propanedioic acid.

Fig. 6 B-comprises the DSC differential thermogram of the cocrystallization (getting self-grind) of Provigil and propanedioic acid.

Fig. 7-Provigil: the accumulation graph of propanedioic acid cocrystallization.

Fig. 8 A and 8B-comprise the PXRD diffractogram of the cocrystallization of Provigil and oxyacetic acid, be respectively remove background and directly collect and obtain.

Fig. 9 A and 9B-comprise the PXRD diffractogram of the cocrystallization of Provigil and toxilic acid, be respectively remove background and directly collect and obtain.

Figure 10-comprise PXRD diffractogram of Provigil and the tartaric cocrystallization of L-.

Figure 11 A-comprises the PXRD diffractogram of the cocrystallization of Provigil and citric acid.

Figure 11 B-comprises the DSC differential thermogram of the cocrystallization of Provigil and citric acid.

Figure 12 A and 12B-comprise the PXRD diffractogram of the cocrystallization of Provigil and succsinic acid, be respectively remove background and directly collect and obtain.

Figure 13-comprise DSC differential thermogram of the cocrystallization of Provigil and succsinic acid.

Figure 14-comprise accumulation graph of the cocrystallization of Provigil and succsinic acid.

Figure 15-comprise PXRD diffractogram of Provigil and the tartaric cocrystallization of DL-.

Figure 16-comprise PXRD diffractogram of the cocrystallization of Provigil and fumaric acid (I type).

Figure 17-comprise accumulation graph of the cocrystallization of Provigil and fumaric acid (I type).

Figure 18-comprise PXRD diffractogram of the cocrystallization of Provigil and fumaric acid (II type).

Figure 19-comprise Provigil and 2, the PXRD diffractogram of the cocrystallization of 5-resorcylic acid.

Figure 20-comprise PXRD diffractogram of the cocrystallization of Provigil and oxalic acid.

Figure 21-comprise PXRD diffractogram of the cocrystallization of Provigil and 1-hydroxyl-2-naphthoic acid.

Figure 22-comprise PXRD diffractogram of the cocrystallization of R-(-)-Provigil and propanedioic acid.

Figure 23-comprise DSC differential thermogram of the cocrystallization of R-(-)-Provigil and propanedioic acid.

Figure 24-comprise PXRD diffractogram of the cocrystallization of R-(-)-Provigil and succsinic acid.

Figure 25-comprise DSC differential thermogram of the cocrystallization of R-(-)-Provigil and succsinic acid.

Figure 26-comprise PXRD diffractogram of the cocrystallization of R-(-)-Provigil and citric acid.

Figure 27-comprise DSC differential thermogram of the cocrystallization of R-(-)-Provigil and citric acid.

Figure 28-comprise PXRD diffractogram of R-(-)-Provigil and the tartaric cocrystallization of DL-.

Figure 29-comprise DSC differential thermogram of R-(-)-Provigil and the tartaric cocrystallization of DL-.

Figure 30-comprise PXRD diffractogram of the cocrystallization of R-(-)-Provigil and 1-hydroxyl-2-naphthoic acid.

Figure 31-comprise DSC differential thermogram of the cocrystallization of R-(-)-Provigil and 1-hydroxyl-2-naphthoic acid.

The PXRD diffractogram of the cocrystallization that comprises R-(-)-Provigil and 1-hydroxyl-2-naphthoic acid of Figure 32-derive from high-throughput experiment.

Figure 33-comprise PXRD diffractogram of the cocrystallization of R-(-)-Provigil and vitamin B13.

Figure 34-comprise DSC differential thermogram of the cocrystallization of R-(-)-Provigil and vitamin B13.

Figure 35-comprise PXRD diffractogram of the solvate of Provigil and acetate.

Figure 36-comprise TGA differential thermogram of the solvate of Provigil and acetate.

Figure 37-comprise DSC differential thermogram of the solvate of Provigil and acetate.

Figure 38-comprise Raman spectrum of the solvate of Provigil and acetate.

Figure 39-comprise PXRD diffractogram of the solvate of Provigil and tetrahydrofuran (THF).

Figure 40-comprise Provigil and 1, the PXRD diffractogram of the solvate of 4-two _ alkane.

Figure 41-comprise PXRD diffractogram of Provigil and methanol solvent compound.

Figure 42-comprise TGA differential thermogram of Provigil and methanol solvent compound.

Figure 43-comprise DSC differential thermogram of Provigil and methanol solvent compound.

Figure 44-comprise PXRD diffractogram of the solvate of Provigil and Nitromethane 99Min..

Figure 45-comprise PXRD diffractogram of the solvate of Provigil and acetone.

Figure 46-comprise PXRD diffractogram of the solvate of Provigil and acetone.

Figure 47-comprise Provigil and 1, the PXRD diffractogram of the solvate of 2-ethylene dichloride.

The PXRD diffractogram of the polymorphic form of Figure 48-Provigil (Form VII).

Figure 49-Provigil: the stability diagram of propanedioic acid cocrystallization in 26 time-of-weeks.

Figure 50-Provigil: the meticulous view of the stability diagram of propanedioic acid cocrystallization in 26 time-of-weeks.

The Provigil of Figure 51-after standing several envrionment conditionss: the PXRD diffractogram of propanedioic acid cocrystallization relatively.

Figure 52-Provigil free form and Provigil: the stripping curve of several preparations of propanedioic acid.

Figure 53-Provigil: the external stripping curve of propanedioic acid cocrystallization in SGF and SIF.

Figure 54-Provigil: the stripping curve of propanedioic acid cocrystallization in HCl.

Figure 55-Provigil: the DVS figure of propanedioic acid cocrystallization.

Figure 56-Provigil: the pharmacokinetics of propanedioic acid in dog.

Figure 57-comprise R-(-)-Provigil and 2, the PXRD diffractogram of the cocrystallization of 5-resorcylic acid.

The accumulation graph of acetone passage (channel) solvate of Figure 58-Provigil.

The other accumulation graph of acetone passage (channel) solvate of Figure 59-Provigil.

The PXRD diffractogram of Figure 60-o-Xylol solvate.

The Raman spectrum of Figure 61-o-Xylol solvate (intermediary spectrum).

The TGA differential thermogram of Figure 62-o-Xylol solvate.

The DSC differential thermogram of Figure 63-o-Xylol solvate.

The PXRD diffractogram of Figure 64-benzene solvent compound.

The Raman spectrum of Figure 65-benzene solvent compound (intermediary spectrum).

The TGA differential thermogram of Figure 66-benzene solvent compound.

The DSC differential thermogram of Figure 67-benzene solvent compound.

The PXRD diffractogram of Figure 68-toluene solvate.

The Raman spectrum of Figure 69-toluene solvate (intermediary spectrum).

The TGA differential thermogram of Figure 70-toluene solvate.

The DSC differential thermogram of Figure 71-toluene solvate.

The PXRD diffractogram of Figure 72-R-(-)-Provigil alcohol solvent compound.

The TGA differential thermogram of Figure 73-R-(-)-Provigil alcohol solvent compound.

The PXRD diffractogram of Figure 74-R-(-)-Provigil phenylcarbinol solvate.

The DSC differential thermogram of Figure 75-R-(-)-Provigil phenylcarbinol solvate.

The TGA differential thermogram of Figure 76-R-(-)-Provigil phenylcarbinol solvate.

The PXRD diffractogram of Figure 77-R-(-)-Provigil isopropanol solvent compound.

The PXRD diffractogram of Figure 78-R-(-)-Provigil acetonitrile solvent compound.

Figure 79-R-(-)-Provigil: the PXRD diffractogram of pentanedioic acid cocrystallization.

Figure 80-R-(-)-Provigil: the PXRD diffractogram of citric acid cocrystallization.

Figure 81-R-(-)-Provigil: the PXRD diffractogram of L-tartrate cocrystallization.

Figure 82 A and 82B-R-(-)-Provigil: the PXRD diffractogram of oxalic acid cocrystallization.

Figure 83-R-(-)-Provigil: the PXRD diffractogram of palmitinic acid cocrystallization.

Figure 84-R-(-)-Provigil: the PXRD diffractogram of L-proline(Pro) cocrystallization.

Figure 85-R-(-)-Provigil: the PXRD diffractogram of Whitfield's ointment cocrystallization.

Figure 86-R-(-)-Provigil: the PXRD diffractogram of lauric acid cocrystallization.

Figure 87-R-(-)-Provigil: the PXRD diffractogram of L MALIC ACID cocrystallization.

Detailed description of the invention

The structure of Provigil comprises stereocenter, so its two isomer that can be used as one of racemoid, two pure isomer or any ratio are to existing.The chemical name of racemize Provigil is (±)-2-[(diphenyl-methyl) sulfinyl] ethanamide.The isomer of racemize Provigil is to being R-(-)-2-[(diphenyl-methyl) sulfinyl] ethanamide or R-(-)-Provigil and S-(+)-2-[(diphenyl-methyl) sulfinyl] ethanamide or S-(+)-Provigil.

As used in this article and unless otherwise mentioned, term " enantiomeric pure " comprises the composition of enantiomeric pure basically, and it comprises for example having at least about the excessive composition of 90,91,92,93,94,95,96,97,98 or 99% enantiomer.Enantiomer is excessive to be defined as enantiomer A%-enantiomer B%, or is defined by following formula:

Ee%=100* ([R]-[S]/([R]+[S]), wherein R is the mole number of R-(-)-Provigil, S is the mole number of S-(+)-Provigil.

As used in this article, term " Provigil " comprises other mixture and the one enantiomer of racemoid, R-and S-isomer, but can be illustrated as any mixture of racemoid, R-isomer, S-isomer or R-and S-isomer particularly.

As used in this article and unless otherwise mentioned, term " racemic cocrystallization " is meant that wait molar mixture, cocrystallization by the enantiomer of Provigil form thing or cocrystallization that both form.For example, comprise cocrystallization that Provigil and non-stereomeric cocrystallization form thing have only when exist the Provigil enantiomer etc. be only " racemic crystal " during molar mixture.Similarly, comprise cocrystallization that Provigil and stereomeric cocrystallization form thing have only when exist the Provigil enantiomer etc. molar mixture and cocrystallization formation thing enantiomer etc. be only " racemic cocrystallization " during molar mixture.

As used in this article and unless otherwise mentioned, term " cocrystallization of enantiomeric pure " is meant by Provigil and stereomeric or non-stereomeric cocrystallization and forms the cocrystallization that thing is formed, wherein the excessive minimum about 90%ee (enantiomer is excessive) that is of the enantiomer of stereoisomerism material.

As used in this article, term " cocrystallization " meaning refers at room temperature the crystalline material that (22 ℃) are made up of two or more unique solids, every kind of solid comprises unique physical property such as structure, fusing point and melting heat, unless at room temperature can be fluid if state API particularly.Cocrystallization of the present invention comprises and Provigil or derivatives thereof H key bonded cocrystallization formation thing.Cocrystallization forms thing can directly and Provigil H bond be closed or can close with the other molecule H bond that is incorporated into Provigil.Other molecule can close with Provigil H bond or with the Provigil ionic bond.Other molecule also can be different API.The solvate that does not comprise the Provigil compound of cocrystallization formation thing in addition is not a cocrystallization of the present invention.Yet cocrystallization can comprise one or more solvate molecules in lattice.That is to say, comprise in addition that at room temperature solvate or cocrystallization for the cocrystallization of fluidic solvent or compound are cocrystallization of the present invention, but a crystalline material of only being made up of Provigil and one or more fluids (at room temperature) not a cocrystallization of the present invention.Also can there be other molecular recognition mode, comprises that pi-is stacked, visitor-main complexing and Van der Waals interact.For above-mentioned interaction, hydrogen-key is for forming the main interaction of cocrystallization, (and being the interaction that the present invention needs) thus form non covalent bond between one hydrogen bond donor in a plurality of parts and another the hydrogen bond receptor.Hydrogen bonding can produce several different intermolecular configurations.For example, hydrogen bond can cause that forming dimer, straight chain or ring texture forms.These configurations may further include prolongation (bidimensional) hydrogen bond network and isolating tlv triple.Optionally to provide wherein cocrystallization to form thing be the cocrystallization of the 2nd API to embodiment.In another embodiment, cocrystallization formation thing is not API.

For purpose of the present invention, the chemistry of the Provigil of cocrystallization form can be compared with the reference compound of multi-form Provigil with physical properties.Reference compound can be appointed as free form, or more specifically, is the dehydrate or the hydrate of free form, or more specifically is semihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, the pentahydrate of for example free form; Or solvate.For example, the reference compound of Provigil that forms the free form of thing cocrystallization with cocrystallization can be the Provigil of free form.Also but the designated reference compound is a crystalline or unbodied.Also but the designated reference compound is the most stable known polymorphic form of the true-to-shape of reference compound.

According to the present invention, the ratio that Provigil and cocrystallization form thing can be stoichiometric or non-stoichiometric.Provigil: the non-limitative example that cocrystallization forms thing is acceptable as the ratio of 1: 1,1: 1.5,1.5: 1,1: 2 and 2: 1.In addition, the cocrystallization that has the room in lattice is included in the present invention.For example, in lattice, have less than or the cocrystallization in about 0.01,0.1,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19 or 20% room be included in the present invention.The room can result from and lack Provigil molecule or disappearance cocrystallization formation thing molecule in lattice, or its both's disappearance.

Be surprised to find that, when the cocrystallization that allows Provigil and selection forms thing formation cocrystallization, the cocrystallization that obtains often produces the Provigil character of comparing improvement with the Provigil of free form, specifically about: solubleness, dissolution rate, bioavailability, stability, Cmax, Tmax, workability (comprising compressibility), more persistent therapeutics plasma concentration, or the like.For example, the cocrystallization form of Provigil since Provigil in water low solubility and particularly advantageous.In addition, the cocrystallization character of giving Provigil is also owing to can improve the bioavailability of Provigil and can improve the plasma concentration of Provigil and/or serum-concentration and useful.This is for the preparation particularly advantageous of Orally-administrable.In addition, can improve the dose response of Provigil, for example by increasing maximum available reaction and/or increasing tiring of Provigil by the biological activity that increases every dose equivalent(DE).

Therefore, in first aspect, the invention provides pharmaceutical composition (or medicine), it comprises that Provigil and cocrystallization form the cocrystallization of thing, makes that Provigil and cocrystallization formation thing can be from liquid phase or by for example grinding or heating from solid-state cocrystallization under crystallization condition.In one aspect of the method, cocrystallization forms thing and has at least a ether that is selected from, thioether, alcohol, mercaptan, aldehyde, ketone, thioketones, nitric ether, phosphoric acid ester, thiophosphatephosphorothioate, ester, thioesters, sulfuric ester, carboxylic acid, phosphonic acids, phospho acid, sulfonic acid, acid amides, primary amine, secondary amine, ammonia, tertiary amine, sp2 amine, thiocyanic ester, cyanamide, oxime, nitrile, diazonium, Organohalogen compounds, nitro, the S-heterocycle, thiophene, the N-heterocycle, the pyrroles, the O-heterocycle, furans, epoxide, hydroxamic acid, the functional group of imidazoles and pyridine, or the functional group in the table of this paper, make that Provigil and cocrystallization formation thing can be from the liquid phase cocrystallization under crystallization condition.

In another embodiment, can use the cocrystallization of excessive (surpassing 1 molar equivalent) to form thing, to promote the formation of stoichiometry cocrystallization for 1: 1 cocrystallization.For example, the cocrystallization that can surpass 2,3,4,5,6,7,8,9,10,15,20,25,50,75,100 times or more amount by the stoichiometric amount that adding is compared to the cocrystallization that provides forms the stoichiometric cocrystallization that thing production has 1: 1,2: 1 or 1: 2.The cocrystallization that is used to form cocrystallization forms this excessive use of thing and can be in solution maybe forms thing employing when causing that cocrystallization forms when grinding Provigil and cocrystallization.

In another embodiment of the invention, the Provigil cocrystallization further comprises by the hydrogen-bonded cocrystallization formation of the preferred interaction between two or more functional groups thing.For example, Provigil and propanedioic acid form carboxylic acid functional and the sulfoxide of Provigil and the interaction cocrystallization of amide functional group of thing by cocrystallization.

In another embodiment of the invention, cocrystallization comprise wherein Provigil by with R ² ₂(8) hydrogen bonding of primitive forms the Provigil of primary amide (primary amide) structure of dimerization.Referring to for example, J.Bernstein, Polymorphism in Molecular Crystals, OxfordUniversity Press, 2002, pp.55-59; Or M.C.Etter, Acct.Chem.Res., 1990,23,120; Or M.C.Etter, J.Phys.Chem., 1991,95,4601.In this structure, NH ₂Part can also be participated in and the donor that forms thing or other (the 3rd) molecule from cocrystallization for example or the hydrogen bonding of acceptor portion; C=O part can be participated in the hydrogen bonding with the donor part that forms thing or other molecule from cocrystallization.In another embodiment, the primary amide structure of dimerization (being formed by two Provigil molecules) comprises one, two, three or four hydrogen bond donors (forming thing from one, two, three or four cocrystallization) in addition.In another embodiment, the primary amide structure of dimerization comprises one or two hydrogen bond receptor (forming thing from one or two cocrystallization) in addition.In another embodiment, the primary amide structure of dimerization comprises the combination of hydrogen bond donor and acceptor in addition.For example, the primary amide structure of dimerization can comprise a hydrogen bond donor and hydrogen bond receptor, hydrogen bond donor and two hydrogen bonds, two hydrogen bond donors and hydrogen bond receptor, two hydrogen bond donors and two hydrogen bond receptors or three hydrogen bond donors and a hydrogen bond receptor in addition.

Cocrystallization of the present invention forms wherein Provigil and cocrystallization and forms thing and be in the same place by hydrogen bonding.Also can there be other noncovalent interaction, comprises the stacked and Van der Waals interaction of pi-.

In one embodiment, cocrystallization forms the cocrystallization formation thing that thing is selected from Table I and Table II.In other embodiments, the cocrystallization of Table I forms thing and is appointed as classification 1, classification 2 or classification 3 cocrystallization formation thing (referring to the row that are labeled as " classification " in the Table I).Table I has been enumerated a plurality of pKa values that the cocrystallization with polyfunctionality forms thing.Concrete to those skilled in the art functional group is conspicuous corresponding to concrete pKa value.

In another embodiment, understand the concrete functional group (row and the Table II value that, is labeled as " functionality " and " molecular structure " referring to for example Table I is labeled as the row of " cocrystallization forms thing functional group ") that forms thing with the interactional cocrystallization of Provigil specifically.

In another embodiment, cocrystallization comprises that the cocrystallization more than forms thing.For example, can with the cocrystallization of Provigil in combine two, three, four, five or more a plurality of cocrystallization and form thing.The cocrystallization that comprises two or more cocrystallization formation things and API is in the same place by hydrogen bonding.In one embodiment, the bonded cocrystallization forms thing and Provigil molecule hydrogen bonding.In another embodiment, cocrystallization forms thing and Provigil molecule or bonded cocrystallization and forms the thing hydrogen bonding.

In every kind of method of the present invention, Provigil and cocrystallization need be formed thing and contact.This may relate to and two solids being ground or with one or both component melts and make their recrystallize together.This may also relate to the dissolving Provigil and add cocrystallization formation thing, perhaps dissolves cocrystallization and forms thing and add Provigil.Provigil and cocrystallization are formed thing application crystallization condition.This may relate to character such as pH or the temperature that changes solution, and may need to concentrate solute, desolvates by removing usually, is typically undertaken by drying solution.Removing desolvates causes that the concentration of Provigil and cocrystallization formation thing increases in time, makes and is convenient to crystallization.For example, can use the contrary solvent of evaporation, cooling or adding to make the cocrystallization crystallization.In another embodiment, use the soup compound that comprises Provigil and cocrystallization formation thing to form cocrystallization.Comprise any crystalline solid in case form, can test it as described herein.

Can easily will be mixed into by the cocrystallization that this processing step obtains in the pharmaceutical composition (or medicine) by ordinary method.Pharmaceutical composition and medicine further go through following generally speaking, and it can further comprise acceptable diluents, vehicle or carrier.

In one aspect of the method, the invention provides the method for cocrystallization of the Provigil of preparation, it comprises:

(a) provide Provigil;

In yet another aspect, the invention provides the method for producing pharmaceutical composition or medicine, this method comprises:

(a) provide Provigil;

(c) under crystallization condition, Provigil and cocrystallization formed that thing grinds, heating, distillation altogether, congruent melting is melted or contact in solution;

(d) separate the cocrystallization that forms thus; With

(e) cocrystallization is mixed in pharmaceutical composition or the medicine.

In another embodiment, the method for formation cocrystallization comprises that Provigil, cocrystallization form thing or its both metastable form.Metastable form can be polymorphic form, solvate or the hydrate such as but not limited to Provigil or cocrystallization formation thing.Though be not bound by theory, can promote cocrystallization to form by increasing thermodynamic driving force in conjunction with metastable form.

Can analyze solid by ordinary method known in the art and form the existing of cocrystallization of thing to determine Provigil and cocrystallization.For example, using the existence of powder x-ray diffraction technological assessment cocrystallization is easily with routine.This can be by the cocrystallization of Provigil, crystal formation thing and supposition relatively diffractogram to determine whether that forming real cocrystallization carries out.Other technology of Shi Yonging comprises dsc (DSC), thermogravimetric analysis (TGA), Infrared spectroscopy (IR) and Raman spectroscopy in a similar manner.The monocrystalline X-ray diffraction is for identifying that the cocrystallization structure is particularly useful.

In one aspect of the method, therefore the present invention provides the method for screening co-crystallization compound, and it comprises:

(a) provide (i) Provigil to form thing, make cocrystallization form thing and can form cocrystallization with different with (ii) compatible multiple different cocrystallization with the functional group of Provigil; With

(i) under crystallization condition, Provigil and various cocrystallization formation thing ground, heat, be total to distillation, congruent melting is melted or in solution, contact the feasible solid phase that forms; With

The present invention includes several Provigil and carboxylic acid cocrystallization of comprising and form the cocrystallization of thing.Its some examples comprise Provigil and propanedioic acid, tartrate (L-and DL-), succsinic acid, citric acid, fumaric acid, 2, the cocrystallization that 5-resorcylic acid, oxalic acid and 1-hydroxyl-2-naphthoic acid forms.That these examples are represented is single, two and the tricarboxylic acid cocrystallization form thing.Other acid comprises carboxylic acid, can be used as with the cocrystallization of Provigil to form thing, and it includes but not limited to palmitinic acid, vitamin B13 and hexanodioic acid or the like.These cocrystallization form thing can comprise one, two, three or more carboxylic acid functionals.Cocrystallization forms thing can also comprise that non-carboxylic acid molecules is such as but not limited to urea, asccharin and caffeine.

In another embodiment, cocrystallization comprises Provigil and forms the carboxylic acid of thing as cocrystallization.In another embodiment, carboxylic acid cocrystallization formation thing has one, two, three or more carboxylic acid functional.

Several cocrystallization can show one or more the concrete interactions between Provigil and the carboxylic acid cocrystallization formation thing.For example, carboxylic acid functional can interact by the primary amide and/or the S=O functional group of hydrogen bond and Provigil.In another embodiment, the carboxylic acid functional from cocrystallization formation thing can interact by the primary amide functional group or the S=O functional group of hydrogen bond and Provigil.In another embodiment, the carboxylic acid functional from cocrystallization formation thing can interact by the dimeric periphery of the acid amides of hydrogen bond and Provigil (periphery).In another embodiment, the carboxylic acid functional from cocrystallization formation thing can interact by the acid amides dimer or the S=O functional group of hydrogen bond and Provigil.In another embodiment, the carboxylic acid functional from cocrystallization formation thing can interact by two acid amides dimers of hydrogen bond and Provigil.

Provigil and cocrystallization more of the present invention form thing and have one or more chiral centres, and can have multiple stereomeric configuration.Because these chiral centres, Provigil and several cocrystallization of the present invention form thing and exist as racemoid, enantiomeric mixture with as independent enantiomer and diastereomer and non-enantiomer mixture.All this racemoid, enantiomer and diastereomers for example comprise cis and trans-isomer(ide), R-and S-enantiomer and (D)-and (L)-isomer all within the scope of the present invention.Cocrystallization of the present invention can comprise that Provigil or cocrystallization form thing or its both isomeric forms.The isomeric forms that Provigil and cocrystallization form thing includes but not limited to steric isomer such as enantiomer and diastereomer.In one embodiment, cocrystallization can comprise that racemize Provigil and/or cocrystallization form thing.In another embodiment, cocrystallization can comprise R-or the S-Provigil and/or the cocrystallization formation thing of enantiomeric pure.In another embodiment, cocrystallization of the present invention can comprise have about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, greater than 99% or the excessive Provigil or the cocrystallization of enantiomer of any intermediate value form thing.The several non-limiting example that stereomeric cocrystallization forms thing comprises tartrate and oxysuccinic acid.In another embodiment, polymorphic form of the present invention or solvate can comprise have about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, greater than 99% or the excessive Provigil of enantiomer of any intermediate value.

" enrichment " of the present invention Provigil comprises more than or equal to about 5,6,7,8,9 or 10 weight % and is less than or equal to R-(-)-and S-(+)-isomer of Provigil of the amount of about 90,91,92,93,94 or 95 weight %.For example, the composition that comprises 67 weight %R-(-)-Provigils and 33 weight %S-(+)-Provigils is the modafinil compositions of enrichment.In this example, composition neither racemic neither enantiomeric pure.Term " R-(-)-Provigil of enrichment " can be used for describing and has greater than 50%R-(-)-Provigil with less than the modafinil compositions of 50%S-(+)-Provigil.Similarly, term " S-(+)-Provigil of enrichment " can be used for describing and has greater than 50%S-(+)-Provigil with less than the modafinil compositions of 50%R-(-)-Provigil.

Term " R-(-)-Provigil " and " S-(+)-Provigil " can be used for describing the Provigil or the Provigil of enantiomeric pure basically of Provigil, the enantiomeric pure of enrichment, but also can get rid of the Provigil and/or the Provigil of enantiomeric pure basically of Provigil, the enantiomeric pure of enrichment particularly.

Cocrystallization, solvate and the polymorphic form that comprises component enantiomeric pure and/or the enantiomer enrichment (forming thing as, Provigil or cocrystallization) can produce with respect to those of the corresponding cocrystallization that comprises racemic component and obtain chemistry and/or physical properties through overregulating.For example, derive from the Provigil of embodiment 1: the propanedioic acid cocrystallization comprises the racemize Provigil.R-(-)-Provigil of enantiomeric pure: propanedioic acid comprises within the scope of the invention.Similarly, S-(+)-Provigil of enantiomeric pure: propanedioic acid comprises within the scope of the invention.The cocrystallization that comprises the component of enantiomeric pure can produce the adjusting to for example active, the bioavailability or the solubleness of the corresponding cocrystallization that comprises racemic component.For example, cocrystallization R-(-)-Provigil: propanedioic acid and racemize Provigil: the propanedioic acid cocrystallization is compared adjusted character.

Can also with the Provigil of racemize Provigil, enantiomeric pure or with R-of the present invention (-)-and any mixture of S-(+)-Provigil prepare the polymorphic form and the solvate of Provigil.

In another embodiment, the present invention includes pharmaceutical composition or medicine, it comprises the Provigil of wherein adjusted with respect to racemic cocrystallization bioavailability enantiomeric pure and/or the cocrystallization that cocrystallization forms thing.In another embodiment, the present invention includes pharmaceutical composition or medicine, it comprises the Provigil of wherein adjusted with respect to racemic cocrystallization activity enantiomeric pure and/or the cocrystallization that cocrystallization forms thing.In another embodiment, the present invention includes pharmaceutical composition or medicine, it comprises the Provigil of wherein adjusted with respect to racemic cocrystallization solubleness enantiomeric pure and/or the cocrystallization that cocrystallization forms thing.

In another embodiment, pharmaceutical composition or medicine can be formulated as the Provigil that comprises as the cocrystallization form of micronized particles or nanoparticle.More specifically, another embodiment will by pure Provigil to the technology of cocrystallization form with produce the technology that is used for the control particle diameter that uses at pharmaceutical dosage form and combine.This embodiment is by merging into a step such as but not limited to the technology of grinding, fusion or sintering (being the heating powder mixture) with two processing steps.These technologies combine and have overcome a series of deficiencies, as have to separate or store the required bulk drug of preparation, and it is difficult to separated (as polymorphic form, chemistry or physical instability) under same case.

Solubleness is regulated

In one aspect of the method, the invention provides the method that increases the solubleness of Provigil in water, simulated gastric fluid (SGF) or simulated intestinal fluid (SIF) that is used for pharmaceutical composition or medicine, this method comprises:

(a) provide Provigil;

(c) under crystalline state, Provigil and cocrystallization formation thing ground, heat, be total to distillation, congruent melting is melted or in solution, contact the feasible solid phase that forms; With

In one embodiment, regulate the solubleness of Provigil, make at least 1.1,1.2,1.3,1.5,2.0,5.0,10.0,20.0,25.0,50.0,75.0 or 100.0 times of water-soluble (mg/mL) specific ionization form increases or more.The solubleness of Provigil can be measured by any ordinary method, for example the chromatography of the amount of Provigil in the saturated solution (as, HPLC) or spectroscopic cell, as UV-spectrography, IR-spectrography, Raman spectroscopy, quantitatively mass spectroscopy or vapor-phase chromatography.

In another embodiment, comprise that the composition of cocrystallization of the present invention, solvate and polymorphic form or medicine can be with (Cephalon, Inc.) Provigil of the free form that obtains of form be compared with PROVIGIL_.(referring to US Reissued Patent No.RE37,516).For example, composition of the present invention or bioavailability of medicament can with the comparing of PROVIGIL.As embodiment of the present invention, by produce with reference to form (as, crystalline or unbodied free form, hydrate or solvate) cocrystallization, solubleness can increase by 2,3,4,5,7,10,15,20,25,50,75 or 100 times.Water-soluble can in simulated gastric fluid (SGF) or simulated intestinal fluid (SIF) rather than water, the measurement in addition.The production of SGF of the present invention (undiluted) passes through 1g/L Triton X-100 and 2g/L NaCl merges in water and regulate pH with 20mM HCl, to obtain the solution of final pH=1.7.SIF be 0.68% 1 alkali valency potassiumphosphate, 1% pancreatin and wherein the pH of final solution be 7.5 sodium hydroxide.The pH of the solvent that uses also can specify be 1,1.1,1.2,1.3,1.4,1.5,1.6,1.7,1.8,1.9,2,2.1,2.2,2.3,2.4,2.5,2.6,2.7,2.8,2.9,3,3.5,4,4.5,5,5.5,6,6.5,7,7.5,8,8.5,9,9.5,10,10.5,11,11.5 12 or successive value between any pH.

The example of embodiment comprises: the water-soluble ratio of 37 ℃ and pH 7.0 with reference to the cocrystallization composition of at least 5 times of form increases, in SGF solubleness than with reference to the cocrystallization composition of at least 5 times of form increases, in SIF solubleness than cocrystallization composition with reference at least 5 times of form increases.

Dissolution rate is regulated

In another aspect of the present invention, regulate the dissolution rate curve of Provigil, water-solublely go out speed or the dissolution rate in simulated gastric fluid or simulated intestinal fluid or a kind of solvent or multiple solvent thereby increase it.Dissolution rate is dissolved in speed in the dissolution medium for the API solid.For uptake rate intrisinc rate of dissolution API (as, steroidal) faster, the rate-limiting step in the absorption process often is a dissolution rate.Because in the limited residence time that absorbs the position, still undissolved API is considered to invalid before being removed from the intestinal absorption position.Therefore, dissolution rate has significant effects for the performance of the API of poorly soluble.Therefore, the dissolution rate of API is important, the conventional quality-controlling parameters that is used for the API production process in the solid dosage.Following equation is an approximation,

Dissolution rate=KS (C _s-C)

Wherein K is the dissolution rate constant, and S is a surface area, and Cs is that apparent solubility and C are the API concentration in dissolution medium.

For API absorption rapidly, Cs-C is approximately equal to Cs.

Can measure the dissolution rate of Provigil by ordinary method as known in the art.

With the reference form (as, free form) compares, can specify cocrystallization than reference form in same solution (as, free form) dissolution rate increases as 10,20,30,40,50,60,70,80,90 or 100% times, or 2,3,4,5,6,7,8,9,10,15,20,25,30,40,50,75,100,125,150,175,200,250,300,350,400,500,1000,10,000 or 100,000 times.The condition of measuring dissolution rate is with above-mentioned discussion.The increase of dissolution rate can further keep oversaturated time explanation by composition before reaching equilibrium solubility.

In one aspect of the method, increase its method at simulated gastric fluid or simulated intestinal fluid or the water-based dissolution rate in solvent or multiple solvent thereby the invention provides the stripping of regulating Provigil, this method comprises:

(a) provide Provigil;

The example of above-mentioned embodiment comprises: 7.0 times dissolution rates in the aqueous solution of 37 ℃ and pH than with reference to the cocrystallization composition of at least 5 times of form increases, in SGF dissolution rate than with reference to the cocrystallization composition of at least 5 times of form increases, in SIF dissolution rate than cocrystallization composition with reference at least 5 times of form increases.

Bioavailability is regulated

Method of the present invention is used to produce the medicinal modafinil formulations with bigger solubleness, stripping and bioavailability.Can be by increasing AUC, shortening the time (reaching the time of serum peak concentration) that reaches Tmax or increase Cmax and improve bioavailability.The present invention can produce with free form (with reference to form) and compare higher Provigil plasma concentration.

AUC is the area under a curve of the plasma concentration (not being the logarithm of concentration) of API after the API administration to the time.This area is measured by " trapezoidal rule " easily: with straight-line segment linking number strong point, vertical line be vertical from X-coordinate to each data point, and calculates the trilateral and the trapezoid area summation of so constructing.When the concentration (Cn is at time tn) of last measurement is not zero, by Cn/k _ElThe AUC of estimation from tn to the infinitely great time.

AUC is at the total body clearance (Cl of the bioavailability of estimating API and estimation API _T) time particularly useful.After the administration of single intravenous dosages, for the one-chamber system of obeying first order kinetics, AUC=D/Cl _T, wherein D is a dosage; Perhaps, AUC=C ₀/ k _El, k wherein _ElBe the API elimination rate constant.For the route of administration that is different from intravenous administration, AUC=FD/Cl _T, wherein F is the absolute bioavailability of API.

In one aspect of the method, increase AUC, shorten the time that reaches Tmax, the time length of concentration more than 1/2nd Tmax or the method for increase Cmax that increases Provigil thereby the invention provides the bioavailability of regulating Provigil, this method comprises:

(a) provide Provigil;

The example of above-mentioned embodiment comprises: the cocrystallization composition of comparing the time increase at least 5% that reaches Tmax with the reference form, reach the cocrystallization composition of the time ratio of Tmax with reference to form increase at least 10%, reach the cocrystallization composition of the time ratio of Tmax with reference to form increase at least 15%, reach the cocrystallization composition of the time ratio of Tmax with reference to form increase at least 20%, reach the cocrystallization composition of the time ratio of Tmax with reference to form increase at least 25%, reach the cocrystallization composition of the time ratio of Tmax with reference to form increase at least 30%, reach the cocrystallization composition of the time ratio of Tmax with reference to form increase at least 35%, reach the cocrystallization composition of the time ratio of Tmax with reference to form increase at least 40%, AUC is than the cocrystallization composition with reference to form increase at least 5%, AUC is than the cocrystallization composition with reference to form increase at least 10%, AUC is than the cocrystallization composition with reference to form increase at least 15%, AUC is than the cocrystallization composition with reference to form increase at least 20%, AUC is than the cocrystallization composition with reference to form increase at least 25%, AUC is than the cocrystallization composition with reference to form increase at least 30%, AUC is than the cocrystallization composition with reference to form increase at least 35%, AUC is than the cocrystallization composition with reference to form increase at least 40%.Other example comprise wherein with reference to form be crystalline, wherein be unbodied with reference to form or wherein be the anhydrous crystal form of Provigil with reference to form.

Dose response is regulated

(a) provide Provigil;

Dose response measure for reaction and the dosage of induced reaction between quantitative relationship, it can be by ordinary method measurement as known in the art.The curve that relates to the dependent interaction to dosage (as independent variable(s)) (as dependent variable) of API-cell system is " dose-response curve ".Typically, the reaction to API to given API dosage (mg/kg) drawing of dose-response curve for measuring.Dose response curve also can be the curve of AUC to given API dosage.

In embodiments of the invention, cocrystallization of the present invention has the dose response curve that increases than corresponding reference compound or has more linear dose response curve.

The stability that increases

(a) provide Provigil;

In preferred embodiments, comprise the composition of the present invention of Provigil cocrystallization, solvate and comprise that the preparation of Provigil has the suitable stability that is used for medicinal application.Preferably, Provigil of the present invention or its preparation are stable, make when storing 2 years for 30 ℃, form to be less than any degradation product (degradant) of 0.2%.Term degradation product herein is meant single product of planting chemical reaction.For example, if the hydrolysis phenomenon of two products takes place molecule is divided into, for purpose of the present invention, it is considered to single degradation product.More preferably, when when storing 2 years down for 40 ℃, formation is less than any degradation product of 0.2%.Perhaps, when when storing 3 months down for 30 ℃, formation is less than any degradation product of 0.2% or 0.15% or 0.1%; Or when when storing 3 months down for 40 ℃, formation is less than any degradation product of 0.2% or 0.15% or 0.1%.Perhaps when when storing for 4 weeks for 60 ℃, formation is less than any degradation product of 0.2 or 0.15% or 0.1%.Relative humidity (RH) can specify to environment RH, 75%RH or be any integer between 1 to 99%RH.In another embodiment, to the object administration time, single dose of the present invention comprises and is less than 0.5%, 0.2% or 0.1% degradation product.

Morphology is regulated

(a) provide Provigil;

In one embodiment, cocrystallization comprises or comprises Provigil and cocrystallization and forms thing, wherein forms the interaction that takes place between the thing between the two the amino of Provigil and cocrystallization with corresponding interaction group in the Table III, as, the H bond is closed.In another embodiment, cocrystallization comprises that the cocrystallization of Provigil and Table I or II forms thing.In one aspect of the invention, the present invention only is included in the cocrystallization that has H key acceptor on first molecule and have H key donor on second molecule, wherein first and second molecules are respectively cocrystallization and form thing and Provigil or Provigil and cocrystallization formation thing, all are included in the present invention.

Cocrystallization can comprise the chemical entities more than two in its cocrystallization structure.For example, cocrystallization can comprise in addition solvent molecule, water molecules, salt, or the like.In addition, cocrystallization can comprise that an API and two or more cocrystallization form thing, a cocrystallization forms thing and two or more API, two or more APIs or two or more cocrystallization and forms thing.

As defined herein, the ternary cocrystallization is the cocrystallization that comprises three different chemical entities of stoichiometric ratio, and wherein every kind at room temperature all is solid (except that API can at room temperature be the fluid).Particularly, the ternary cocrystallization comprises three different chemical entities such as API: cocrystallization forms thing (1): cocrystallization forms thing (2), wherein the ratio of component can be such as but not limited to 1: 1: 1,2: 1: 1,2: 1: 2,2: 1: 0.5,2: 2: 1, or the like.The ternary cocrystallization can also comprise other combination of component, and such as but not limited to API (1): API (2): cocrystallization forms thing, API (1): API (2): API (3) and cocrystallization and forms thing (1): cocrystallization forms thing (2): cocrystallization formation thing (3).

In another embodiment, the invention provides following Provigil solvate: acetate, tetrahydrofuran (THF), 1,4-two _ alkane, methyl alcohol, Nitromethane 99Min., acetone, o-Xylol, benzene and toluene.

Pharmaceutically useful cocrystallization can or prolong the method administration that discharges by sustained release.The medicinal products of sustained release has and improves the common objective that pharmacological agent surpasses the pharmacological agent that is realized by its non-sustained release counterpart.Ideally, in medical treatment, use being characterized as in the shortest time of sustained release preparation of optimum design to treat or the control situation with minimum drug substance.The advantage of sustained release preparation comprises: 1) prolong drug activity; 2) reduce the dosage administration frequency; 3) increase patient compliance; 4) total dosage still less; 5) side effect of part or system reduces; 6) Zui Xiao drug accumulation; 7) the blood levels fluctuation reduces; 8) treatment is renderd a service and is improved; 9) enhancing of pharmaceutical activity or loss reduce; With 10) speed improvement of control disease or situation.(Kim，Cherng-ju，Controlled Release Dosage Form Design，2 TechnomicPublishing，Lancaster，Pa.：2000)。

Conventional formulation provide usually from preparation rapidly or drug release immediately.The pharmacology and the pharmacokinetics that depend on medicine are used conventional formulation can cause at patient's blood and are organized the wide fluctuation of Chinese traditional medicine concentration with other.These fluctuations can influence many parameters, as the maintenance of time length of dosed administration frequency, effect onset, effectiveness, treatment blood levels, toxicity, side effect, or the like.Advantageously, the sustained release preparation can be used for controlling the time length of pharmaceutically-active onset, effect, blood plasma level and the blood peak concentration in the treatment window.Particularly, sustained release or prolongation release dosage form or preparation can be used for guaranteeing to realize the maximum validity of medicine, and potential side effect and safety problem are minimized, it can take place when (that is, below minimum treatment level) takes place for the dosed administration deficiency (under dosing) of medicine and surpass the toxic level of medicine.

Most of sustained release preparations are used for the initial medicine (active ingredient) that produces required therapeutic action rapidly that discharges to be measured, and little by little and continuously discharges other amount of medicine, is used for keeping this treatment or prophylactic effect level in the time that prolongs.In order to keep medicine in the intravital this constant level of body, medicine must discharge from formulation by metabolism with from the speed of the amount of body excretes to replace medicine.The sustained release of active ingredient is subjected to the stimulation of multiple condition, and it includes but not limited to pH, ionic strength, seepage water pressure, temperature, enzyme, water and other physiological condition or compound.

Multiple known sustained release is arranged or prolong release dosage form, preparation and device and can be suitable for using with cocrystallization of the present invention and composition.Its example includes but not limited at United States Patent (USP) 3,845 770,3,916,899,3,536,809,3,598,123,4,008,719,5,674,533,5,059,595,5,591,767,5,120,548,5,073,543,5,639,476,5,354,556,5,733,566 and 6,365, those described in the 185B1.Its each all be merged in this paper as a reference.These formulations can be used for providing the slow release or the sustained release of one or more active ingredients, it for example uses HPMC, other polymer matrix, gelifying agent, permeable membrane, osmosis system (as OROS_ (Alza Corporation, Mountain View, Calif.USA)), multiple coatings, particulate, liposome or microsphere or its combination, so that the release profiles of required different ratios to be provided.In addition, ion-exchange material can be used for preparing the cocrystallization that fixed is adsorbed, thereby and realizes that controlled delivery of pharmaceutical agents sends.The example of concrete anionite includes but not limited to Duolite_A568 and Duolite_AP143 (Rohm ﹠amp; Haas, Spring House, PA.USA).

One embodiment of the invention comprise unit dosage form, it comprises pharmaceutically useful cocrystallization or its solvate, hydrate, dehydrate, anhydride, amorphous form, with one or more pharmaceutically useful vehicle or thinner, wherein compounding pharmaceutical composition, medicine or formulation are used for sustained release.Concrete formulation adopts the osmosis type drug delivery system.

Concrete and known osmosis type drug delivery system be referred to as OROS_ (AlzaCorporation, Mountain View, Calif.USA).This technology can easily be suitable for sending compound of the present invention and composition.The many aspects of this technology are at United States Patent (USP) 6,375,978B1,6,368,626B1,6,342,249B1,6,333,050B2,6,287,295B1,6,283,953B1,6,270,787B1,6,245,357B1 and 6,132, open in 420, its each be merged in this paper as a reference.The concrete OROS_ remodeling that can be used for administration compound of the present invention and composition includes but not limited to OROS_Push-Pull ^TM, Delayed Push-Pull ^TM, Multi-Layer Push-Pull ^TMAnd Push-Stick ^TMSystems, it all is well-known.Referring to for example, Http:// www.alza.comThe other OROS_ system that can be used for the in check oral delivery of compound of the present invention and composition comprises OROS_-CT and L-OROS_.Id., also referring to Delivery Times, and vol.II, issue II (Alza Corporation).

The production of conventional OROS_ oral dosage form is tablet coating by with the hard tablet of drug powder (as cocrystallization) boil down to derivatived cellulose, to form semipolar linkage, boring on dressing then (as, use laser).Kim，Cherng-ju，Controlled Release Dosage FormDesign，231-238(Technomic Publishing，Lancaster，Pa.：2000)。The advantage of this formulation is that the delivery rate of medicine is not subjected to the influence of physiology or experiment condition.Also can send even have the deliquescent medicine of pH dependency with constant speed, and regardless of the pH of delivery media.But because these advantages are to be provided by the accumulation of the seepage water pressure in formulation after administration, conventional OROS_ drug delivery system can not be used for sending effectively the medicine with low water solubility.Id.at 234。Because easier being dissolved in the water of the comparable Provigil of cocrystallization of the present invention itself, they are very suitable for the patient based on osmotic delivery.Yet, the present invention includes the crystallinity Provigil of routine (forming the pure Provigil of thing as there being cocrystallization) and isomer thereof and isomer mixture are mixed in the OROS_ formulation.

Concrete formulation of the present invention comprises: limit the wall in chamber, wall has the outlet that forms therein, and at least a portion wall is semi-permeable; Be positioned at the chamber away from the expandable layer that exports and be communicated with the semipermeability segment fluid flow of wall; Be positioned at chamber and outlet in abutting connection with and with expandable layer be the dry of direct or indirect contact relation or the medicine layer that is essentially drying regime; And be inserted in the mobile promoting layer between the outside surface at least of the internal surface of wall and the medicine layer in the chamber, wherein medicine layer comprises cocrystallization or its solvate, hydrate, dehydrate, anhydride or amorphous substance.Referring to United States Patent (USP) 6,368,626, it is merged in this paper as a reference in full.

Another concrete formulation of the present invention comprises: limit the wall in chamber, wall has the outlet that forms therein, and at least a portion wall is semi-permeable; Be positioned at the chamber away from the expandable layer that exports and be communicated with the semipermeability segment fluid flow of wall; Be positioned at the chamber with the outlet in abutting connection with and with expandable layer be the medicine layer of direct or indirect contact relation; Medicine layer comprises fluid, is absorbed in the active agent formulation in the porous granule, porous granule is suitable for resisting the force of compression of the medicine layer that enough forms compactness and does not have significantly oozing out of fluid, active agent formulation, dosage form selection ground has placebo layer between outlet and medicine layer, wherein active agent formulation comprises cocrystallization or its solvate, hydrate, dehydrate, anhydride or amorphous substance.Referring to United States Patent (USP) 6,342,249, it is merged in this paper as a reference in full.

In another embodiment, pharmaceutical composition or medicine comprise the mixture of the Provigil of the new form (as, cocrystallization) of Provigil of the present invention and free form.This embodiment can be used as for example sustained release, lasting release or the prolongation release dosage form.In another embodiment, prolong Provigil and cocrystallization of the present invention or the solvate that release dosage form comprises free form.This prolongation release dosage form comprise have specific ionization form Provigil more the Provigil form of mcroorganism availability (as, Provigil: the propanedioic acid cocrystallization).In addition, the Cmax of this form can help to have the more therapeutic action of long duration than independent free form Provigil greater than the Cmax of free form Provigil.

In another embodiment, pharmaceutical composition or medicine comprise the release profiles of one or more change in racemize Provigil, R-(-)-Provigil and S-(+)-Provigil.The release profiles that changes can comprise for example two or more maximal plasma concentration, as double release profiles.The release profiles of this change may help to use composition of the present invention or pharmacological agent to experience for example patient of awakening disappearance in afternoon (loss of wakefulness in the afternoon)." break out (burst) " or discharge to have the second time of at least 2,3,4,5 or 6 hours API after administration and help overcome this effect.In another embodiment, can adopt and be included in the little loading dose that discharges immediately after the administration, in 2,3,4,5 or 6 hours, be pharmaceutical composition or medicine subsequently near the zero level release profiles.In this composition, the peak blood plasma level can reached approximately noon.

In another embodiment, the pharmaceutical composition or the medicine that comprise the change release profiles of Provigil comprise R-(-)-Provigil and S-(+)-Provigil, wherein R-(-)-Provigil provides the initial increase (because Cmax of R-(-)-Provigil) of plasma concentration, and S-(+)-Provigil provides the increase (because Cmax subsequently of S-(+)-Provigil) of the delay of plasma concentration.Because the Cmax of the delay of S-(+)-Provigil increases can be because after the initial Cmax of R-(-)-Provigil 2,3,4,5,6 hours or more of a specified duration.In another embodiment, the Cmax of delay is approximately equal to initial Cmax.In another embodiment, the Cmax of delay is greater than initial Cmax.In another embodiment, the Cmax of delay is less than initial Cmax.In another embodiment, the Cmax of delay is owing to the racemize Provigil, rather than S-(+)-Provigil.In another embodiment, the Cmax of delay is because R-(-)-Provigil rather than S-(+)-Provigil.In another embodiment, initial Cmax is owing to the racemize Provigil, rather than R-(-)-Provigil.In another embodiment, initial Cmax is because S-(+)-Provigil rather than R-(-)-Provigil.In another embodiment, the release profiles of change has 3,4,5 or more a plurality of " outbursts " of plasma concentration.

In another embodiment, pharmaceutical composition or medicine comprise the release profiles of the change of Provigil, and wherein one or more forms with cocrystallization, its solvate, free form or polymorphic form exist in racemize Provigil, R-(-)-Provigil or S-(+)-Provigil.

In another embodiment, comprise that wherein the pharmaceutical composition or the medicine of the release profiles of the change of R-(-)-Provigil are used for oral preparations.This composition can make Provigil minimize to the first pass metabolism of sulfone.In another embodiment, comprise that wherein the pharmaceutical composition or the medicine of the release profiles of the change of racemize Provigil are used for oral preparations.In another embodiment, comprise that wherein the pharmaceutical composition or the medicine of the release profiles of the change of S-(+)-Provigil are used for oral preparations.In another embodiment, comprise that wherein the pharmaceutical composition or the medicine of the release profiles of the change of racemize Provigil and R-(-)-Provigil are used for oral preparations.In another embodiment, comprise that wherein the pharmaceutical composition or the medicine of the release profiles of the change of racemize Provigil and S-(+)-Provigil are used for oral preparations.In another embodiment, comprise that wherein the pharmaceutical composition or the medicine of the release profiles of the change of S-(+)-Provigil and R-(-)-Provigil are used for oral preparations.In another embodiment, comprise racemize Provigil wherein, S-(+)-Provigil and and the pharmaceutical composition or the medicine of the release profiles of the change of R-(-)-Provigil be used for oral preparations.

In another embodiment, the pharmaceutical composition or the medicine of release profiles that comprises the change of Provigil is used for transdermal administration.This transdermal (TD) is sent and can be avoided first pass metabolism.In addition, can adopt " pill-and-patch " strategy, wherein only the part of per daily dose be passed through dermal delivery,, increase oral administration on its basis to guarantee the awakening effect to form the system level on basis.

The vehicle that is used for pharmaceutical composition of the present invention and medicine can be solid, semisolid, fluid or its combination.Preferably, vehicle is a solid.The composition of the present invention and the medicine that comprise vehicle can be by comprising vehicle and API or the known pharmaceutical technology preparation of therapeutical agent blended.Every dosage device of pharmaceutical composition of the present invention or medicine comprises the API of desired amount, if and be used for oral administration, any other form that it can be tablet for example, capsule sheet, pill, hard or soft capsule, lozenge, cachet, assignable powder, particle, suspension, elixir, dispersion, fluid or reasonably is suitable for this administration.If be used for parenterai administration, it can be the form of suspension for example or percutaneous plaster.If be used for rectal administration, it can be for example form of suppository.The present preferably unitary oral dosage form of discrete doses of the API of each self-contained predetermined amount is as tablet or capsule.

The non-limitative example of vehicle that can be used for preparing pharmaceutical composition of the present invention or medicine is as follows.

Pharmaceutical composition of the present invention and drug selectivity ground comprise that one or more pharmaceutically acceptable carrier or thinner are as vehicle.Carrier that is fit to or thinner illustrative ground includes but not limited to, and is independent or make up, and lactose comprises lactose hydrous and Spherolac 100; Starch comprises that the starch that can directly compress and hydrolyzed starch are (as, Celutab ^TMAnd Emdex ^TM); N.F,USP MANNITOL; Sorbitol Powder; Xylitol; Glucose (as, Cerelose ^TM2000) and Glucose monohydrate; Bibasic calcium phosphate dihydrate; The thinner of sucrose system; The candy manufacturing is with sugared; Monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, particulate calcium lactate trihydrate; Dextrates; Inositol; Hydrolyzed cereal solids; Amylose starch; Mierocrystalline cellulose, comprise Microcrystalline Cellulose, food grade source and α-and amorphous cellulose (as, RexcelJ), cellulose powder, hydroxypropylcellulose (HPC) and HPMC (HPMC); Lime carbonate; Glycine; Wilkinite; Segmented copolymer; Polyvinylpyrrolidone; Or the like.If exist, this carrier or thinner amount to account for composition total weight about 5% to about 99%, preferred about 10% to about 85%, more preferably from about 20% to about 80%.Preferred carrier, variety carrier, thinner or the plurality of diluent of selecting shows suitable flow characteristics, and shows suitable compressibility when tablet needs.

Lactose, N.F,USP MANNITOL, Di-Sodium Phosphate and Microcrystalline Cellulose (particularly Avicel PH Microcrystalline Cellulose such as Avicel PH 101), independent or combination, be preferable absorbent.These thinners and API are that chemistry is compatible.The use of outer (extragranular) Microcrystalline Cellulose of particle (that is, be added in the particulate composition Microcrystalline Cellulose) can be used for improving hardness (for tablet) and/or disintegration time.Preferred especially lactose, particularly Spherolac 100.Lactose typically provides the composition with suitable API rate of release, stability, precompression flowability and/or dry property with low relatively thinner cost.It provides the high-density substrate that helps compacting in granulation process (wherein using wet granulation) and therefore improve mixture flow dynamic characteristic and tablet character.

Pharmaceutical composition of the present invention and drug selectivity ground comprise that one or more pharmaceutically acceptable disintegrating agents are as vehicle, especially for tablet formulation.The disintegrating agent that is fit to includes but not limited to, and is independent or combination, and starch comprises that Explotab is (as, the Explotab of PenWest ^TM) and pregelatinised W-Gum (as, the National of National Starch and Chemical Company ^TM1551, National ^TM1550 and Colocorn ^TM1500), clay is (as, the Veegum of R.T.Vanderbilt ^TMHV), Mierocrystalline cellulose such as pure Mierocrystalline cellulose, Microcrystalline Cellulose, methylcellulose gum, Cellulose,ether with glycolic acid and Xylo-Mucine, cross-linked carboxymethyl cellulose sodium are (as, Ac-Di-Sol ^TM, derive from FMC), alginates, Crospovidone and natural gum is as agar, guar gum, Viscogum BE, kuteera gum, pectin and tragacanth gum.

Disintegrating agent can add in any suitable step in the preparation composition process, particularly adds before granulation or in the lubricated step process before the compression.If exist, this disintegrating agent amount to account for composition total weight about 0.2% to about 30%, preferred about 0.2% to about 10%, more preferably from about 0.2% to about 5%.

Cross-linked carboxymethyl cellulose sodium is the preferred disintegrating agent that is used for tablet or capsule disintegration, if exist, preferably its account for composition total weight about 0.2% to about 10%, more preferably from about 0.2% to about 7%, more preferably from about 0.2% to about 5%.Cross-linked carboxymethyl cellulose sodium is given through the pharmaceutical composition of the present invention of granulation and the higher interior disintegration ability of particle of medicine.

Pharmaceutical composition of the present invention and drug selectivity ground comprise that one or more pharmaceutically acceptable binding agents or tackiness agent are as vehicle, especially for tablet formulation.Preferred this binding agent and tackiness agent are given by the powder of compressing tablet with sufficient cohesion, allowing conventional technological operation such as gluing, lubricated, compression and packing, but allow still that disintegration of tablet and composition are absorbed when picked-up.This binding agent also can prevent or suppress crystallization or the recrystallization of API of the present invention when salt has been dissolved in the solution.The binding agent and the tackiness agent that are fit to include but not limited to, and be independent or combination, gum arabic; Tragacanth gum; Sucrose; Gelatin; Glucose; Starch such as but not limited to pregelatinized Starch as, National ^TM1511 and National ^TM1500); Mierocrystalline cellulose such as but not limited to methylcellulose gum and carmethose (as, Tylose ^TM); Lalgine and alginates; Magnesium aluminum silicate; PEG; Guar gum; Polysaccharide acid; Wilkinite; Polyvidone, for example 30 POVIDONE K 30 BP/USP-15, K-30 and K-29/32; Polymethacrylate; HPMC; Hydroxypropylcellulose (as, the Klucel of Aqualon ^TM); And ethyl cellulose (as, the Ethocel of the Dow Chemical Company ^TM).If exist, this binding agent and/or tackiness agent amount to the gross weight that constitutes pharmaceutical composition or medicine about 0.5% to about 25%, preferred about 0.75% to about 15%, more preferably from about 1% to about 10%.

Many binding agents are the polymkeric substance that comprises acid amides, ester, ether, alcohol or ketone group, thereby are preferably included in pharmaceutical composition of the present invention and the medicine.Special preferably polyethylene pyrrolidone such as 30 POVIDONE K 30 BP/USP-30.The polymer-type binding agent can have different molecular weight, degree of crosslinking and polymer grade.The polymer-type binding agent can also be multipolymer, as comprises the segmented copolymer of the mixture of oxyethane and propylene oxide units.The variable effect character and the performance of these unitary ratios in known polymer.Example with segmented copolymer of different block unit compositions is poloxamer 188 and poloxamer 237 (BASF Corporation).

Pharmaceutical composition of the present invention and drug selectivity ground comprise that one or more pharmaceutically acceptable wetting agents are as vehicle.This wetting agent of preferred selection is to keep combining closely of API and water, and water is considered to improve the condition of composition bioavailability.

The non-limitative example that can be used as the tensio-active agent of wetting agent in pharmaceutical composition of the present invention and medicine comprises quaternary ammonium compound, as benzalkonium chloride, benzethonium chloride and hexadecylpyridinium chloride; Dioctyl sodium sulfosuccinate; Polyoxyethylene alkyl phenyl ether such as nonoxynolum (nonoxynol) 9, nonoxinol 10 and hot menthylphenoxypolyethoxy ethanol 9, poloxamer (polyoxyethylene and polyoxypropylene block copolymers), polyoxyethylene fatty acid glyceryl ester and oils such as polyoxyethylene (8) caprylic/capric direactive glyceride and two glyceryl ester (as, the Labrasol of Gattefosse ^TM), polyoxyethylene (35) Viscotrol C and polyoxyethylene (40) hydrogenated castor oil; Voranol EP 2001 such as polyoxyethylene (20) hexadecanol stearyl alcohol ether; Polyoxyethylene fatty acid ester such as polyoxyethylene (40) stearate, polyoxyethylene sorbitan such as polysorbas20 and tween 80 (as, the Tween of ICI ^TM80); Propylene glycol fatty acid ester such as propylene glycol lauric acid fat (as, the Lauroglycol of Gattefosse ^TM); Sodium lauryl sulphate; Its lipid acid and salt such as oleic acid, sodium oleate and triethanolamine oleate ester, glycerin fatty acid ester such as glyceryl monostearate; Sorbitan such as sorbitan laurate, dehydrating sorbitol monooleate, sorbitan-monopalmityl ester and anhydrosorbitol monostearate, tyloxapol, and composition thereof.If exist, this wetting agent amount to the gross weight that constitutes pharmaceutical composition or medicine about 0.25% to about 15%, preferred about 0.4% to about 10%, more preferably from about 0.5% to about 5%.

The wetting agent of preferred anionic tensio-active agent.Sodium lauryl sulphate is particularly preferred wetting agent.If exist, sodium lauryl sulphate amount to the gross weight that constitutes pharmaceutical composition or medicine about 0.25% to about 7%, preferred about 0.4% to about 4%, more preferably from about 0.5% to about 2%.

Pharmaceutical composition of the present invention and drug selectivity ground comprise that one or more pharmaceutically acceptable lubricants (comprising release agent and/or glidant) are as vehicle.The lubricant that is fit to includes but not limited to, and is independent or combination, Glyceryl Behenate (as, the Compritol of Gattefosse ^TM888); Stearic acid and salt thereof comprise Magnesium Stearate, calcium and sodium; Hydrogenated vegetable oil (as, the Sterotex of Abitec ^TM); Colloided silica; Talcum; Wax; Boric acid; Sodium Benzoate; Sodium acetate; Sodium fumarate; Sodium-chlor; The DL-leucine; PEG (as, the Carbowax of the Dow Chemical Company ^TM4000 and Carbowax ^TM6000); Sodium oleate; Sodium lauryl sulphate; And Stepanol MG.If exist, this lubricant amount to the gross weight that constitutes pharmaceutical composition or medicine about 0.1% to about 10%, preferred about 0.2% to about 8%, more preferably from about 0.25% to about 5%.

Magnesium Stearate is to be used for for example reducing the preferred lubricant that rubs between tablet formulation compression process equipment and granulation mixture.

The release agent that is fit to includes but not limited to talcum, W-Gum, DL-leucine, sodium lauryl sulphate and metallic stearate.Talcum is to be used for for example reducing to the bonding of equipment surface and minimizing preferred release agent of mixture electrostatic or glidant.If exist, talcum constitute pharmaceutical composition or medicine gross weight about 0.1% to about 10%, preferred about 0.25% to about 5%, more preferably from about 0.5% to about 2%.

Glidant can be used for promoting the flow of powder of solid dosage.The glidant that is fit to includes but not limited to colloidal silica, starch, talcum, tribasic calcium phosphate, Solka-floc and Magnesium Trisilicate.Preferred especially colloidal silica.

Other vehicle such as tinting material, seasonings and sweeting agent are known in the pharmaceutical field, can be used in pharmaceutical composition of the present invention and the medicine.Tablet can or not have dressing with the enteric coating dressing.Composition of the present invention can comprise for example buffer reagent in addition.

Optionally, can use one or more effervescent as disintegrating agent and/or the organoleptic property that improves pharmaceutical composition of the present invention and medicine.In being present in pharmaceutical composition of the present invention and medicine when promoting the formulation disintegration, the total amount of preferred one or more effervescent is that about 30 weight % of pharmaceutical composition or medicine arrive about 75 weight %, preferred about 45 weight % are to about 70 weight %, and the amount of for example about 60 weight % exists.

The particularly preferred embodiment according to the present invention provides the dispersion of API in aqueous medium of improvement to be present in effervescent in the solid dosage less than the amount that effectively promotes the formulation disintegration.Be not bound by theory, think that effervescent effectively quickens API and disperse from formulation in gi tract, absorb and the rapid onset of therapeutic action thereby further improve.In being present in pharmaceutical composition of the present invention or medicine but when not improving disintegration to promote gi tract to disperse, preferred effervescent arrives about 20 weight % with about 1 weight % of pharmaceutical composition or medicine, more preferably from about 2.5 weight % are to about 15 weight %, and more preferably from about 5 weight % exist to the amount of about 10 weight %.

" effervescent " in this article refers to and is included in the reagent of emitting one or more compounds of gas when contacting with water, and compound works together or works respectively.The gas of emitting is oxygen or be generally carbonic acid gas most normally.Preferred effervescent is included in the existence of water and reacts down to form the bronsted lowry acids and bases bronsted lowry of carbon dioxide gas.Preferably, alkali comprises basic metal or alkaline earth metal carbonate or supercarbonate, and acid comprises aliphatic carboxylic acid.

As the non-limitative example of the alkali that is fit to that can be used for the effervescent component among the present invention comprise carbonate (as, lime carbonate), supercarbonate (as, sodium bicarbonate), sesquicarbonate, and composition thereof.Lime carbonate is preferred alkali.

As the non-limitative example of the acid that is fit to that can be used for effervescent component of the present invention and/or solid acid comprise citric acid, tartrate (as D-, L-or D/L-tartrate), oxysuccinic acid, toxilic acid, fumaric acid, hexanodioic acid, succsinic acid, these sour acid anhydrides, these sour acid-salts, and composition thereof.Citric acid is preferred acid.

Effervescent comprises in the preferred embodiments of the invention of bronsted lowry acids and bases bronsted lowry therein, and acid is about 1: 100 to about 100: 1 with the weight ratio of alkali, more preferably about 1: 50 to about 50: 1, and more preferably about 1: 10 to about 10: 1.Effervescent comprises in the further preferred embodiment of the present invention of bronsted lowry acids and bases bronsted lowry therein, and acid is stoichiometric approximately with the ratio of alkali.

The vehicle of the metal-salt of dissolving API typically has hydrophilic and hydrophobic zone simultaneously, or is preferably amphipathic or has the amphipathic zone.A type of amphipathic or part amphipathic vehicle comprises amphiphilic polymer or is amphiphilic polymer.Concrete amphiphilic polymer is a polyalkylene glycol, and it is made up of ethylene glycol and/or propylene glycol subunit usually.This polyglycol can be at its end by carboxylic acid, ester, acid anhydrides or other group esterification that is fit to.The example of this vehicle comprises that the polyalkylene glycol acid esters of poloxamer (the symmetric segmented copolymer of ethylene glycol and propylene glycol as, poloxamer 237), vitamin-E (comprises by two or the ester that forms of polyfunctional carboxylic acid; As, d-alpha-tocopherol polyoxyethylene glycol-1000 succinate) and polyethylene glycol glycerol ester (macrogolglyceride) (form by the alcoholysis of oil and the esterification of polyglycol, to produce list, two and the mixture of Witepsol W-S 55 and list and di-esters; As, stearyl polyoxyethylene glycol-32 glyceryl ester).This pharmaceutical composition and medicine be oral administration advantageously.

Pharmaceutical composition of the present invention and medicine can comprise that about 10 weight % arrive about 45 weight % or the about 30 weight % API to about 35 weight % to about 50 weight %, about 25 weight % to about 50 weight %, about 30 weight %; The about 50 weight % of about 10 weight %, about 25 weight % arrive about 50 weight %, about 30 weight % arrive about 35 weight % to about 45 weight % or about 30 weight % inhibition crystalline vehicle; Arrive about 35 weight % or about 30 weight % binding agent to about 50 weight %, about 10 weight % to about 40 weight %, about 15 weight % with about 5 weight % to about 35 weight %.In an example, API and inhibition crystalline vehicle are about 1: 1: 1 to the weight ratio of binding agent.

Solid dosage of the present invention can be not limited to described method herein by any suitable method preparation.

Illustrative method comprise (a) with salt of the present invention and one or more mixed with excipients with the step that forms mixture with (b) with mixture compressing tablet or incapsulate respectively to form tablet or capsular step.

In a preferred method, prepare solid dosage by the method that may further comprise the steps: (a) with API salt of the present invention and one or more mixed with excipients to form the step of mixture, (b) with mixture pelleting with the step that forms granule with (c) with mixture compressing tablet or incapsulate respectively to form tablet or capsular step.Step (b) can be finished by any dry method as known in the art or wet granulation technology, but preferred dry granulation step.Salt of the present invention advantageously arrives about 25 micron particle to form about 1 micron to about 100 microns, about 5 microns to about 50 microns or about 10 microns through granulation.Preferably add one or more thinners, one or more disintegrating agents and one or more binding agents at for example mixing step, optionally increase and add wetting agent and preferably after granulation, still add one or more disintegrating agents at compressing tablet or before incapsulating in for example granulation step.Preferably before compressing tablet, add lubricant.Mixing and granulation can be carried out under low or high-shear independently.The particulate API content that method for preferential selection forms evenly, disintegration easily, fully easily flow make can in filled capsules or compressing tablet process, control reliably weight differential and in bulk enough dense make can be in the equipment of selecting processing batch of material and concrete dosage is filled in appointment capsule or the tablet mould.

In embodiment optionally, prepare solid dosage by the method that comprises the spraying drying step, wherein API and one or more vehicle are suspended in one or more sprayable fluids, preferred non-proton (as, non-water or non-alcohol) can spray fluid, spraying drying promptly on hot blast then.

The particle spraying dry powder that is produced by above-mentioned illustrative method can compress or is molded with the preparation tablet or incapsulate with the preparation capsule.Can use conventional compressing tablet as known in the art and encapsulation technology.During the need of coating sheet, conventional packaging technique is fit to therein.

The preferred vehicle of selecting to be used for tablet composition of the present invention, be provided at the standard disintegration analyze in less than about 30 minutes, preferred the longest be about 25 minutes, more preferably the longest be about 20 minutes, more preferably the longest be about 15 disintegration time.

In another embodiment of the invention, can prepare and comprise Provigil and other pharmaceutical composition or medicine.Provigil and other API can be the form of cocrystallization, and the mixture or the combination that perhaps can be used as active medicine component are included in wherein.For example, composition can comprise Provigil and the caffeine as combination.The composition useful as therapeutics that comprises Provigil and caffeine is with the treatment situation identical with Provigil.In comprising this composition of Provigil and caffeine, caffeine can produce the characteristics (with respect to the little Tmax of Provigil) of snap-out release for solubility curve, and Provigil causes that there is therapeutic action in a few hours after administration.For example, the Tmax of caffeine can be 0.001,0.01,0.05,0.1,0.2,0.3,0.4,0.5,0.6,0.7 or 0.8 times of Provigil.Combination therapy is included in two or more API of administration in the same preparation, or in the preparation of two or more co-administereds two or more API of administration.API administration together simultaneously, or with appointed interval administration respectively.

Being applied as of Provigil is well-known, and it comprises that hypnolepsy, fatigue, Infertility, eating disorder, attention that multiple sclerosis is relevant lack the treatment of hyperkinetic syndrome (ADHD), Parkinson's disease, incontinence, sleep apnea or myopathy.In another embodiment, any one or more in the modafinil compositions of the present invention can be used for treating one or more above-mentioned conditions.The dosage of modafinil compositions of the present invention and administration can use the ordinary method in this area to measure, but are generally about 50 to about 700mg/ days.

In another embodiment, composition of the present invention can be by injection to the Mammals administration.Injection includes but not limited to intravenous injection, subcutaneous injection and intramuscular injection.In another embodiment, composition of the present invention is formulated as and is used for being expelled to the Mammals that needs result of treatment.

Embodiment

Prepare its crystalline general method

A) high-throughput crystallization of use CrystalMax_ platform

CrystalMax_ comprises the sequence of automatic, integrated high-throughput automatic control station, and it can generate, identifies and characterize polymorphic form, salt and the cocrystallization of API and AP thing rapidly.Use special designs software Architect ^TMCarry out the mixture design that worksheet generates and makes up.Typically, be assigned to test tube and under nitrogen gas stream drying from organic solvent API or API material standed for.Salt and/or cocrystallization formation thing also can distribute in an identical manner and be dry.Use the hyperchannel divider that water and organic solvent combination are assigned in the test tube.In 15 seconds of combination distribution, each test tube in the 96 pipe arrays are sealed to avoid solvent evaporation then.Keep and ℃ made the mixture supersaturation with 1 ℃/minute cooling ramp to 5 subsequently in 2 hours by being heated to 70 ℃ then.Carry out optical check then to detect crystal and/or solid material.In case in test tube, identified solid, it separated and drying by sucking-off.Obtain Raman spectrum and use special software (Inquire from solid then ^TM) carry out the cluster classification (cluster classfication) of spectral pattern.

B) from solution crystallization

Obtaining of cocrystallization can be by also joining independent components dissolved in the another kind with a kind of in solvent.Then can be along with evaporating solvent mixture at leisure makes cocrystallization precipitation or crystallization.Also can be by two components dissolved are obtained cocrystallization in identical solvent or solvent mixture.Also can add crystal seed by saturated solution and carry out seeding and obtain cocrystallization with the cocrystallization mixture that grinds to two components.

C) from melts crystallization (congruent melting is melted)

Can be by with two component melts (that is, congruent melting be melted) and recrystallization allow to take place obtain cocrystallization together.In some cases, can add contrary solvent so that crystallization.

D) thermomicroscopy (Thermal microscopy)

Cocrystallization obtain can by on slide glass with the component melts of higher melt and allow its recrystallize.Then second component melts is also also allowed its recrystallize.Cocrystallization can form the phase/band that separates between the congruent melting band of two original components.

E) elder brother closes and/or grinds

Can be by two components be obtained cocrystallization with solid-state mixing together or grinding.For example, embodiment 12 has described by adding the Provigil that mill under a small amount of appropriate solvent (wet grinding) obtains: 1-hydroxyl-2-naphthoic acid cocrystallization synthetic.Similarly, embodiment 5 has described by having and not adding the Provigil that obtains by milling under a small amount of appropriate solvent: citric acid monohydrate compound cocrystallization synthetic.In one embodiment, mill or grind (dry grinding) preparation cocrystallization by Provigil and cocrystallization being formed thing.In another embodiment, by Provigil, cocrystallization formation thing and a small amount of solvent being milled or grinding (wet grinding) preparation cocrystallization.

In another embodiment, by adding under the solvent, not adding under the solvent or both prepare cocrystallization its.The solvent that is used for this cocrystallization method can be such as but not limited to acetone, methyl alcohol, ethanol, Virahol, ethyl acetate, isopropyl acetate, Nitromethane 99Min., methylene dichloride, chloroform, toluene, propylene glycol, methyl-sulphoxide (DMSO), dimethyl formamide (DMF), ether, ethyl formate, hexane, acetonitrile, phenylcarbinol, water or the another kind of organic solvent that comprises alcohol.

F) distillation altogether

Can be by heating, mix or place vacuum to obtain cocrystallization in mixture from the mixture that forms thing as the API of intimate mixture and cocrystallization is distilled altogether at same sample hose.Can obtain cocrystallization by the common distillation of using the Kneudsen device, wherein API and cocrystallization formation thing are included in the independent sample hose that is connected in single cold finger, each sample hose is maintained identical or different temperature two components are sublimate into altogether the cocrystallization that forms expectation on the cold finger under vacuum atmosphere.

Analytical procedure

The differential scanning calorimetric (DSC) of sample is analyzed and is used Q1000 Differential ScanningCalorimeter (TA Instruments, New Castle, DE, U.S.A.) carry out, it uses Advantage for QW-Series, version 1.0.0.78, Thermal Advantage Release2.0 (2001 TA Instruments-Water LLC).In addition, the analysis software of use is the Universal Analysis 2000 that is used for Windows 95/98/2000/NT, version 3 .1E; Build3.1.0.40 (2001 TA Instruments-Water LLC).

For dsc analysis, the purgative gas that uses is drying nitrogen, the empty aluminium dish of reference material for curling, and sample cleaned to 50mL/ minute.

The dsc analysis of sample is undertaken by the Provigil sample being placed the aluminium dish with curling disk cover.Starting temperature typically is 20 ℃, and heating rate is 10 ℃/minute, and end temp is 200 ℃.Unless otherwise indicated, the DSC indicator of all reports is shown in their temperature of changing of the neither endothermic nor exothermic at peak separately, and error is+/-2 ℃.

The thermogravimetric analysis of sample (TGA) is analyzed and is used Q500Differential ScanningCalorimeter (TA Instruments, New Castle, DE, U.S.A.) carry out, it uses Advantage for QW-Series, version 1.0.0.78, Thermal Advantage Release2.0 (2001 TA Instruments-Water LLC).In addition, the analysis software of use is the Universal Analysis 2000 that is used for Windows 95/98/2000/NT, version 3 .1E; Build3.1.0.40 (2001 TA Instruments-Water LLC).

For the TGA experiment, the purgative gas that uses is drying nitrogen, and balance is cleaned the N for 40mL/ minute ₂, and sample cleans the N for 60mL/ minute ₂

By placing the platinum dish that sample is carried out TGA in the Provigil sample.Starting temperature typically is 20 ℃, and heating rate is 10 ℃/minute, and end temp is 300 ℃.

The powder x-ray diffraction of sample (PXRD) pattern uses D/Max Rapid, Contact (Rigaku/MSC, The Woodlands, TX, U.S.A.) obtain, it uses RINTRapid Control Software, Rigaku Rapid/XRD, and version 1.0.0 (1999 Rigaku Co.) is as its control software.In addition, the analysis software that uses is RINT Rapid display software, version 1.18 (Rigaku/MSC); With JADE XRD Pattern Processing, version 5.0 and 6.0 ((1995-2002, Materials Data, Inc.).

Analyze for PXRD, acquisition parameter is as follows: gamma ray source is the Cu of K line at 1.5406_; The x-y Stage microscope is manual; Collimator tube is of a size of 0.3mm; (MA U.S.A.) is 0.3mm ID to kapillary for Charles SupperCompany, Natick; Use reflective-mode; Power to X-ray tube is 46kV; Electric current to X-ray tube is 40mA; The ω axle with 1 degree/minute speed in the vibration of the scope of 0-5 degree; The φ axle rotates with the angle of 360 degree with the speed of 2 degree/seconds; 0.3mm collimator tube; Acquisition time is 60 minutes; Temperature is a room temperature; Do not use well heater.Sample is presented to x-ray source in being rich in the glass capillary of boron.

In addition, analytical parameters is as follows: integration 2 θ scopes are the 2-60 degree; Integration χ scope is the 0-360 degree; The number of χ part is 1; The step-length of using is 0.02; Integration utility is cylint; Use normalization method; Dark counts is 8; The Ω skew is 180; Skew is 0 with χ and φ.

Also obtain the PXRD diffractogram by Bruker AXS D8Discover X-ray Diffractometer.This instrument and equipment have GADDS ^TM(General Area Diffraction DetectionSystem), according to x-y-z Stage microscope and the 0.5mm collimator tube of system calibration in the Bruker of 15.05cm distance AXS HI-STAR AreaDetector, Tong Yuan (Cu/K α 1.54056 dusts), automatization.With sample boil down to granule form and be installed on the x-y-z Stage microscope.Under reflective-mode, keep sample to be fixed under the envrionment conditions (25 ℃) simultaneously and obtain diffractogram with the power setting of 40kV and 40mA.For each sample exposure asynchronism(-nization) and to each sample is the fixed time.The diffractogram that obtains is through how much pincushion distortions of the heavy conversion process in space with explanation area wave-detector, then along χ from-118.8 to-61.8 degree and 2 θ 2.1-37 degree with the 0.02 step-length integration of spending, normalization method is set to scale-of-two normalization method.

In the diffractogram relative intensity at peak unnecessary be the restriction of PXRD pattern because different sample peak intensities may be different, for example since crystalline impurities cause.In addition, the angle at each peak can be made an appointment with+/-0.1 degree difference, and is preferred+/-0.05 degree.Owing to change at other of calibration, setting and different instrument and different operator, most of peaks of whole pattern or pattern also can have an appointment+/-0.1 spend the displacement of degree approximately+/-0.2.At the PXRD peak of all reports in accompanying drawing, embodiment and other places herein all with the Discrepancy Report of 2 θ of ± 0.1 degree approximately.

For PXRD data herein, comprise table and figure, each composition of the present invention can by any, any two, wantonly three, wantonly four, wantonly five, wantonly six, wantonly seven or wantonly eight or more a plurality of 2 θ horns sign.Can also use any, two, three, four, five or six DSC change and characterize compositions of the present invention.The various combination characterize combinations that can also use PXRD peak and DSC to change.

On Zeiss Axioplan 2 microscopes that are equipped with Mettler Toledo FP90 controller, carry out heat (hot platform (hotstage)) microscopy.The hot platform that uses is Mettler ToledoFP82HT.All fusing point tests are all undertaken by sample being placed on the slide glass and covering with cover glass.Starting temperature be set to 30 ℃ and temperature with 10 ℃/speed increase.Observe fusion by the 5x micro objective.

HPLC method: (adapt from people such as Donovan Therapeutic Drug Monitoring25:197-202.

Post: Astec Cyclobond I 2000RSP 250x4.6mm (Part No.411121)

Mobile phase A: the 20mM sodium phosphate, pH 3.0

B:70: 30 mobile phase A: acetonitrile

Flow velocity: 1.0mL/min (～1500PSI)

Flow program: gradient

Working time: 35 minutes

Detect: UV@225nm

Injection volume: 10 microlitres

Column temperature: 30+/-1 ℃

Standard thinner: 90: 10 (v/v) mobile phase A: acetonitrile

Pin washing: acetonitrile

Qing Xirongji ﹠amp; Sealing washing: 90: 10 (v/v) water: acetonitrile

The moving phase preparation:

1. preparation 1M SODIUM PHOSPHATE, MONOBASIC: the 120g SODIUM PHOSPHATE, MONOBASIC is dissolved in the water and makes it to be 1000mL; Filter.

2. prepare mobile phase A (20mM sodium phosphate, pH 3.0): for one liter, dilute with water 20mL 1M sodium phosphate is to 1000mL; Regulate pH to 3.0 with phosphoric acid.

3. (70: 30 (v/v) 20mM sodium phosphates, pH 3.0: acetonitrile): for one liter, the 700mL mobile phase A is mixed with the 300mL acetonitrile for the preparation Mobile phase B.

Specimen preparation:

With sample dissolution at 90: 10 (v/v) 20mM sodium phosphates, pH 3.0: in the acetonitrile near the concentration of 20 micrograms/mL.

Raman is gathered

Sample is stayed in the vial of processed sample therein or and transferred on the slide glass the aliquot of sample.Vial or slide glass are placed the combustion chamber.The Almega of 785nm laser source is equipped with in use ^TMDispersive Raman (Almega ^TMDispersive Raman, Thermo-Nicolet, 5225 Verona Road, Madison, WI 53711-4495) system measures.The microscope with 10x object lens (unless otherwise mentioned) of using appts is partially manually with focal in the sample sets, thus with laser orientation to sample surfaces.Use the parameter of describing in the Table A to obtain spectrum.(duration of contact may be different with frequency of exposure; Indicate the variation of parameter for each collection)

Table A. the Raman spectrum acquisition parameter

Parameter	The setting of using
Parameter	The setting of using	Duration of contact (s)	2.0
Frequency of exposure	10	Duration of contact (s)	2.0
Frequency of exposure	10	Laser source wavelength (nm)	785
Laser power (%)	100	Laser source wavelength (nm)	785
Laser power (%)	100	Iris shape	Pin hole
Aperture scale (um)	100	Iris shape	Pin hole
Aperture scale (um)	100	Spectral range	104-3428
Stop position	Single	Spectral range	104-3428
Stop position	Single	Temperature during collection (℃)	24.0

IR gathers

Use NexusTM 470 FT-IR, Thermo-Nicolet, 5225 Verona Road, Madison, WI 53711-4495 obtain IR spectrum and use Control and Analysissoftware:OMNIC, Version 6.0a, (C) Thermo-Nicolet, 1995-2004 analyzes.The data of cocrystallization are illustrated in Table IV and the accompanying drawing.

Embodiment 1

Racemize Provigil: propanedioic acid cocrystallization

To comprise the racemize Provigil (150mg, add in acetate 0.549mm0l) (600 microlitre) solution propanedioic acid (114.9mg, 1.104mmol).Then with mixture at hot plate 67 ℃ of heating, up to all substance dissolves.Then that solution is dry under nitrogen gas stream, obtain 1: 1 Provigil: the propanedioic acid cocrystallization is colorless solid.Use PXRD to characterize this solid matter.With this material dried overnight under nitrogen gas stream, obtain having the slight excessive same substance of propanedioic acid then.Colorless solid is characterized with PXRD (Bruker), DSC, TGA, IR and Raman spectrum.Provigil: the PXRD data list of propanedioic acid (1: 1) cocrystallization is in Table IV, and diffractogram is (data former state) as shown in fig. 1.DSC is illustrated in about 106 ℃ endothermic transition, and differential thermogram as shown in Figure 2.The TGA differential thermogram as shown in Figure 3.Fig. 4 A and 4B represent Provigil respectively: three Raman spectrums of the Raman spectrum of propanedioic acid cocrystallization and Provigil, propanedioic acid and cocrystallization.Fig. 5 A and 5B represent Provigil respectively: three IR spectrum of the IR spectrum of propanedioic acid cocrystallization and Provigil, propanedioic acid and cocrystallization.Provigil: the propanedioic acid cocrystallization can by among Fig. 1 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 5.00,9.17,10.08,16.81,18.26,19.43,21.36,21.94,22.77,24.49,25.63,26.37 and 28.45 2 θ that spend.

Also, API grinds the preparation Provigil: the propanedioic acid cocrystallization by being formed thing with cocrystallization.With racemize Provigil (2.50g, 0.009mol) and propanedioic acid (1.01g, 0.0097mmol) in big mortar, mix in the time be incorporated in seven days and grind (and in 7 days being that the increment of about 1: 1.05 ratio adds propanedioic acid with respect to first day, in next seven days to produce 1: 2 Provigil: the increment of propanedioic acid ratio adds propanedioic acid).Ground 20 minutes with mixture grinding 45 minutes and after adding more propanedioic acid at every turn at first.At the 7th day, the mixture of cocrystallization with the beginning component heated about 35 minutes down at 80 ℃ in the 20mL bottle of sealing, so that finish cocrystallization formation.The material that obtains is carried out PXRD analyze (Bruker), and be illustrated in (data former state) among Fig. 6 A.Provigil: the propanedioic acid cocrystallization can by among Fig. 6 A any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 5.08,9.28,16.81,18.27,19.45,21.39,21.99,22.83,23.50,24.58,25.12 and 28.49 2 θ that spend.The DSC differential thermogram of the cocrystallization among Fig. 6 B shows at about 116 ℃ endothermic transition.Obtain Provigil: the monocrystalline data of propanedioic acid cocrystallization also are reported as follows.Fig. 7 represents Provigil: the accumulation graph of propanedioic acid.

Crystal data: C ₁₈H ₁₉NO ₆S, M=377.40, the C2/c of monocline; A=18.728 (8) dust, b=5.480 (2) dust, c=33.894 (13) dust, α=90 degree, β=91.864 (9) degree, γ=90 degree, T=100 (2) K, Z=8, Dc=1.442Mg/m ³, V=3477 (2) cubic angstroms, λ=0.71073 dust measures 6475 reflections, 3307 independent point diffractions (unique) (R _Int=0.1567).Final discrepancy factor (Final residual) for I＞2 σ (I) is R ₁=0.1598, wR ₂=0.3301 and be R for 3307 all data ₁=0.2544, wR ₂=0.3740.

Also use other method to prepare Provigil: the propanedioic acid cocrystallization.By (30mg 0.0001mol) places the stainless steel bottle to carry out the 3rd preparation with excessive propanedioic acid with Provigil.The acetone that in bottle, adds 20 microlitres.Then bottle is placed shredder (wig-l-bug, BrattTechnologies, 115V/60Hz) in and solid mixture milled 5 minutes.Collect the powder that obtains then and use PXRD and the DSC sign.At Provigil: in another preparation of propanedioic acid cocrystallization, do not add solvent and carry out above-mentioned the 3rd preparation.It is identical cocrystallization by PXRD with dsc analysis that all aforesaid methods of use propanedioic acid show generation.

Embodiment 2

Racemize Provigil: oxyacetic acid cocrystallization

With the racemize Provigil (1mg, 0.0037mmol) and oxyacetic acid (0.30mg 0.0037mmol) is dissolved in the acetone (400 microlitre).Characterize with PXRD (Rigaku) with the solution evaporate to dryness and with the solid that obtains.Provigil: the PXRD data list of oxyacetic acid cocrystallization is in Table IV.Referring to Fig. 8 A and 8B.Fig. 8 A is illustrated in the PXRD diffractogram after the subtracting background noise.Fig. 8 B represents primary PXRD data former state.

Also carried out the preparation Provigil: the process for selective of oxyacetic acid cocrystallization.Provigil in the mixture that is dissolved in acetone and methyl alcohol (3: 1,100 microlitres) (1mg, 0.0037mmol) add in the solution oxyacetic acid be dissolved in the methyl alcohol (50 microlitre) (0.28mg, 0.0037mmol).Solvent evaporated under nitrogen gas stream obtains two mixtures that begin components then.Add acetone (200 microlitre) to mixture then, be heated 70 ℃ and kept 2 hours at 70 ℃.Then sample is cooled to 5 ℃ and it is maintained this temperature 1 day.After 1 day, remove bottle cap and solvent evaporated from bottle, obtain Provigil: the oxyacetic acid cocrystallization is colorless solid.Characterize Provigil by PXRD: the oxyacetic acid cocrystallization.Provigil: the oxyacetic acid cocrystallization can by among Fig. 8 A any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 9.51,14.91,15.97,19.01,20.03,21.59,22.75,25.03 and 25.71 2 θ that spend.Similarly, Provigil: the oxyacetic acid cocrystallization can by among Fig. 8 B any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 9.53,14.93,15.99,19.05,20.05,21.61,22.77 and 25.05 2 θ that spend.

Embodiment 3

Racemize Provigil: toxilic acid cocrystallization

To comprise Provigil (150mg, add in acetate 0.549mmol) (600 microlitre) solution toxilic acid (30.7mg, 0.264mmol).Then with mixture at hot plate 67 ℃ of heating, up to all substance dissolves.Then that solution is dry under nitrogen gas stream, obtain colourless amorphous substance.Amorphous substance at room temperature is stored in the sealed vial.After 2 days, begin to form solid matter, its collection and use PXRD (Rigaku) are characterized, be Provigil: the toxilic acid cocrystallization, shown in Fig. 9 A and 9B.Fig. 9 A is illustrated in the PXRD diffractogram after the subtracting background noise.Fig. 9 B represents primary PXRD data.Provigil: the PXRD data list of toxilic acid cocrystallization is in Table IV.Provigil: the toxilic acid cocrystallization can by among Fig. 9 A any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 4.69,6.15,9.61,10.23,15.65,16.53,17.19,18.01,19.97,21.83 and 22.45 2 θ that spend.Similarly, Provigil: the toxilic acid cocrystallization can by among Fig. 9 B any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 4.69,6.17,9.63,10.25,15.67,16.53,17.21,18.05,19.99,21.85 and 22.47 2 θ that spend.

Embodiment 4

Racemize Provigil: L-tartrate cocrystallization

To the racemize Provigil (10.12mg, add in methyl alcohol 0.037mmol) (2mL) solution L-tartrate (5.83mg, 0.039mmol).Solution is at room temperature evaporated, obtain colourless viscous substance.With this material further under nitrogen gas stream dry 2 days, place bottle and cover lid then.After 6 days, form a small amount of colorless solid.In first observed a day after the solid, it is solid-state to keep about 60% of clarifying unbodied amount to become.The sample of this material is analyzed by PXRD (Bruker), as shown in figure 10.Provigil: L-tartrate cocrystallization can by among Figure 10 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 6.10,7.36,9.38,14.33,16.93,17.98,18.81,20.15,20.71,22.49 and 25.04 2 θ that spend.

Embodiment 5

Racemize Provigil: citric acid cocrystallization

(25.3mg, 93mmol) (26.8mg 128mmol) grinds 3 minutes together with the citric acid monohydrate compound with the racemize Provigil.Be dissolved in the mixture that obtains of 1mg in the acetone (100 microlitre) then and be heated to 70 ℃, under this temperature, kept 2 hours.Then solution is cooled to 5 ℃ and it is maintained this temperature 2 days.After 2 days, remove lid and add a water from bottle.Evaporating solvent then, obtain Provigil: citric acid monohydrate compound cocrystallization is colorless solid.With Provigil: citric acid monohydrate compound cocrystallization characterizes by PXRD (Rigaku), shown in Figure 11 A (subtracting background).Provigil: the citric acid cocrystallization can by among Figure 11 A any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 5.29,7.29,9.31,12.41,13.29,17.29,17.97,18.79,21.37 and 23.01 2 θ that spend.

Also use other method to prepare Provigil: citric acid monohydrate compound cocrystallization.By (30mg 0.0001mol) places the stainless steel bottle to carry out second preparation with excessive citric acid monohydrate compound with Provigil.The acetone that in bottle, adds 20 microlitres.Then bottle is placed shredder (wig-l-bug, Bratt Technologies, 115V/60Hz) in and solid mixture milled 5 minutes.Collect the powder that obtains then and use PXRD and the DSC sign.The DSC differential thermogram is as shown in Figure 11 B.At Provigil: in another preparation of citric acid monohydrate compound cocrystallization, do not add solvent and carry out above-mentioned second preparation.It is identical cocrystallization by PXRD with dsc analysis that all aforesaid methods of use citric acid monohydrate compound show generation.

Embodiment 6

Racemize Provigil: succsinic acid cocrystallization

With the racemize Provigil (25mg, 90mmol) and succsinic acid (10.6mg 90mmol) places vial and be dissolved in methyl alcohol (20 microlitre).The solution that obtains was cooled to 5 ℃ and maintain this temperature 2 days in 2 hours then 70 ℃ of heating.After 2 days, remove lid and at 65 ℃ of following evaporating solvents, obtain 2: 1 Provigil from bottle: the succsinic acid cocrystallization is colorless solid.Cocrystallization is 2: 1 cocrystallization that comprise every mole of succsinic acid and two moles of Provigils.With Provigil: the succsinic acid cocrystallization is by PXRD (Rigaku) and DSC sign, shown in Figure 12 A, 12B and 13.Figure 12 A represents the PXRD diffractogram after the subtracting background noise.Figure 12 B represents primary PXRD data.Figure 13 represents the DSC differential thermogram.

Also carried out the preparation Provigil: the process for selective of succsinic acid cocrystallization.Racemize Provigil in round-bottomed flask (49.7mg, 0.182mmol) and succsinic acid (21.6mg adds methyl alcohol (1.5mL) in 0.182mmol).Then with the hot plate dissolving of mixture at 65 ℃.Add by the above-mentioned Provigil for preparing to flask then: the crystal seed of succsinic acid cocrystallization.Use rotatory evaporator and 65 hot water baths evaporation methyl alcohol then, obtain Provigil: the succsinic acid cocrystallization is colorless solid.Confirm Provigil by the solid PXRD (Rigaku) that collects: succsinic acid cocrystallization synthetic.Provigil: the succsinic acid cocrystallization can by among Figure 12 A any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 5.45,9.93,15.85,17.97,18.73,19.95,21.33,21.93,23.01 and 25.11 2 θ that spend.Similarly, Provigil: the succsinic acid cocrystallization can by among Figure 12 B any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 5.45,9.93,15.87,17.99,18.75,19.95,21.95,23.03 and 25.07 2 θ that spend.Obtain Provigil: the monocrystalline data of succsinic acid cocrystallization also are reported as follows.Figure 14 represents Provigil: the accumulation graph of succsinic acid cocrystallization.

Crystal data: C ₁₇H ₁₈NO ₄S, three oblique P-1; A=5.672 (4) dust, b=8.719 (6) dust, c=16.191 (11) dust, α=93.807 (14) degree, β=96.471 (17) degree, γ=92.513 (13) degree, T=100 (2) K, Z=2, Dc=1.392Mg/m ³, V=792.8 (9) cubic angstroms, λ=0.71073 dust measures 2448 reflections, 1961 independent point diffractions (Rint=0.0740).Final discrepancy factor for I＞2 σ (I) is R ₁=0.1008, wR ₂=0.2283, for 1961 all data, R ₁=0.1593, wR ₂=0.2614.

Also use third party's legal system to be equipped with Provigil: the succsinic acid cocrystallization.By (30mg 0.0001mol) places the stainless steel bottle to carry out these methods with excessive succsinic acid with Provigil.The acetone that in bottle, adds 20 microlitres.And with bottle place shredder (wig-l-bug, BrattTechnologies, 115V/60Hz) in and solid mixture milled 5 minutes.Collect the powder that obtains then and use PXRD and the DSC sign.It is identical cocrystallization by PXRD with dsc analysis that all aforesaid methods of use succsinic acid show generation.

Embodiment 7

Racemize Provigil: DL-tartrate cocrystallization

With racemize Provigil (162mg; 0.591mmol) and DL-tartrate (462mg; 3.08mmol) suspension reflux in acetone (10mL) 1 minute.Suspension is filtered undissolved DL-tartrate by 0.2 micron PTFE filter paper while hot.Make the rest solution cool to room temperature, be cooled to 0 ℃ then, kept 1 hour.After 1 hour, observe big clear crystal.The mother liquor decant is fallen and make solid air-dry, characterize by PXRD (Rigaku), as shown in figure 15.Provigil: DL tartrate cocrystallization can by among Figure 15 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 4.75,9.53,10.07,15.83,17.61,19.37,20.25,21.53,22.55 and 23.75 2 θ (former state of collection) that spend.

Embodiment 8

Racemize Provigil: fumaric acid cocrystallization (I type)

With Provigil (30mg, 0.0001mol) and fumaric acid (2.3mg 0.0002mol) places the stainless steel bottle.The acetone that in bottle, adds 20 microlitres.And with bottle place shredder (wig-l-bug, Bratt Technologies, 115V/60Hz) in and solid mixture milled 5 minutes.Collect the powder that obtains then and use PXRD (Rigaku) to be characterized by Provigil: fumaric acid cocrystallization (I type), as shown in figure 16.Cocrystallization is 2: 1 cocrystallization that comprise every mole of fumaric acid and two moles of Provigils.Provigil: fumaric acid cocrystallization (I type) can by among Figure 16 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 5.45,9.95,10.91,15.93,18.03,18.81,19.93,20.25,21.37,21.95,23.09 and 25.01 2 θ (former state of collection) that spend.Obtain Provigil: the monocrystalline data of fumaric acid cocrystallization (I type) also are reported as follows.Figure 17 represents Provigil: the accumulation graph of fumaric acid cocrystallization (I type).

Crystal data: C ₁₇H ₁₇NO ₄S, M=331.38, anorthic P-1; A=5.7000 (15) dust, b=8.735 (2) dust, c=16.204 (4) dust, α=93.972 (6) degree, β=97.024 (6) degree, γ=93.119 (7) degree, T=100 (2) K, Z=2, Dc=1.381Mg/m ₃, V=797.2 (4) cubic angstroms, λ=0.71073 dust measures 4047 reflections, 2615 independent point diffractions (Rint=0.0475).Final discrepancy factor for I＞2 σ (I) is R ₁=0.0784, wR ₂=0.1584, be R for 2615 all data ₁=0.1154, wR ₂=0.1821.

Embodiment 9

Racemize Provigil: fumaric acid cocrystallization (II type)

With Provigil (30mg, 0.0001mol) and fumaric acid (1.2mg 0.0001mol) places the stainless steel bottle.The acetone that in bottle, adds 20 microlitres.And with bottle place shredder (wig-l-bug, Bratt Technologies, 115V/60Hz) in and solid mixture milled 5 minutes.Collect the powder that obtains then and use PXRD (Rigaku) to be characterized by Provigil: fumaric acid cocrystallization (II type), as shown in figure 18.Provigil: fumaric acid cocrystallization (II type) can by among Figure 18 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 6.47,8.57,9.99,13.89,14.53,16.45,17.13,17.51,18.39,20.05,20.79,25.93 and 27.95 2 θ (former state of collection) that spend.

Embodiment 10

The racemize Provigil: 2,5-resorcylic acid cocrystallization

(30mg, 0.0001mol) with 2, (1.5mg 0.0001mol) places the stainless steel bottle to the 5-resorcylic acid with Provigil.The acetone that in bottle, adds 20 microlitres.And with bottle place shredder (wig-l-bug, Bratt Technologies, 115V/60Hz) in and solid mixture milled 5 minutes.Collect the powder that obtains then and use PXRD (Bruker) to characterize, as shown in figure 19.Provigil: 2,5-resorcylic acid cocrystallization can by among Figure 19 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 6.96,12.92,14.76,17.40,18.26,20.10,20.94,23.46 and 24.36 2 θ (former state of collection) that spend.

Embodiment 11

Racemize Provigil: oxalic acid cocrystallization

By with the racemize Provigil (30mg, 0.0001mol) and oxalic acid (1-2mg 0.0001-0.0002mol) places the stainless steel bottle to carry out Provigil: the preparation of oxalic acid cocrystallization.The acetone that in bottle, adds 20 microlitres.And with bottle place shredder (wig-l-bug, BrattTechnologies, 115V/60Hz) in and solid mixture milled 5 minutes.Collect the powder that obtains then and use PXRD (Bruker) to characterize, as shown in figure 20.At Provigil: in another preparation of oxalic acid cocrystallization, do not add solvent and carry out above-mentioned preparation.Analyze by PXRD, two kinds of methods all produce identical cocrystallization.Provigil: the oxalic acid cocrystallization can by among Figure 20 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 5.98,13.68,14.80,17.54,19.68,21.12,21.86 and 28.90 2 θ (former state of collection) that spend.

Embodiment 12

Racemize Provigil: 1-hydroxyl-2-naphthoic acid cocrystallization

(30mg, 0.0001mol) (21mg 0.0001mol) places the stainless steel bottle with 1-hydroxyl-2-naphthoic acid with the racemize Provigil.The acetone that in bottle, adds 20 microlitres.And with bottle place shredder (wig-l-bug, Bratt Technologies, 115V/60Hz) in and solid mixture milled 5 minutes.Collect the powder that obtains then and use PXRD (Bruker) to characterize, as shown in figure 21.Provigil: 1-hydroxyl-2-naphthoic acid cocrystallization can by among Figure 21 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 5.72,7.10,11.48,14.16,15.66,17.92,19.18,20.26,21.28,21.94,24.38 and 26.86 2 θ (former state of collection) that spend.PXRD peak at 10.05 and 26.36 degree, 2 θ may form deposits yields by excessive cocrystallization.

Embodiment 13

R-(-)-Provigil: propanedioic acid cocrystallization

By (11.9mg 0.114mmol) grinds preparation R-(-)-Provigil: the propanedioic acid cocrystallization with propanedioic acid with R-(-)-Provigil (29.7mg, 0.109mmol, 82.2%R-isomer).With the mixture heating up to 80 of grinding ℃, kept 10 minutes then.Powder is by PXRD (Bruker) and dsc analysis, respectively shown in Figure 22 and 23.The PXRD pattern is confirmed to have formed cocrystallization, and shows and the racemize Provigil: many similaritys of the PXRD pattern of propanedioic acid cocrystallization.R-(-)-Provigil: the propanedioic acid cocrystallization can by among Figure 22 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 5.04,9.26,16.73,18.23,19.37,21.90,22.74,24.44 and 25.67 2 θ (the data former state of collection) that spend.DSC represents 111.5-114.7 ℃ melting range, and melting heat is 112.9J/g.

Embodiment 14

R-(-)-Provigil: succsinic acid cocrystallization

By (14.8mg 0.125mmol) grinds preparation R-(-)-Provigil: the succsinic acid cocrystallization with succsinic acid with R-(-)-Provigil (30.9mg, 0.113mmol, 82.2%R-isomer).With the mixture heating up to 145 of grinding ℃, kept 5 minutes then.Powder is by PXRD (Bruker) and dsc analysis, respectively shown in Figure 24 and 25.The PXRD pattern is confirmed to have formed cocrystallization, and the racemize Provigil that shows and make from solution: many similaritys of the PXRD pattern of succsinic acid cocrystallization.R-(-)-Provigil: the succsinic acid cocrystallization can by among Figure 24 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 5.36,9.83,15.80,17.88,18.70,19.87,21.21,21.85 and 25.96 2 θ (the data former state of collection) that spend.DSC represents 143.3-145.2 ℃ melting range, and melting heat is 140.7J/g.

Embodiment 15

R-(-)-Provigil: citric acid cocrystallization

By (27.1mg 0.129mmol) grinds preparation R-(-)-Provigil: the citric acid cocrystallization with the citric acid monohydrate compound with R-(-)-Provigil (30.0mg, 0.110mmol, 82.2%R-isomer).Powder is by PXRD (Bruker) and dsc analysis, respectively shown in Figure 26 and 27.The PXRD pattern is confirmed to have formed cocrystallization, and shows and the racemize Provigil: many similaritys of the PXRD pattern of citric acid cocrystallization.R-(-)-Provigil: the citric acid cocrystallization can by among Figure 26 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 5.18,7.23,9.23,12.32,13.23,17.25,17.92,18.76,20.25,21.30 and 23.71 2 θ (the data former state of collection) that spend.DSC represents 83.5-89.0 ℃ melting range, and melting heat is 39.8J/g.

Embodiment 16

R-(-)-Provigil: DL-tartrate cocrystallization

Obtain R-(-)-Provigil from the high-throughput crystallization experiment of using methylene dichloride: DL-tartrate cocrystallization.Bottle comprises R-(-)-Provigil (surpassing the 98%R-isomer) and tartaric 1: 2 mixture of DL-.Also find cocrystallization in tartaric 1: 1 mixture of R-(-)-Provigil from Nitromethane 99Min. (surpass 98%R-isomer) and DL-.Collect solid matter and use PXRD (Bruker) and the DSC sign, respectively shown in Figure 28 and 29.R-(-)-Provigil: DL-tartrate cocrystallization can by among Figure 28 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 4.67,15.41,17.97,19.46,20.50,22.91 and 24.63 2 θ (former state of collection) that spend.There is endothermic transition at about 107,152 and 187 ℃.

Embodiment 17

R-(-)-Provigil: 1-hydroxyl-2-naphthoic acid cocrystallization

To R-(-)-Provigil (98.6mg; 0.361mmol, surpass the 98%R-isomer) and 1-hydroxyl-2-naphthoic acid (71.2mg; 0.378mmol) solid mixture in add o-Xylol (4.5mL).Mixture heating up to refluxing, is continued to be shorter than one minute, and at this moment two kinds of solids all dissolve.Make solution cool to room temperature at leisure then, at this moment solid crystal.By solid collected by filtration and dry air.Powder characterizes with PXRD (Bruker), as shown in figure 30.Use aforesaid method to prepare identical material from benzene, toluene and acetone.R-(-)-Provigil: 1-hydroxyl-2-naphthoic acid cocrystallization can by among Figure 30 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 5.27,8.85,10.60,12.11,14.47,17.80,18.80,21.20,23.03 and 25.61 2 θ (former state of collection) that spend.

Also use the bottle of 1: 1 mixture of R-(-)-Provigil (surpassing the 98%R-isomer) comprise in the Nitromethane 99Min. and 1-hydroxyl-2-naphthoic acid to test and obtain R-(-)-Provigil: 1-hydroxyl-2-naphthoic acid cocrystallization from high-throughput crystallization.Collect solid matter and use PXRD (Bruker) and the DSC sign, respectively shown in Figure 31 and 32.R-(-)-Provigil: 1-hydroxyl-2-naphthoic acid cocrystallization can by among Figure 32 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 5.34,8.99,10.68,12.15,14.51,21.28,23.14 and 24.50 2 θ (former state of collection) that spend.DSC is illustrated in about 118 and 179 ℃ endothermic transition.

Embodiment 18

R-(-)-Provigil: vitamin B13 cocrystallization

Use is included in R-(-)-Provigil in the acetone (100 microlitre) (1mg, 0.0036mmol surpass the 98%R-isomer) and vitamin B13, and (1.14mg 0.0073mmol) tests from high-throughput crystallization and obtains R-(-)-Provigil: the vitamin B13 cocrystallization.Collect solid matter and use PXRD (Bruker) and the DSC sign, respectively shown in Figure 33 and 34.R-(-)-Provigil: the vitamin B13 cocrystallization can by among Figure 33 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 9.77,17.85,20.52,20.95,24.03 and 26.80 2 θ (former state of collection) that spend.PXRD peak 14.61 and 28.60 can form thing corresponding to excessive cocrystallization.There is endothermic transition at about 116,130 and 169 ℃.

Table IV: the cocrystallization of Provigil

Cocrystallization forms thing	Representational PXRD peak (degree, 2 θ)
Cocrystallization forms thing	Representational PXRD peak (degree, 2 θ)	Propanedioic acid	5.00、9.17、10.08、16.81、18.26、19.43、21.36、 21.94、22.77、24.49、25.63、26.37、28.45

Oxyacetic acid	9.53、14.93、15.99、19.05、20.05、21.61、22.77、 25.05
Oxyacetic acid	9.53、14.93、15.99、19.05、20.05、21.61、22.77、 25.05	Toxilic acid	4.69、6.17、9.63、10.25、15.67、16.53、17.21、 18.05、19.99、21.85、22.47
L-tartrate	6.10、7.36、9.38、14.33、16.93、17.98、18.81、 20.15、20.71、22.49、25.04	Toxilic acid
L-tartrate		Citric acid	5.29、7.29、9.31、12.41、13.29、17.29、17.97、 18.79、21.37、23.01
Succsinic acid	5.45、9.93、15.87、17.99、18.75、19.95、21.95、 23.03、25.07	Citric acid	5.29、7.29、9.31、12.41、13.29、17.29、17.97、 18.79、21.37、23.01
Succsinic acid	5.45、9.93、15.87、17.99、18.75、19.95、21.95、 23.03、25.07	DL-tartrate	4.75、9.53、10.07、15.83、17.61、19.37、20.25、 21.53、22.55、23.75
Fumaric acid (I type)	5.45、9.95、10.91、15.93、18.03、18.81、19.93、 20.25、21.37、21.95、23.09、25.01	DL-tartrate	4.75、9.53、10.07、15.83、17.61、19.37、20.25、 21.53、22.55、23.75
Fumaric acid (I type)		Fumaric acid (II type)	6.47、8.57、9.99、13.89、14.53、16.45、17.13、 17.51、18.39、20.05、20.79、25.93、27.95
2, the 5-resorcylic acid	6.96、12.92、14.76、17.40、18.26、20.10、20.94、 23.46、24.36	Fumaric acid (II type)
2, the 5-resorcylic acid	6.96、12.92、14.76、17.40、18.26、20.10、20.94、 23.46、24.36	Oxalic acid	5.98、13.68、14.80、17.54、19.68、21.12、21.86、 28.90
1-hydroxyl-2-naphthoic acid	5.72、7.10、11.48、14.16、15.66、17.92、19.18、 20.26、21.28、21.94、24.38、26.86	Oxalic acid	5.98、13.68、14.80、17.54、19.68、21.12、21.86、 28.90
1-hydroxyl-2-naphthoic acid		^*Propanedioic acid	5.04、9.26、16.73、18.23、19.37、21.90、22.74、 24.44、25.67
^*Succsinic acid	5.36、9.83、15.80、17.88、18.70、19.87、21.21、 21.85、25.96	^*Propanedioic acid	5.04、9.26、16.73、18.23、19.37、21.90、22.74、 24.44、25.67
^*Succsinic acid	5.36、9.83、15.80、17.88、18.70、19.87、21.21、 21.85、25.96	^*Citric acid	5.18、7.23、9.23、12.32、13.23、17.25、17.92、 18.76、20.25、21.30、23.71
^**DL-tartrate	4.67、15.41、17.97、19.46、20.50、22.91、24.63	^*Citric acid

^**1-hydroxyl-2-naphthoic acid	5.27、8.88、10.60、12.11、14.47、17.80、18.80、 21.20、23.03、25.61
^**1-hydroxyl-2-naphthoic acid	5.27、8.88、10.60、12.11、14.47、17.80、18.80、 21.20、23.03、25.61	^**Vitamin B13	9.77、17.85、20.52、20.95、24.03、26.80
^**2, the 5-resorcylic acid	7.07、7.51、9.07、12.31、16.03、17.63、18.39、 19.83、21.27、23.57、26.93、28.85	^**Vitamin B13	9.77、17.85、20.52、20.95、24.03、26.80

^*=API is R-(-)-Provigil, and it has 82.2% (purity) R-(-)-Provigil (17.8%S-(+)-Provigil)

^*=API is R-(-)-Provigil, and it has 98% (purity) R-(-)-Provigil of surpassing and (is less than 2%S-(+)-Provigil

All other cocrystallization comprise the racemize Provigil.

Embodiment 19

The acetic acid solvent compound of racemize Provigil

To racemize Provigil (12.9mg, 0.047mmol) the middle acetate (40 microlitre) that adds.Mixture is heated so that solid dissolves fully at 50 ℃.Make solution cool to room temperature and standing over night, do not produce precipitation.Then under nitrogen gas stream evaporating solns up to observing precipitation.The solid that obtains is further dry under nitrogen gas stream.Characterize product by PXRD (Rigaku), TGA, DSC and Raman spectrum, respectively shown in Figure 35-38.Also carried out the process for selective of the acetic acid solvent compound of preparation Provigil.By with the racemize Provigil (12.9mg, 0.047mmol) be dissolved in the acetate (40 microlitre) and 65 ℃ of insulations 30 minutes with dissolving, be cooled to the sample that 25 ℃ of incubated overnight prepare Provigil acetic acid solvent compound then.Evaporate sample then to about 1/3 amount.After sample is centrifugal, observing rapidly, nucleus formed and crystal growth.Add 20 other microlitre acetate then.Sample is dissolved up to observing crystal block section 50 ℃ of heating.Then in 1 hour time with the sample cool to room temperature, then at 3 hour time internal cooling to 5 ℃, to induce crystal growth.Then that sample is dry under nitrogen.Observing rapidly, crystal occurs.Provigil acetic acid solvent compound can by among Figure 35 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 6.17,9.63,15.69,17.97,19.99 and 21.83 2 θ (the data former state of collection) that spend.

Embodiment 20

The tetra oxygen furyl solvate of racemize Provigil

By (10.4mg 0.038mmol) places tetrahydrofuran (THF) (1mL) to prepare tetrahydrofuran (THF) (THF) solvate of Provigil with the racemize Provigil.Powder not exclusively is dissolved in THF and is converted into long, thin, needle-like crystal after spending the night, and collects and analyze by PXRD (Rigaku), as shown in figure 39.Provigil tetrahydrofuran solvent compound can by among Figure 39 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 6.97,9.79,10.97,16.19,19.03,19.71,20.59,22.25 and 25.13 2 θ (the data former state of collection) that spend.

Embodiment 21

1 of racemize Provigil, 4-two _ alkane solvents compound

To racemize Provigil (11.6mg, 0.042mmol) middle adding 1,4-two _ alkane (1mL).With the mixture standing over night, it is converted into long, thin, needle-like crystal then, with its collection and carry out PXRD (Rigaku) and analyze, as shown in figure 40.Provigil 1,4-two _ alkane solvents compound can by among Figure 40 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 6.93,9.85,10.97,16.19,18.97,19.61,20.33,20.65 and 22.07 2 θ (the data former state of collection) that spend.The PXRD pattern also comprises several spikes, and it is the result of instrumental error, can not remove.

Embodiment 22

The methanol solvate compound of racemize Provigil

The racemize Provigil methanol solution of the 30mg/mL that evaporates 2mL by spending the night under nitrogen gas stream obtains the methanol solvate compound of Provigil.Characterize the methanol solvate compound by PXRD (Rigaku), TGA and DSC, respectively shown in Figure 41,42 and 43.Provigil methanol solvate compound can by among Figure 41 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 6.15,9.89,12.25,15.69,17.97,20.07,21.85 and 22.73 2 θ (the data former state of collection) that spend.

Embodiment 23

The Nitromethane 99Min. solvate of racemize Provigil

(12.9mg 0.047mmol) adds Nitromethane 99Min. (1mL) to the racemize Provigil.With incomplete dissolved mixture standing over night, it is converted into big rectangular crystal.Collect solid and pass through PXRD (Rigaku) analysis, as shown in figure 44.Provigil Nitromethane 99Min. solvate can by among Figure 44 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 6.17,9.77,15.89,18.11,20.07,22.17,22.91,25.31 and 25.83 2 θ (the data former state of collection) that spend.

Embodiment 24

The acetone solvent compound of racemize Provigil

To in acetone (3mL), comprise the racemize Provigil (300mg, 0.001mol) and pentanedioic acid (150mg, the heating of 0.001mol) solution is up to boiling, with the dissolving entire solid matters.In case solid dissolving places solution on 5 ℃ the aluminium block.After 5 ℃ were placed 15 minutes, beginning formed crystal in the bottom of bottle.Decant falls solution and collects single crystal then, analyzes with PXRD (Rigaku), as shown in figure 45.Measuring crystal is the acetone solvent compound of Provigil.The acetone solvent compound of Provigil can by among Figure 45 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 6.11,9.53,15.81,18.11,20.03,21.63,22.45,25.23,25.65,28.85,30.23 and 32.93 2 θ (former state of collection) that spend.Also can use several other cocrystallization to form thing according to aforesaid method obtains the acetone solvent compound, comprises hexanodioic acid, lactobionic acid, toxilic acid and oxyacetic acid.

Embodiment 25

With the racemize Provigil (1mg, 0.0037mmol) and amygdalic acid (0.55mg 0.0037mmol) is dissolved in the acetone (400 microlitre).Characterize the solid that obtains with the solution evaporate to dryness and with PXRD (Rigaku), as shown in figure 46.The solid that obtains is the mixture of acetone solvent compound and another Provigil product.This formation can by among Figure 46 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 6.11,9.53,15.77,18.03,20.01 and 21.61 2 θ (removing background) that spend.Comprise that other peak of 6.75,10.31,14.77 and 23.27 can be corresponding to the Provigil polymorphic form.

Embodiment 26

With the racemize Provigil (1mg, 0.0037mmol) and fumaric acid (0.42mg 0.0037mmol) is dissolved in 1, in the 2-ethylene dichloride (400 microlitre).Characterize the solid that obtains with the solution evaporate to dryness and with PXRD (Rigaku), as shown in figure 47.The solid that obtains may be the solvate of Provigil.This formation can by among Figure 47 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 5.87,8.95,12.49,13.99,18.19,19.99,21.57 and 25.01 2 θ (removing background) that spend.

Embodiment 27

The new form of racemize Provigil

Distribute the racemize Provigil from the stock solution that 15: 5 acetone/methanol mixtures of 20mL, comprises the 50mg Provigil.Evaporate to dryness solution under nitrogen gas stream then.Distribute phenylformic acid and with mixture evaporate to dryness once more from acetone soln.Add the Virahol or the methyl alcohol of 200 microlitres then and will be the bottle cover lid.After room temperature leaves standstill one day, except that decap and with solvent evaporation.Sample is carried out PXRD (Rigaku), as shown in figure 48.The new form that may be the racemize Provigil of polymorphic form or cocrystallization is expressed as VII shape.VII shape can by among Figure 48 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 5.47,9.99,15.73,17.85,18.77,20.05,21.23,22.05,23.15 and 25.13 2 θ (the data former state of collection) that spend.

Embodiment 28

Racemize Provigil: the pharmacokinetic of propanedioic acid cocrystallization in dog

In pharmacokinetic, with the racemize Provigil: propanedioic acid cocrystallization (deriving from embodiment 1) is to the dog administration.The about 16 microns Provigil of administration median particle diameter under study for action: propanedioic acid cocrystallization particle.As a reference, go back the about 2 microns micronization Provigil of administration median particle diameter under study for action.Measure Provigil: the AUC of propanedioic acid cocrystallization is higher by 40 to 60% than the AUC of pure Provigil.This high bioavailability explanation embodiment of the present invention are to the adjusting of important pharmacokinetic parameter.The compilation of the important pharmacokinetic parameter of measuring in zooscopy is included in the Table V.

The Provigil of Table V-in dog: the pharmacokinetic parameter of propanedioic acid cocrystallization and pure Provigil

Parameter	Pure Provigil	Provigil: propanedioic acid cocrystallization
Parameter	Pure Provigil	Provigil: propanedioic acid cocrystallization	Median particle diameter	2 microns	16 microns
C _max(ng/mL)	11.0±5.9	10.3±3.4	Median particle diameter	2 microns	16 microns
C _max(ng/mL)	11.0±5.9	10.3±3.4	T _max(hour)	1.3±0.6	1.7±0.6
AUC (relative)	1.0	1.4-1.6	T _max(hour)	1.3±0.6	1.7±0.6
AUC (relative)	1.0	1.4-1.6	Transformation period (hour)	2.1±0.7	5.1±2.4

Embodiment 29

Racemize Provigil: propanedioic acid cocrystallization solid-state stability

Measuring the racemize Provigil under different temperature and the relative humidity: the stability of propanedioic acid cocrystallization in the time all around.Do not find degraded at 20 or 40 ℃.At 60 ℃, measure about 0.14% degraded every day according to simple exponential model.At 80 ℃, measure about 8% degraded every day.

Also measuring Provigil under different temperature and the relative humidity: the stability of propanedioic acid cocrystallization in the time in 26 weeks.The impurity area % that the sample that Figure 49 and 50 expressions are measured by HPLC stores under different condition is to the figure in time (week), and described condition comprises 25 ℃, 60%RH; 40 ℃, 75%RH; 40 ℃, environment RH; 60 ℃, environment RH; 80 ℃, environment RH; With-20 ℃.These data show that when storing at least 26 weeks under being equal to or less than 40 ℃, compound is stable.Figure 51 has compared Provigil: propanedioic acid cocrystallization sample initial and with sample through several temperature and the PXRD pattern of RH level after 26 weeks.

Embodiment 30

Racemize Provigil: the preparation of propanedioic acid cocrystallization

Use lactose to finish the racemize Provigil: the preparation of propanedioic acid cocrystallization.With two kinds of mixtures, a kind of is Provigil and lactose, and second kind is Provigil: propanedioic acid cocrystallization and lactose, grind together with pestle in mortar respectively.The mixture target is 1: 1 weight ratio of Provigil and lactose.In Provigil and milk-sugar mixture, the Provigil of 901.2mg and the lactose of 901.6mg are ground together.At Provigil: in propanedioic acid cocrystallization and the milk-sugar mixture, the cocrystallization of 1221.6mg and the lactose of 871.4mg are ground together.The powder that obtains is by PXRD and dsc analysis.The PXRD pattern of mixture and DSC differential thermogram show with both components separately and do not change.The DSC of cocrystallization mixture is only at 113.6 ℃ of melting peaks that show cocrystallization, and melting heat is 75.9J/g.59.5% of the value of being found when this melting heat is the independent cocrystallization of use (127.5J/g).This result meets 58.4% weight ratio of cocrystallization in the mixture.The DSC of Provigil and milk-sugar mixture has 165.7 ℃ fusing point.This slightly reduces than the Provigil fusing point of measuring (168.7 ℃).The melting heat of mixture (59.3J/g) be independent Provigil melting heat (126.6J/g) 46.9%, it meets 50% estimated value.

In capsule, tested Provigil: the external stripping of propanedioic acid cocrystallization and pure Provigil.In stripping research, all use gelatin and HPMC (HPMC) capsule.Have and do not have lactose in the presence of prepare capsule.Before in transferring to capsule, all preparations are ground in mortar and pestle.Test capsular stripping (referring to Figure 52) in 0.01M HCl.

In 0.01N HCl, in capsule, use material through sieving and grinding:

With Provigil and Provigil: the propanedioic acid cocrystallization is by 38 tm screen.With Provigil, 280.4mg the Provigil through sieve of 200.0mg: propanedioic acid cocrystallization, 200.2mg Provigil or the Provigil of 280.3mg through grinding through grinding through sieving: the propanedioic acid cocrystallization fill gelatine capsule (No. 0, B﹠amp; B Pharmaceuticals, Lot#15-01202).In having the Vankel VK 7000BenchsaverDissolution Testing Apparatus of the VK750D heating/circulator that is set to 37 ℃, carry out stripping research.At 0 minute, capsule is fallen into the container that comprises 900mL 0.01M HCl and stir by stirring rake.

Use Cary 50 spectrophotometers (wavelength is set to 260nm) to read the absorbancy reading at following time point: 0,5,10,15,20,25,30,40,50 and 60 minutes.Absorbance is compared with standard, and calculate the Provigil concentration of solution.

In 0.01N HCl, in gelatin or HPMC capsule, having and do not have lactose in the presence of use material through grinding:

With Provigil and Provigil: the lactose of propanedioic acid cocrystallization and equivalent (Spectrum, Lot QV0460) mixed about 5 minutes.With the Provigil of 400.2mg and the Provigil of lactose (about 200mg Provigil) or 561.0mg: propanedioic acid cocrystallization and lactose (about 200mg Provigil) fill gelatine capsule (No. 0, B﹠amp; B Pharmaceuticals, Lot#15-01202), Provigil with the Provigil of 399.9mg and lactose, 560.9mg: propanedioic acid cocrystallization and lactose, 199.9mg Provigil or 280.5mg Provigil: the propanedioic acid cocrystallization is filled the HPMC capsule (No. 0, Shionogi, Lot#A312A6).Carry out stripping research as mentioned above.

Embodiment 31

External stripping

Figure 53 represents micronization racemize Provigil: propanedioic acid cocrystallization and the micronization Provigil external stripping data in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF).Two kinds of samples are mixed with lactose and be filled in the HPMC capsule.All being cocrystallization in SGF and SIF more promptly is discharged into Provigil in the solution than the free form of Provigil.Figure 54 has compared and has used and lactose blended Provigil: the capsular stripping of HPMC that the propanedioic acid cocrystallization is filled and the stripping of PROVIGIL tablet.Figure 55 represents Provigil: dynamic steam absorption (DVS) isothermal map of propanedioic acid cocrystallization.This figure is illustrated in does not have tangible water absorption under the highest 40% RH under 26 ℃.

Embodiment 32

In vivo test

Use and the formulated racemize Provigil of lactose: propanedioic acid and PROVIGIL tablet (200mg) carry out pharmacokinetic to dog.Use Provigil: propanedioic acid cocrystallization and lactose are filled seven capsules, for 476.24+/-2mg, each self-contained 200mg Provigil.Figure 56 represents to have the cocrystallization preparation of the bioavailability of the Cmax of increase and increase.Several important pharmacokinetic parameters are described in Table VI.In Table VI, " Cmax " is maximal plasma concentration, and " AUC (inf) " is the area under curve of extrapolation, " t _1/2" for beginning half time that blood plasma level drops to the Cmax level from the beginning administration, " Tmax " for begin to reach the time of maximal plasma concentration from administration, " CL " be that clearance rate and " F% " of Provigil is the % bioavailability.

Table VI-Provigil: the PK parameter during propanedioic acid cocrystallization and PROVIGIL test in vivo

PROVIGIL(200mg)
PROVIGIL(200mg)								Cmax	AUC(inf)	t _1/2	Tmax	CL	F％
On average	7838.33	41193.33	1.76	2.00	524.17	66.48		Cmax	AUC(inf)	t _1/2	Tmax	CL	F％
On average	7838.33	41193.33	1.76	2.00	524.17	66.48	SD	2734.35	8104.32	0.88	0.63	146.98	13.08
％CV	34.9	19.7	49.7	31.6	28.0	19.7	SD	2734.35	8104.32	0.88	0.63	146.98	13.08
％CV	34.9	19.7	49.7	31.6	28.0	19.7	Provigil: propanedioic acid (200mg Provigil)
	Cmax	AUC(inf)	t _1/2	Tmax	CL	F％	Provigil: propanedioic acid (200mg Provigil)
	Cmax	AUC(inf)	t _1/2	Tmax	CL	F％	On average	11246.67	50545.00	1.63	2.00	368.33	81.57
SD	1662.13	10635.46	0.64	0.89	165.60	17.16	On average	11246.67	50545.00	1.63	2.00	368.33	81.57
SD	1662.13	10635.46	0.64	0.89	165.60	17.16	％CV	14.8	21.0	39.5	44.7	45.0	21.0

Embodiment 33

R-(-)-Provigil: 2,5-resorcylic acid cocrystallization

With R-(-)-Provigil (50mg, 0.183mmol surpass the 98%R-isomer) and 2, (28.2mg 0.183mmol) places the stainless steel bottle to the 5-resorcylic acid.The acetone that in bottle, adds 10 microlitres.And with bottle place shredder (wig-l-bug, Bratt Technologies, 115V/60Hz) in and solid mixture milled 5 minutes.Collect the powder that obtains then and use PXRD (Rigaku) to characterize, shown in Figure 57.R-(-)-Provigil: 2,5-resorcylic acid cocrystallization can by among Figure 57 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 7.07,9.07,12.31,13.03,14.09,18.93,19.83 and 21.27 2 θ (former state of collection) that spend.Other PXRD peak at 7.51,16.03,17.63,18.39,23.57,26,93 and 28.85 2 θ that spend forms thing corresponding to excessive cocrystallization.

Embodiment 34

The passage of racemize Provigil (channel) solvate

Found the passage solvate of Provigil unexpectedly.By at 60 ℃ of hot plate dissolved racemize Provigil 97.9mg, 0.358mmol) (68.8mg, acetone 0.366mmol) (3.15mL) solution makes the passage solvate with 1-hydroxyl-2-naphthoic acid.Then while hot under nitrogen gas stream evaporating solns to the cumulative volume of 1.6mL.After cooling, use the racemize Provigil through grinding: 1-hydroxyl-2-naphthoic acid cocrystallization is the solution seeding.Obtain single crystal and use the monocrystalline X-ray analysis to characterize.Monocrystalline X ray parameter: P2 (1)/n, a=12.737 (3) dust, b=5.5945 (11) dust, c=22.392 (5) dust, α=90 degree, β=104.140 (4) degree, γ=90 degree, V=1547.3 (5) cubic angstroms, Z=2.The accumulation graph of the acetone passage solvate of Figure 58 and 59 expression Provigils.This accumulation graph represents that acetone has variable position in channel architecture.Also use ethyl acetate to replace acetone to prepare ethyl acetate passage solvate according to aforesaid method.

Embodiment 35

O-Xylol half solvate of racemize Provigil

By prepare 1: 2 the racemize Provigil (49.6mg, 0.181mmol) and 1-hydroxyl-2-naphthoic acid (68.3mg, 0.363mmol) solution in o-Xylol (4.5mL) forms o-Xylol half solvate.Mixture is heated at hot plate under vortex, up to all solid dissolvings.Then with solution left standstill the sealing bottle in crystallization.In centrifugal filter, collect the powder obtain and analyze, shown in Figure 60 by PXRD (Bruker).Also use Raman spectrum (Figure 61), TGA (Figure 62) and DSC (Figure 63) to analyze and characterize half solvate.The o-Xylol solvate can by among Figure 60 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 5.31,6.53,6.96,10.68,14.20,17.64,19.93,25.69 and 26.79 2 θ that spend.The o-Xylol solvate can pass through Figure 61 (any in the intermediary spectrum, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak characterize, it includes but not limited to 1641,1407,1379,1211,1024 and 721cm ^-1

Embodiment 36

Benzene half solvate of racemize Provigil

By prepare 1: 2 the racemize Provigil (50.6mg, 0.181mmol) and 1-hydroxyl-2-naphthoic acid (70.1mg, 0.373mmol) solution in benzene (1.8mL) forms o-Xylol half solvate.Mixture is heated at hot plate under vortex, up to all solid dissolvings.Then with solution left standstill the sealing bottle in crystallization.In centrifugal filter, collect the powder obtain and analyze, shown in Figure 64 by PXRD (Bruker).Also use Raman spectrum (Figure 65), TGA (Figure 66) and DSC (Figure 67) to analyze and characterize half solvate.The benzene solvent compound can by among Figure 64 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 5.82,6.09,8.11,10.28,12.06,13.28,14.73,17.03,19.11,19.93,21.23,25.38 and 26.43 2 θ that spend.The benzene solvent compound can pass through among Figure 65 (intermediary spectrum) any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak characterize, it includes but not limited to 1637,1600,1409,1380,1214,1025,998 and 721cm ^-1

Embodiment 37

Toluene half solvate of racemize Provigil

By constitute 1: 2 the racemize Provigil (37.3mg, 0.136mmol) and 1-hydroxyl-2-naphthoic acid (51.3mg, 0.273mmol) solution in toluene (1mL) forms toluene half solvate.Mixture is heated at hot plate under vortex, up to all solid dissolvings.Then with solution left standstill the sealing bottle in crystallization.In centrifugal filter, collect the powder obtain and analyze, shown in Figure 68 by PXRD (Bruker).Also use Raman spectrum (Figure 69), TGA (Figure 70) and DSC (Figure 71) to analyze and characterize half solvate.Toluene solvate can by among Figure 68 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 5.30,5.96,10.65,12.90,14.51,17.60 and 18.15 2 θ that spend.Toluene solvate can pass through among Figure 69 (intermediary spectrum) any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak characterize, it includes but not limited to 1640,1581,1408,1380,1209,1024,1001 and 722cm ^-1

Embodiment 38

The pharmacokinetics of Provigil isomer

Carry out the dog pharmacokinetic (N=6) of R-(-)-Provigil single intravenous dosages administration.The purity of R-(-)-Provigil is about 80% in the preparation of administration.In cross-over design with this preparation with also the racemize modafinil formulations of identical dog administration is compared by intravenous route.The result reports in Table VII.In Table VII, " Cmax " is maximal plasma concentration, and " AUC (inf) " is the area under curve of extrapolation, " t _1/2" for beginning half time that blood plasma level drops to the Cmax level, " V from the beginning administration _d" be that distribution volume and " CL " are the clearance rate of Provigil.

Table VII-the derive from PK parameter of the racemize Provigil and R-(-)-Provigil of in vivo test

Racemize Provigil (5mg/kg IV)
Racemize Provigil (5mg/kg IV)							C _max (ng/mL)	AUC(inf) (ng/mL×hr)	t _1/2 (hr)	V _d (mL/kg)	CL (mL/hr×kg)
On average	8682.83	15117.50	1.05	588.83	341.00		C _max (ng/mL)	AUC(inf) (ng/mL×hr)	t _1/2 (hr)	V _d (mL/kg)	CL (mL/hr×kg)
On average	8682.83	15117.50	1.05	588.83	341.00	SD	1413.71	2870.24	0.16	96.41	65.63
％CV	16.3	19.0	15.4	16.4	19.2	SD	1413.71	2870.24	0.16	96.41	65.63
％CV	16.3	19.0	15.4	16.4	19.2	R-(-)-Provigil (5mg/kg IV)
On average	7806.67	15905.17	1.53	646.67	340.33	R-(-)-Provigil (5mg/kg IV)
On average	7806.67	15905.17	1.53	646.67	340.33	SD	827.97	4958.47	1.11	68.10	102.39
％CV	10.6	31.2	72.5	10.5	30.1	SD	827.97	4958.47	1.11	68.10	102.39

These results show do not have significant difference between the pharmacokinetics of R-(-)-Provigil and racemize Provigil after intravenous administration.

The pharmacokinetics opposite (referring to United States Patent (USP) 4,927,855, it is incorporated into this paper as a reference in full) of these results and the isomer of oral administration.In described research, be R-(-)-Provigil (40-982), S-(+)-Provigil (40-983) or the racemize Provigil (40-476) of four dog administration 30mg/kg oral dosages.Calculate the AUC value from the form (40-476) of measurement in 2 to 9 hours behind the dosed administration and the plasma concentration of sulfone metabolite.Table VIII is represented pharmacokinetic data.

Table VIII-the derive from PK parameter of racemize Provigil, R-(-)-Provigil and S-(+)-Provigil of in vivo test

The compound of administration (30mg/kg)	Average A UC (racemoid) (mg/L * hr)	Average A UC (sulfone) (mg/L * hr)
The compound of administration (30mg/kg)	Average A UC (racemoid) (mg/L * hr)	Average A UC (sulfone) (mg/L * hr)	40-476 (racemoid)	46.76+/-6.95	35.12+/-6.93
40-982 (R-(-)-Provigil)	97.22+/-12.58	8.69+/-1.22	40-476 (racemoid)	46.76+/-6.95	35.12+/-6.93
40-982 (R-(-)-Provigil)	97.22+/-12.58	8.69+/-1.22	40-983 (S-(+)-Provigil)	50.94+/-8.77	83.12+/-21.66

These results show, have significant difference in the metabolism of two kinds of isomer of Provigil, cause the formation difference of nonactive sulfone metabolite, thereby are producing higher API contact when as R-(-)-Provigil administration.The formation that observed different distribution plan can be by the sulfone metabolite between intravenous route and oral route mainly by in intestines and the cytochrome C YP3A4 catalysis that exists of liver level and CYP3A4 to the statement of facts of the avidity higher (stereoselectivity metabolism) of avidity comparison R-(-)-Provigil of S-(+)-Provigil.This can cause S-(+)-Provigil to have metabolite formation faster, can shorten the API contact.

Embodiment 39

R-(-)-Provigil alcohol solvent compound

Preparation comprises R-(-)-Provigil (100mg, 0.366mmol, 85.4%R-isomer) and racemize Provigil (40mg, ethanol 0.146mmol) (3mL) solution.Mixture heating up is arrived backflow, so that all solids dissolving, cool to room temperature (25 ℃) then.After room temperature keeps 15 minutes, place 5 ℃ to spend the night solution.After 1 day, observe solid sediment, with its collection, drying, and characterize (Figure 72 and 73) with PXRD and TGA.Measuring solid is the alcohol solvent compound of R-(-)-Provigil.

R-(-)-Provigil alcohol solvent compound can by among Figure 72 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 2 θ (Rigaku PXRD, the data former state of collection) of 6.13,9.59,15.69,17.97,20.05,21.55,22.35,25.77 and 29.07 degree.

The TGA of the R-(-) that characterizes in Figure 73-Provigil alcohol solvent compound is presented at about 25 ℃ and about 140 ℃ 5.4% weight loss.

Embodiment 40

R-(-)-Provigil phenylcarbinol solvate

(100mg 0.366mmol) ground 5 minutes with phenylcarbinol (40 microlitre) with R-(-)-Provigil.Then the ground powder is analyzed (Figure 74,75 and 76) by PXRD, DSC and TGA.Measuring powder is the phenylcarbinol solvate of R-(-)-Provigil.

R-(-)-Provigil phenylcarbinol solvate can by among Figure 74 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 2 θ (Bruker PXRD, the data former state of collection) of 5.77,7.76,10.48,15.78,17.80,18.57,21.53,22.97 and 27.73 degree.

The DSC of the R-(-) that characterizes in Figure 75-Provigil phenylcarbinol solvate shows the endothermic transition at 83 ℃.

The TGA of the R-(-) that characterizes in Figure 76-Provigil phenylcarbinol solvate is presented at about 25 ℃ and about 125 ℃ 28.5% weight loss.

Embodiment 41

R-(-)-Provigil isopropanol solvent compound

R-(-)-Provigil pulled an oar in Virahol spend the night.In centrifugal filter, leach fluid, then dry under nitrogen gas stream under 5 ℃.Analyze the solid that obtains by PXRD.

R-(-)-Provigil isopropanol solvent compound can by among Figure 77 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 2 θ (Bruker PXRD, the data former state of collection) of 5.76,7.77,10.49,15.79,18.58,21.53,25.76 and 27.74 degree.

Embodiment 42

R-(-)-Provigil acetonitrile solvent compound

R-(-)-Provigil of 100mg was pulled an oar in acetonitrile 2 days.Analyze from the suspension filtered solid and by PXRD.

R-(-)-Provigil acetonitrile solvent compound can by among Figure 78 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 2 θ (Bruker PXRD, the data former state of collection) of 5.29,6.17,8.16,10.19,11.19 and 21.86 degree.

Embodiment 43

R-(-)-Provigil: pentanedioic acid cocrystallization

In the presence of a phenylcarbinol, R-(-)-Provigil (20 to 30mg, surpass the 98%R-isomer) and pentanedioic acid (15-20mg) are ground together.

The solid that obtains characterizes (referring to Figure 79) and may comprise cocrystallization by PXRD.R-(-)-Provigil: the pentanedioic acid cocrystallization can by among Figure 79 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 2 θ (Bruker PXRD, the data former state of collection) of 4.30,8.67,9.78,17.99,18.92,19.74,20.50,21.36,22.25,23.87,27.16,29.24 and 32.46 degree.

Also carried out using acetone and the wet grinding that makes water, the both produces the formation of cocrystallization.

Embodiment 44

R-(-)-Provigil: citric acid cocrystallization

In the presence of a phenylcarbinol, R-(-)-Provigil (20 to 30mg, surpass the 98%R-isomer) and citric acid monohydrate compound (15-20mg) are ground together.

The solid that obtains characterizes (referring to Figure 80) and may comprise cocrystallization by PXRD.R-(-)-Provigil: the citric acid cocrystallization can by among Figure 80 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 2 θ (Bruker PXRD, the data former state of collection) of 5.23,7.06,9.10,12.43,13.18,14.37,17.34,17.95,20.85,21.39,22.03,22.96,23.54 and 24.93 degree.

Also carried out using the wet grinding of acetone, it produces the formation of cocrystallization.

Embodiment 45

R-(-)-Provigil: L-tartrate cocrystallization

In the presence of a phenylcarbinol, R-(-)-Provigil (20 to 30mg, surpass the 98%R-isomer) and L-tartrate (15-20mg) are ground together.

The solid that obtains characterizes (referring to Figure 81) and may comprise cocrystallization by PXRD.R-(-)-Provigil: L-tartrate cocrystallization can by among Figure 81 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 2 θ (Bruker PXRD, the data former state of collection) of 4.56,10.33,14.45,17.29,19.91,21.13,23.10,24.10 and 26.76 degree.

Embodiment 46

R-(-)-Provigil: oxalic acid cocrystallization

In the presence of a phenylcarbinol, R-(-)-Provigil (20 to 30mg, surpass the 98%R-isomer) and oxalic acid (15-20mg) are ground together.

The solid that obtains is characterized (referring to Figure 82 A and 82B) by PXRD, and may comprise one or more cocrystallization.R-(-)-Provigil: oxalic acid (I type) cocrystallization can by among Figure 82 A any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 2 θ (Bruker PXRD, the data former state of collection) of 5.99,14.73,16.59,17.38,18.64,25.66 and 28.85 degree.R-(-)-Provigil: oxalic acid (II type) cocrystallization can by among Figure 82 B any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 2 θ (Bruker PXRD, the data former state of collection) of 5.66,14.76,17.20,17.63,19.60,24.90 and 28.84 degree.

Embodiment 47

R-(-)-Provigil: palmitinic acid cocrystallization

In the presence of a phenylcarbinol, R-(-)-Provigil (20 to 30mg, surpass the 98%R-isomer) and palmitinic acid (15-20mg) are ground together.

The solid that obtains characterizes (referring to Figure 83) and may comprise cocrystallization by PXRD.R-(-)-Provigil: the palmitinic acid cocrystallization can by among Figure 83 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 20 (Bruker PXRD, the data former states of collection) of 3.80,6.55,7.66,10.24,11.49,19.48,21.09,21.74,22.20,22.97 and 23.99 degree.

Embodiment 48

R-(-)-Provigil: L-proline(Pro) cocrystallization

In the presence of a phenylcarbinol, R-(-)-Provigil (20 to 30mg, surpass the 98%R-isomer) and L-proline(Pro) (15-20mg) are ground together.

The solid that obtains characterizes (referring to Figure 84) and may comprise cocrystallization by PXRD.R-(-)-Provigil: L-proline(Pro) cocrystallization can by among Figure 84 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 2 θ (Bruker PXRD, the data former state of collection) of 6.52,8.53,10.25,14.69,19.06,19.71,20.75,22.29,22.75,25.08 and 26.27 degree.

Also carried out using the wet grinding of acetone and use methyl alcohol, the both produces the formation of cocrystallization.

Embodiment 49

R-(-)-Provigil: Whitfield's ointment cocrystallization

In the presence of a phenylcarbinol, R-(-)-Provigil (20 to 30mg, surpass the 98%R-isomer) and Whitfield's ointment (15-20mg) are ground together.

The solid that obtains characterizes (referring to Figure 85) and may comprise cocrystallization by PXRD.R-(-)-Provigil: the Whitfield's ointment cocrystallization can by among Figure 85 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 2 θ (Bruker PXRD, the data former state of collection) of 8.92,10.85,12.18,14.04,17.07,17.59,18.81,21.24,23.32,25.22 and 28.59 degree.

Embodiment 50

R-(-)-Provigil: lauric acid cocrystallization

In the presence of a phenylcarbinol, R-(-)-Provigil (20 to 30mg, surpass the 98%R-isomer) and lauric acid (15-20mg) are ground together.

The solid that obtains characterizes (referring to Figure 86) and may comprise cocrystallization by PXRD.R-(-)-Provigil: the lauric acid cocrystallization can by among Figure 86 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 2 θ (Bruker PXRD, the data former state of collection) of 3.12,6.55,10.24,13.97,16.40,17.62,19.02,20.05,21.38,22.24,23.81 and 25.96 degree.

Embodiment 51

R-(-)-Provigil: L MALIC ACID cocrystallization

In the presence of an acetone, R-(-)-Provigil (20 to 30mg, surpass the 98%R-isomer) and L MALIC ACID (15-20mg) are ground together.

The solid that obtains characterizes (referring to Figure 87) and may comprise cocrystallization by PXRD.R-(-)-Provigil: the L MALIC ACID cocrystallization can by among Figure 87 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 2 θ (Bruker PXRD, the data former state of collection) of 4.62,9.32,10.32,15.83,16.71,17.38,19.30,19.93,21.48,23.07,24.26 and 27.25 degree.

Embodiment 52

Prepare the diphenyl-methyl thioacetic acid from diphenyl-carbinol

At room temperature (about 22 ℃) in 20 minutes to diphenyl-carbinol (100g, drip in trifluoroacetic acid 0.542mol) (300mL) solution thioglycolic acid (50g, 0.542mol).By tlc (TLC) monitoring reaction progress.Be reflected in one hour and finish, at this moment, in reaction mixture, add entry (1000mL) at leisure and make the product precipitation.The throw out that filtration obtains, wash with water and under high vacuum dried overnight, obtain diphenyl-methyl thioacetic acid (139.3g, 99.3%), be light yellow solid.Referring to Prisinzano, people such as T., Tetrahedron Asymm., 2004,15,1053-1058)

Embodiment 53

Prepare diphenyl-methyl thioacetic acid (method of cooking different foods in one pot) from the bromo ditane

Under 42 ℃ to thiocarbamide (30.4g, add in water 0.399mol) (200mL) solution bromo ditane (98.8g, 0.399mol).Mixture is heated to backflow gradually, kept 10 minutes.Reaction mixture is cooled to 50 ℃ then, adds 5N NaOH (200mL) subsequently.The reacting by heating mixture was kept 30 minutes to refluxing (101-102 ℃) then, was cooled to 60 ℃ subsequently.In 45 minutes, in reaction mixture, slowly add chloracetic acid (53.4g, 0.565mol) and water (150mL) solution of NaOH (22.2g).30 minutes that the reaction mixture restir is other.To react cool to room temperature then and also wash, to remove any non-carboxylic acid impurity with t-butyl methyl ether (200ml).With water layer with dense HCl (50mL) acidifying (pH 2.0).The throw out that filtration obtains, water (2 * 200mL) and heptane (200mL) wash, and it is air-dry, obtain diphenyl-methyl thioacetic acid (116.8g, 100%), be colorless solid.Referring to United States Patent (USP) 4,066,686)

Embodiment 54

The trifluoroacetic acid that is used in the methylene dichloride prepares the diphenyl-methyl thioacetic acid from diphenyl-carbinol

In 20 minutes to diphenyl-carbinol (90g, drip 0.488mol) and in methylene dichloride (300mL) solution of trifluoroacetic acid (90mL) thioglycolic acid in methylene dichloride (60mL) (40g, 0.488mol).Be reflected in 1 hour and finish.Remove in a vacuum and desolvate, obtain thick solid, its dried overnight under high vacuum.Solid is handled with 2N NaOH (1.0L) and washed, to remove non-carboxylic acid impurity with t-butyl methyl ether (200ml).Then the aqueous solution is also collected the throw out that obtains with dense HCl acidifying, wash with water and drying, obtain diphenyl-methyl thioacetic acid (128.5g), be colorless solid.

Embodiment 55

Prepare the benzhydrylsulfinyl guanidine-acetic acid from the diphenyl-methyl thioacetic acid

At room temperature (about 22 ℃) are to diphenyl-methyl thioacetic acid (63.7g, 0.246mol) the dense H of adding in the suspension in methyl alcohol (250mL) ₂SO ₄Virahol (1.6mL) (65mL) solution.In 25 minutes, in suspension, drip 30% H in water ₂O ₂(65mL).By TLC monitoring reaction, it was finished in 2 hours.With solution NaHSO ₃Water (125mg) (700mL) solution dilution.The throw out that filtration obtains washes with water, uses methyl alcohol then: water (1: 1) is washed and is dry, obtains benzhydrylsulfinyl guanidine-acetic acid (47.6g). ¹H-NMR shows and has obtained required product, and 10% starting raw material and some impurity.Compound is ground with ethanol (100mL), filter and drying, obtain pure benzhydrylsulfinyl guanidine-acetic acid (33.4g, 49.4%), be colorless solid.(referring to Prisinzano, people such as T., Tetrahedron Asymm., 2004,15,1053-1058)

Embodiment 56

The thiacetic oxidation of diphenyl-methyl

In the 50L three neck round-bottomed flasks that are equipped with mechanical stirrer, 2L dropping funnel, nitrogen inlet and internal temperature probe, add the diphenyl-methyl thioacetic acid (3.5kg, 13.54mol), methyl alcohol (14L) and H ₂SO ₄Virahol (72g) (6.5L) solution.In 80 minutes, in this mixture, drip 30% H ₂O ₂The aqueous solution (3.75L) keeps temperature to be lower than 30 ℃.Reaction mixture was further stirred 7 hours, cause the formation of crystalline solid.With TLC and HPLC monitoring reaction.The solid filtering and the water (4.0L) that obtain are washed, obtained benzhydrylsulfinyl guanidine-acetic acid (2.5kg), be colorless solid.Superoxide NaHSO ₃The solution cancellation.

Embodiment 57

Use S-(-)-Alpha-Methyl benzylamine to split the benzhydrylsulfinyl guanidine-acetic acid

(62.4g, (30mL 0.236mol) and with it stirred 10 minutes down at reflux (101-102 ℃) to add S-(-)-Alpha-Methyl benzylamine in water 0.227mol) (300mL) solution to 80 ℃ (±)-benzhydrylsulfinyl guanidine-acetic acid.Solution is cooled to 40 ℃ gradually also filters the throw out that obtains, wash with water and drying, obtain colorless solid (71.4g).With salt recrystallize in water (500ml), obtain another colorless solid (53.5g).Then with salt suspension in water (200mL), with dense HCl (50mL) acidifying, and stirred 10 minutes.The suspension that filtration obtains also washes with water, obtains R-(-)-benzhydrylsulfinyl guanidine-acetic acid (21.5g), is colorless solid.The chiral purity of measuring by HPLC is＞99.9%ee.(referring to United States Patent (USP) 4,927,855)

Embodiment 58

Use N, the N-carbonyl dimidazoles with R-(-)-benzhydrylsulfinyl guanidine-acetic acid amidation obtain R-(-)- Provigil

In preparation has the 50L three neck round-bottomed flasks of mechanical stirrer, nitrogen inlet and internal temperature probe, add R-(-)-benzhydrylsulfinyl guanidine-acetic acid (1.32kg, 4.81mol) and tetrahydrofuran (THF) (7.0L).Be added in the N in the tetrahydrofuran (THF) (7L) in soup compound, (1.215kg 7.49mol), obtains colourless solution to the N-carbonyl dimidazoles.Then with solution stirring 30 minutes and with NH ₃(191g, 2.5eq.) bubbling passed through reaction mixture 3.5 hours to gas.Then, remove volatile matter in a vacuum, obtain thick solid, its methyl alcohol solution in t-butyl methyl ether (7.0L) with 20% is ground together spend the night.Collect solid matter then and by solid is further purified, is about to solid and in 1: 1 mixture (3L) of ethanol and t-butyl methyl ether, refluxes.To react cool to room temperature then and, obtain R-(-)-Provigil (501g, 99.6% chemical purity and 100%ee), be colorless solid solid matter filtration and dry.

Embodiment 59

By using N, N-carbonyl dimidazoles (CDI) activation preparation racemize Provigil

(10.0g 0.036mol) adds N in the suspension in tetrahydrofuran (THF) (100mL), and (7.1g 0.043mol), produces colourless solution to the N-carbonyl dimidazoles to (±)-benzhydrylsulfinyl guanidine-acetic acid.Solution stirring was being emitted CO in 10 minutes ₂The time form throw out.With NH ₃Gas bell passed through reaction mixture 10 minutes, made temperature of reaction be elevated to 33 ℃ from 16 ℃.Then the reaction mixture dilute with water is also used ethyl acetate extraction (3x 50mL).Merge organic layer, water, salt washing are also used Na ₂SO ₄Dry.The vacuum concentration organic layer obtains thick Provigil (11.5g) then.Obtain pure Provigil (6.0g) from 60% methanol aqueous solution recrystallization, be colorless solid.

Embodiment 60

From synthetic (±)-Provigil of diphenyl-carbinol

(30g drips methylene dichloride (30mL) solution of mercaptoethanol acid methyl esters (0.178mol) 0.162mol) and in the solution of trifluoroacetic acid (15mL) to diphenyl-carbinol in 20 minutes in methylene dichloride (120mL).To react and at room temperature stir 1 hour and the slow saturated NaHCO of adding ₃Solution.Organic layer is separated and vacuum concentration, obtain thick diphenyl-methyl thioacetate (38.2g, 89%).

To NH ₄Cl (0.29mol, 2.0eq) and NH ₄(38.2g, methyl alcohol 0.145mol) (50ml) solution keep temperature to be lower than 20 ℃ to add the diphenyl-methyl thioacetic acid in methyl alcohol (200mL) solution of OH (300ml).To react and stir 1 hour and water (100) dilution, cause that throw out forms.The collecting precipitation thing washes with water and drying, obtains benzhydryl thioacetamide (31g), is colorless solid.

According to prepare the identical method use H that R-(-)-Provigil uses at oxidation diphenyl-methyl thioacetic acid ₂O ₂The oxidation benzhydryl thioacetamide obtains the racemize Provigil.

Table I

Table I

Table I

Table I

Table I

Table I

Table I

Table I

Table II

Cocrystallization forms thing	Cocrystallization forms thing functional group	Reactive group
Cocrystallization forms thing	Cocrystallization forms thing functional group	Reactive group							1, the 5-naphthalene disulfonic acid	Sulfonic acid	Pyridine	Ketone	Aldehyde	Ether	Ester	Acid amides	Carboxylic acid
1-hydroxyl-2-naphthoic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	1, the 5-naphthalene disulfonic acid	Sulfonic acid	Pyridine	Ketone	Aldehyde	Ether	Ester	Acid amides	Carboxylic acid
1-hydroxyl-2-naphthoic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	1-hydroxyl-2-naphthoic acid	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
The 4-benzaminic acid	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	1-hydroxyl-2-naphthoic acid	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
The 4-benzaminic acid	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	The 4-benzaminic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
4-aminopyridine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	The 4-benzaminic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
4-aminopyridine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	4-aminopyridine	Pyridine	^*Alcohol	Pyridine _	^*	^*Acid amides	Nitro	^*Amine	^*Carboxylic acid
The 4-chlorobenzenesulfonic acid	Sulfonic acid	Pyridine	Ketone	Aldehyde	Ether	Ester	Acid amides	Carboxylic acid	4-aminopyridine	Pyridine	^*Alcohol	Pyridine _	^*	^*Acid amides	Nitro	^*Amine	^*Carboxylic acid
The 4-chlorobenzenesulfonic acid	Sulfonic acid	Pyridine	Ketone	Aldehyde	Ether	Ester	Acid amides	Carboxylic acid	4-ethoxyl phenenyl urea	Acid amides	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
4-ethoxyl phenenyl urea	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	4-ethoxyl phenenyl urea	Acid amides	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
4-ethoxyl phenenyl urea	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	7-oxo-DHEA	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
7-oxo-DHEA	Ketone	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	7-oxo-DHEA	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
7-oxo-DHEA	Ketone	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Acesulfame	Sulfone	Pyridine	Ketone	Aldehyde	Ether	Ester	Acid amides	Carboxylic acid
Acesulfame	Acid amides	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Acesulfame	Sulfone	Pyridine	Ketone	Aldehyde	Ether	Ester	Acid amides	Carboxylic acid
Acesulfame	Acid amides	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Acetohydroxamic acid	Acid amides	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Acetohydroxamic acid	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Acetohydroxamic acid	Acid amides	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Acetohydroxamic acid	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Acetohydroxamic acid	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
VITAMIN B4	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Acetohydroxamic acid	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
VITAMIN B4	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	VITAMIN B4	N	^*Alcohol	Pyridine _	^*	^*Acid amides	Nitro	^*Amine	^*Carboxilic acid
Hexanodioic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	VITAMIN B4	N	^*Alcohol	Pyridine _	^*	^*Acid amides	Nitro	^*Amine	^*Carboxilic acid
Hexanodioic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	L-Ala	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
L-Ala	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	L-Ala	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
L-Ala	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Zyloric	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Zyloric	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Zyloric	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Zyloric	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Arginine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Arginine	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Arginine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Arginine	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Xitix	Ketone	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Xitix	Alcohol	Alcohol		Mercaptan	Acid amides	Amine	Aniline	Phenol	Xitix	Ketone	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Xitix	Alcohol	Alcohol		Mercaptan	Acid amides	Amine	Aniline	Phenol	Xitix	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol

Table II

Cocrystallization forms thing
Cocrystallization forms thing										1, the 5-naphthalene disulfonic acid	Amine	Metal	Thioether		Sulfuric ester	Alcohol
1-hydroxyl-2-naphthoic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxilic acid	Metal	Aldehyde	Ester	1, the 5-naphthalene disulfonic acid	Amine	Metal	Thioether		Sulfuric ester	Alcohol
1-hydroxyl-2-naphthoic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxilic acid	Metal	Aldehyde	Ester	1-hydroxyl-2-naphthoic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxilic acid	Metal	Aldehyde	Ester
The 4-benzaminic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	1-hydroxyl-2-naphthoic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxilic acid	Metal	Aldehyde	Ester
The 4-benzaminic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	The 4-benzaminic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
4-aminopyridine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	The 4-benzaminic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
4-aminopyridine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	4-aminopyridine	^*Sulphonamide	^*Ketone	Ether	Triazole		Ammonium	Oxime	^*Chlorine
The 4-chlorobenzenesulfonic acid	Amine	Metal	Thioether		Sulfuric ester	Alcohol				4-aminopyridine	^*Sulphonamide	^*Ketone	Ether	Triazole		Ammonium	Oxime	^*Chlorine
The 4-chlorobenzenesulfonic acid	Amine	Metal	Thioether		Sulfuric ester	Alcohol				4-ethoxyl phenenyl urea	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
4-ethoxyl phenenyl urea	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	4-ethoxyl phenenyl urea	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
4-ethoxyl phenenyl urea	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	7-oxo-DHEA	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxilic acid	Metal	Aldehyde	Ester
7-oxo-DHEA	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde	7-oxo-DHEA	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxilic acid	Metal	Aldehyde	Ester
7-oxo-DHEA	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde	Acesulfame	Amine	Metal	Thioether		Sulfuric ester	Alcohol
Acesulfame	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde	Acesulfame	Amine	Metal	Thioether		Sulfuric ester	Alcohol
Acesulfame	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde	Acetohydroxamic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Acetohydroxamic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Acetohydroxamic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Acetohydroxamic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Acetohydroxamic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
VITAMIN B4	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Acetohydroxamic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
VITAMIN B4	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	VITAMIN B4	^*Sulphonamide	^*Ketone	Ether	Triazole		Ammonium	Oxime	^*Chlorine
Hexanodioic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	VITAMIN B4	^*Sulphonamide	^*Ketone	Ether	Triazole		Ammonium	Oxime	^*Chlorine
Hexanodioic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	L-Ala	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
L-Ala	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	L-Ala	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
L-Ala	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Zyloric	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Zyloric	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Zyloric	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Zyloric	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Arginine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Arginine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Arginine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Arginine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Xitix	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Xitix	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde	Xitix	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Xitix	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde	Xitix	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde

Table II

Cocrystallization forms thing
Cocrystallization forms thing									1, the 5-naphthalene disulfonic acid
1-hydroxyl-2-naphthoic acid	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Pyridine	1, the 5-naphthalene disulfonic acid
1-hydroxyl-2-naphthoic acid	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Pyridine	1-hydroxyl-2-naphthoic acid	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Pyridine
The 4-benzaminic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	1-hydroxyl-2-naphthoic acid	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Pyridine
The 4-benzaminic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	The 4-benzaminic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
4-aminopyridine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	The 4-benzaminic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
4-aminopyridine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	4-aminopyridine	Mercaptan	The N-heterocycle	Thionedisufide	Pyrrolidine-diones	Iodine	Hydrazone	Thiocyanide	^*Bromine
The 4-chlorobenzenesulfonic acid									4-aminopyridine	Mercaptan	The N-heterocycle	Thionedisufide	Pyrrolidine-diones	Iodine	Hydrazone	Thiocyanide	^*Bromine
The 4-chlorobenzenesulfonic acid									4-ethoxyl phenenyl urea	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
4-ethoxyl phenenyl urea	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	4-ethoxyl phenenyl urea	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
4-ethoxyl phenenyl urea	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	7-oxo-DHEA	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Pyridine
7-oxo-DHEA	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	7-oxo-DHEA	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Pyridine
7-oxo-DHEA	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Acesulfame
Acesulfame	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Acesulfame
Acesulfame	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Acetohydroxamic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Acetohydroxamic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Acetohydroxamic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Acetohydroxamic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Acetohydroxamic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
VITAMIN B4	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Acetohydroxamic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
VITAMIN B4	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	VITAMIN B4	Mercaptan	The N-heterocycle	Thionedisufide	Pyrrolidine-diones	Iodine	Hydrazone	Thiocyanide	^*Bromine
Hexanodioic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	VITAMIN B4	Mercaptan	The N-heterocycle	Thionedisufide	Pyrrolidine-diones	Iodine	Hydrazone	Thiocyanide	^*Bromine
Hexanodioic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	L-Ala	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
L-Ala	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	L-Ala	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
L-Ala	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Zyloric	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Zyloric	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Zyloric	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Zyloric	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Arginine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Arginine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Arginine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Arginine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Xitix	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Xitix	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Xitix	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Xitix	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Xitix	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle

Table II

Cocrystallization forms thing
Cocrystallization forms thing								1, the 5-naphthalene disulfonic acid
1-hydroxyl-2-naphthoic acid	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Carbamate	1, the 5-naphthalene disulfonic acid
1-hydroxyl-2-naphthoic acid	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Carbamate	1-hydroxyl-2-naphthoic acid	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Carbamate
The 4-benzaminic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	1-hydroxyl-2-naphthoic acid	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Carbamate
The 4-benzaminic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	The 4-benzaminic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
4-aminopyridine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	The 4-benzaminic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
4-aminopyridine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	4-aminopyridine		Hydroxamic acid	Cyano group	Carboxylic acid amides	^*Sulfonic acid	^*Phosphoric acid	The N-oxide compound
The 4-chlorobenzenesulfonic acid								4-aminopyridine		Hydroxamic acid	Cyano group	Carboxylic acid amides	^*Sulfonic acid	^*Phosphoric acid	The N-oxide compound
The 4-chlorobenzenesulfonic acid								4-ethoxyl phenenyl urea	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
4-ethoxyl phenenyl urea	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	4-ethoxyl phenenyl urea	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
4-ethoxyl phenenyl urea	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	7-oxo-DHEA	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Carbamate
7-oxo-DHEA	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	7-oxo-DHEA	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Carbamate
7-oxo-DHEA	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Acesulfame
Acesulfame	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Acesulfame
Acesulfame	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Acetohydroxamic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Acetohydroxamic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Acetohydroxamic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Acetohydroxamic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Acetohydroxamic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
VITAMIN B4	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Acetohydroxamic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
VITAMIN B4	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	VITAMIN B4		Hydroxamic acid	Cyano group	Carboxylic acid amides	^*Sulfonic acid	^*Phosphoric acid	The N-oxide compound
Hexanodioic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	VITAMIN B4		Hydroxamic acid	Cyano group	Carboxylic acid amides	^*Sulfonic acid	^*Phosphoric acid	The N-oxide compound
Hexanodioic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	L-Ala	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
L-Ala	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	L-Ala	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
L-Ala	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Zyloric	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Zyloric	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Zyloric	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Zyloric	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Arginine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Arginine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Arginine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Arginine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Xitix	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Xitix	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Xitix	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Xitix	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Xitix	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine

Table II

Cocrystallization forms thing
Cocrystallization forms thing								The 15-naphthalene disulfonic acid
1-hydroxyl-2-naphthoic acid	Imidazoles	BF4						The 15-naphthalene disulfonic acid
1-hydroxyl-2-naphthoic acid	Imidazoles	BF4						1-hydroxyl-2-naphthoic acid	Imidazoles	BF4
The 4-benzaminic acid	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		1-hydroxyl-2-naphthoic acid	Imidazoles	BF4
The 4-benzaminic acid	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		The 4-benzaminic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
4-aminopyridine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		The 4-benzaminic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
4-aminopyridine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		4-aminopyridine	Ester	Ether	Fluorine	Ethyl acetate	thione	Dithia diazacyclo pentadiene base
The 4-chlorobenzenesulfonic acid								4-aminopyridine	Ester	Ether	Fluorine	Ethyl acetate	thione	Dithia diazacyclo pentadiene base
The 4-chlorobenzenesulfonic acid								4-ethoxyl phenenyl urea	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide
4-ethoxyl phenenyl urea	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		4-ethoxyl phenenyl urea	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide
4-ethoxyl phenenyl urea	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		7-oxo-DHEA	Imidazoles	BF4
7-oxo-DHEA	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		7-oxo-DHEA	Imidazoles	BF4
7-oxo-DHEA	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Acesulfame
Acesulfame	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine	Epoxide	Acesulfame
Acesulfame	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine	Epoxide	Acetohydroxamic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide
Acetohydroxamic acid	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Acetohydroxamic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide
Acetohydroxamic acid	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Acetohydroxamic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide
VITAMIN B4	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Acetohydroxamic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide
VITAMIN B4	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		VITAMIN B4	Ester	Ether	Fluorine	Ethyl acetate	Thione	Dithia diazacyclo pentadiene base
Hexanodioic acid	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		VITAMIN B4	Ester	Ether	Fluorine	Ethyl acetate	Thione	Dithia diazacyclo pentadiene base
Hexanodioic acid	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		L-Ala	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
L-Ala	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		L-Ala	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
L-Ala	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Zyloric	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide
Zyloric	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Zyloric	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide
Zyloric	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Arginine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Arginine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Arginine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Arginine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Xitix	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Xitix	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine	Epoxide	Xitix	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Xitix	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine	Epoxide	Xitix	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine

Table II

Cocrystallization forms thing
Cocrystallization forms thing		1, the 5-naphthalene disulfonic acid
1-hydroxyl-2-naphthoic acid		1, the 5-naphthalene disulfonic acid
1-hydroxyl-2-naphthoic acid		1-hydroxyl-2-naphthoic acid
The 4-benzaminic acid		1-hydroxyl-2-naphthoic acid
The 4-benzaminic acid		The 4-benzaminic acid
4-aminopyridine		The 4-benzaminic acid
4-aminopyridine		4-aminopyridine
The 4-chlorobenzenesulfonic acid		4-aminopyridine
The 4-chlorobenzenesulfonic acid		4-ethoxyl phenenyl urea	Superoxide
4-ethoxyl phenenyl urea		4-ethoxyl phenenyl urea	Superoxide
4-ethoxyl phenenyl urea		7-oxo-DHEA
7-oxo-DHEA		7-oxo-DHEA
7-oxo-DHEA		Acesulfame
Acesulfame	Superoxide	Acesulfame
Acesulfame	Superoxide	Acetohydroxamic acid	Superoxide
Acetohydroxamic acid		Acetohydroxamic acid	Superoxide
Acetohydroxamic acid		Acetohydroxamic acid
VITAMIN B4		Acetohydroxamic acid
VITAMIN B4		VITAMIN B4
Hexanodioic acid		VITAMIN B4
Hexanodioic acid		L-Ala
L-Ala		L-Ala
L-Ala		Zyloric
Zyloric		Zyloric
Zyloric		Arginine
Arginine		Arginine
Arginine		Xitix
Xitix		Xitix
Xitix		Xitix

Table II

Cocrystallization forms thing	Cocrystallization forms thing functional group	Reactive group
Cocrystallization forms thing	Cocrystallization forms thing functional group	Reactive group							L-asparagine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
L-asparagine	Acid amides	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	L-asparagine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
L-asparagine	Acid amides	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	L-asparagine	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Aspartic acid	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	L-asparagine	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Aspartic acid	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Aspartic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Phenylsulfonic acid	Sulfonic acid	Pyridine	Ketone	Aldehyde	Ether	Ester	Acid amides	Carboxylic acid	Aspartic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Phenylsulfonic acid	Sulfonic acid	Pyridine	Ketone	Aldehyde	Ether	Ester	Acid amides	Carboxylic acid	Phenylformic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Caffeine	Ketone	Alcohol		Mercaptan	Acid amides	Amine	Aniline	Phenol	Phenylformic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Caffeine	Ketone	Alcohol		Mercaptan	Acid amides	Amine	Aniline	Phenol	Dextrocamphoric acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Capric acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Dextrocamphoric acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Capric acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Genistein	Ketone	Alcohol		Mercaptan	Acid amides	Amine	Aniline	Phenol
Genistein	Phenol	Amine	Acid amides	Sulfoxide	n	Pyridine	Cyano group	Aldehyde	Genistein	Ketone	Alcohol		Mercaptan	Acid amides	Amine	Aniline	Phenol
Genistein	Phenol	Amine	Acid amides	Sulfoxide	n	Pyridine	Cyano group	Aldehyde	Genistein	Ether	Fragrance-N	Acid amides	Amine	Fragrance-S	SP2 amine	Sulfoxide	The chlorate
Styracin	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Genistein	Ether	Fragrance-N	Acid amides	Amine	Fragrance-S	SP2 amine	Sulfoxide	The chlorate
Styracin	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Citric acid	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Citric acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Citric acid	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Citric acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	The carat imidazoles	Tetramethyleneimine	^*Alcohol	Pyridine _	^*	^*Acid amides	Nitro	^*Amine	^*Carboxilic acid
Cyclohexane sulfamic acid	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	The carat imidazoles	Tetramethyleneimine	^*Alcohol	Pyridine _	^*	^*Acid amides	Nitro	^*Amine	^*Carboxilic acid
Cyclohexane sulfamic acid	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Cyclohexane sulfamic acid	Sulfonic acid	Pyridine	Ketone	Aldehyde	Ether	Ester	Acid amides	Carboxylic acid
Halfcystine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Cyclohexane sulfamic acid	Sulfonic acid	Pyridine	Ketone	Aldehyde	Ether	Ester	Acid amides	Carboxylic acid
Halfcystine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Halfcystine	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Halfcystine	Mercaptan	Carboxylic acid	Sodium	Aldehyde	Ketone	-N	Cadmium		Halfcystine	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Halfcystine	Mercaptan	Carboxylic acid	Sodium	Aldehyde	Ketone	-N	Cadmium		N-methylsarcosine	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
N-methylsarcosine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	N-methylsarcosine	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
N-methylsarcosine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	D-ribose	Ether	Fragrance-N	Acid amides	Amine	Fragrance-S	SP2 amine	Sulfoxide	The chlorate
D-ribose	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	D-ribose	Ether	Fragrance-N	Acid amides	Amine	Fragrance-S	SP2 amine	Sulfoxide	The chlorate
D-ribose	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Fumaric acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Tetrahydroxyadipic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Fumaric acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Tetrahydroxyadipic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Tetrahydroxyadipic acid	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Chrysin	Ketone	Alcohol		Mercaptan	Acid amides	Amine	Aniline	Phenol	Tetrahydroxyadipic acid	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol

Table II

Cocrystallization forms thing
Cocrystallization forms thing										L-asparagine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
L-asparagine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde	L-asparagine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
L-asparagine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde	L-asparagine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Aspartic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	L-asparagine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Aspartic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Aspartic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Phenylsulfonic acid	Amine	Metal	Thioether		Sulfuric ester	Alcohol				Aspartic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Phenylsulfonic acid	Amine	Metal	Thioether		Sulfuric ester	Alcohol				Phenylformic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Caffeine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde	Phenylformic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Caffeine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde	Dextrocamphoric acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Capric acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Dextrocamphoric acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Capric acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Genistein	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Genistein		Alcohol		Ester	Ether	The N-oxide compound	Chlorine	Fluorine	Bromine	Genistein	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Genistein		Alcohol		Ester	Ether	The N-oxide compound	Chlorine	Fluorine	Bromine	Genistein	Chlorine		Cyano group	Ester	Amine	Nitro	Nitric ether	Bromine	Aldehyde
Styracin	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Genistein	Chlorine		Cyano group	Ester	Amine	Nitro	Nitric ether	Bromine	Aldehyde
Styracin	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Citric acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Citric acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Citric acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Citric acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	The carat imidazoles	^*Sulphonamide	^*Ketone	Ether	Triazole		Ammonium	Oxime	^*Chlorine
Cyclohexane sulfamic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	The carat imidazoles	^*Sulphonamide	^*Ketone	Ether	Triazole		Ammonium	Oxime	^*Chlorine
Cyclohexane sulfamic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Cyclohexane sulfamic acid	Amine	Metal	Thioether		Sulfuric ester	Alcohol
Halfcystine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Cyclohexane sulfamic acid	Amine	Metal	Thioether		Sulfuric ester	Alcohol
Halfcystine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Halfcystine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Halfcystine	Arsenic	Chlorine	Alcohol	Potassium	Ru		Rb	Sb		Halfcystine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Halfcystine	Arsenic	Chlorine	Alcohol	Potassium	Ru		Rb	Sb		N-methylsarcosine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
N-methylsarcosine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	N-methylsarcosine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
N-methylsarcosine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	D-ribose	Chlorine		Cyano group	Ester	Amine	Nitro	Nitric ether	Bromine	Aldehyde
D-ribose	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde	D-ribose	Chlorine		Cyano group	Ester	Amine	Nitro	Nitric ether	Bromine	Aldehyde
D-ribose	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde	Fumaric acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Tetrahydroxyadipic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Fumaric acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Tetrahydroxyadipic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Tetrahydroxyadipic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxilic acid	Metal	Aldehyde	Ester
Chrysin	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde	Tetrahydroxyadipic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxilic acid	Metal	Aldehyde	Ester

Table II

Cocrystallization forms thing
Cocrystallization forms thing									L-asparagine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
L-asparagine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	L-asparagine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
L-asparagine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	L-asparagine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Aspartic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	L-asparagine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Aspartic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Aspartic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Phenylsulfonic acid									Aspartic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Phenylsulfonic acid									Phenylformic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Caffeine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Phenylformic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Caffeine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Dextrocamphoric acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Capric acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Dextrocamphoric acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Capric acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Genistein	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Genistein	Iodine	Ketone	Sulfonic acid	Sulfuric ester	Phosphoric acid ester	Phosphonic acids	Carboxylic acid	Nitro	Genistein	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Genistein	Iodine	Ketone	Sulfonic acid	Sulfuric ester	Phosphoric acid ester	Phosphonic acids	Carboxylic acid	Nitro	Genistein	Ketone	Superoxide	Epoxide			Heterocycle-S	Iodine	Ester
Styracin	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Genistein	Ketone	Superoxide	Epoxide			Heterocycle-S	Iodine	Ester
Styracin	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Citric acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Citric acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Citric acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Citric acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	The carat imidazoles	Mercaptan	The N-heterocycle	Thionedisulfide	Pyrrolidine-diones	Iodine	Hydrazone	Thiocyanide	^*Bromine
Cyclohexane sulfamic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	The carat imidazoles	Mercaptan	The N-heterocycle	Thionedisulfide	Pyrrolidine-diones	Iodine	Hydrazone	Thiocyanide	^*Bromine
Cyclohexane sulfamic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Cyclohexane sulfamic acid
Halfcystine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Cyclohexane sulfamic acid
Halfcystine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Halfcystine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Halfcystine									Halfcystine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Halfcystine									N-methylsarcosine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
N-methylsarcosine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	N-methylsarcosine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
N-methylsarcosine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	D-ribose	Ketone	Superoxide	Epoxide			Heterocycle-S	Iodine	Ester
D-ribose	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	D-ribose	Ketone	Superoxide	Epoxide			Heterocycle-S	Iodine	Ester
D-ribose	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Fumaric acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Tetrahydroxyadipic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Fumaric acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Tetrahydroxyadipic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Tetrahydroxyadipic acid	Ester	Cyano group		Furans	Bromine	Bromine	The S-heterocycle	Pyridine
Chrysin	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Tetrahydroxyadipic acid	Ester	Cyano group		Furans	Bromine	Bromine	The S-heterocycle	Pyridine

Table II

Cocrystallization forms thing
Cocrystallization forms thing							L-asparagine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
L-asparagine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	L-asparagine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
L-asparagine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	L-asparagine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Aspartic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	L-asparagine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Aspartic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Aspartic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Phenylsulfonic acid							Aspartic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Phenylsulfonic acid							Phenylformic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Caffeine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Phenylformic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Caffeine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Dextrocamphoric acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Capric acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Dextrocamphoric acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Capric acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Genistein	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Genistein	Sulfone	Aniline					Genistein	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Genistein	Sulfone	Aniline					Genistein	Ether	Carboxylic acid	Sulfuric ester	Sulfone		Alcohol
Styracin	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Genistein	Ether	Carboxylic acid	Sulfuric ester	Sulfone		Alcohol
Styracin	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Citric acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Citric acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Citric acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Citric acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	The carat imidazoles		Hydroxamic acid	Hydroxyl	Carboxylic acid amides	^*Sulfonic acid	^*Phosphoric acid	The N-oxide compound
Cyclohexane sulfamic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	The carat imidazoles		Hydroxamic acid	Hydroxyl	Carboxylic acid amides	^*Sulfonic acid	^*Phosphoric acid	The N-oxide compound
Cyclohexane sulfamic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Cyclohexane sulfamic acid
Halfcystine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Cyclohexane sulfamic acid
Halfcystine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Halfcystine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Halfcystine							Halfcystine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Halfcystine							N-methylsarcosine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
N-methylsarcosine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	N-methylsarcosine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
N-methylsarcosine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	D-ribose	Ether	Carboxylic acid	Sulfuric ester	Sulfone		Alcohol
D-ribose	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	D-ribose	Ether	Carboxylic acid	Sulfuric ester	Sulfone		Alcohol
D-ribose	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Fumaric acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Tetrahydroxyadipic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Fumaric acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Tetrahydroxyadipic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Tetrahydroxyadipic acid	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Carbamate
Chrysin	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Tetrahydroxyadipic acid	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Carbamate

Table II

Cocrystallization forms thing
Cocrystallization forms thing								L-asparagine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
L-asparagine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine	Epoxide	L-asparagine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
L-asparagine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine	Epoxide	L-asparagine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Aspartic acid	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		L-asparagine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Aspartic acid	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Aspartic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Phenylsulfonic acid								Aspartic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Phenylsulfonic acid								Phenylformic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Caffeine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Phenylformic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Caffeine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Dextrocamphoric acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Capric acid	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Dextrocamphoric acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Capric acid	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Genistein	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Genistein								Genistein	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Genistein								Genistein	Phosphoric acid ester	Cyanamide
Styracin	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Genistein	Phosphoric acid ester	Cyanamide
Styracin	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Citric acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide
Citric acid	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Citric acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide
Citric acid	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		The carat imidazoles	Ester	Ether	Fluorine	Ethyl acetate	Thione	Dithia diazacyclo pentadiene base
Cyclohexane sulfamic acid	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		The carat imidazoles	Ester	Ether	Fluorine	Ethyl acetate	Thione	Dithia diazacyclo pentadiene base
Cyclohexane sulfamic acid	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Cyclohexane sulfamic acid
Halfcystine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Cyclohexane sulfamic acid
Halfcystine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Halfcystine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Halfcystine								Halfcystine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Halfcystine								N-methylsarcosine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
N-methylsarcosine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		N-methylsarcosine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
N-methylsarcosine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		D-ribose	Phosphoric acid ester	Cyanamide
D-ribose	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine	Epoxide	D-ribose	Phosphoric acid ester	Cyanamide
D-ribose	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine	Epoxide	Fumaric acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Tetrahydroxyadipic acid	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Fumaric acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Tetrahydroxyadipic acid	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Tetrahydroxyadipic acid	Imidazoles	BF4
Chrysin	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Tetrahydroxyadipic acid	Imidazoles	BF4

Table II

Cocrystallization forms thing
Cocrystallization forms thing		L-asparagine
L-asparagine	Superoxide	L-asparagine
L-asparagine	Superoxide	L-asparagine
Aspartic acid		L-asparagine
Aspartic acid		Aspartic acid
Phenylsulfonic acid		Aspartic acid
Phenylsulfonic acid		Phenylformic acid
Caffeine		Phenylformic acid
Caffeine		Dextrocamphoric acid
Capric acid		Dextrocamphoric acid
Capric acid		Genistein
Genistein		Genistein
Genistein		Genistein
Styracin		Genistein
Styracin		Citric acid
Citric acid		Citric acid
Citric acid		The carat imidazoles
Cyclohexane sulfamic acid		The carat imidazoles
Cyclohexane sulfamic acid		Cyclohexane sulfamic acid
Halfcystine		Cyclohexane sulfamic acid
Halfcystine		Halfcystine
Halfcystine		Halfcystine
Halfcystine		N-methylsarcosine
N-methylsarcosine		N-methylsarcosine
N-methylsarcosine		D-ribose
D-ribose		D-ribose
D-ribose		Fumaric acid
Tetrahydroxyadipic acid		Fumaric acid
Tetrahydroxyadipic acid		Tetrahydroxyadipic acid
Chrysin		Tetrahydroxyadipic acid

Table II

Cocrystallization forms thing	Cocrystallization forms thing functional group	Reactive group
Cocrystallization forms thing	Cocrystallization forms thing functional group	Reactive group							Chrysin	Phenol	Amine	Acid amides	Sulfoxide	N	Pyridine	Cyano group	Aldehyde
Chrysin	Ether	Fragrance-N	Acid amides	Amine	Fragrance-S	SP2 amine	Sulfoxide	The chlorate	Chrysin	Phenol	Amine	Acid amides	Sulfoxide	N	Pyridine	Cyano group	Aldehyde
Chrysin	Ether	Fragrance-N	Acid amides	Amine	Fragrance-S	SP2 amine	Sulfoxide	The chlorate	2, the 5-protocatechuic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
2, the 5-protocatechuic acid	Phenol	Amine	Acid amides	Sulfoxide	N	Pyridine	Cyano group	Aldehyde	2, the 5-protocatechuic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
2, the 5-protocatechuic acid	Phenol	Amine	Acid amides	Sulfoxide	N	Pyridine	Cyano group	Aldehyde	Glycosamine, the N-methyl	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Glycosamine, the N-methyl	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Glycosamine, the N-methyl	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Glycosamine, the N-methyl	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Glyconic acid	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Glyconic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Glyconic acid	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Glyconic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Glucosamine	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Glucuronic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Glucosamine	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Glucuronic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Glucuronic acid	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Glucuronic acid	Aldehyde	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Glucuronic acid	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Glucuronic acid	Aldehyde	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	L-glutamic acid	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
L-glutamic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	L-glutamic acid	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
L-glutamic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Glutamine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Glutamine	Acid amides	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Glutamine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Glutamine	Acid amides	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Glutamine	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Pentanedioic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Glutamine	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Pentanedioic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Glycine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Glycine	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Glycine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Glycine	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Oxyacetic acid	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Oxyacetic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Oxyacetic acid	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Oxyacetic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Urobenzoic acid	Acid amides	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Urobenzoic acid	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Urobenzoic acid	Acid amides	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Urobenzoic acid	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Urobenzoic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Histidine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Urobenzoic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Histidine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Histidine	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Histidine	Imidazoles	Imidazoles	Chlorine	Ethanamide	Carboxylate salt		Thione	Nitro	Histidine	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Histidine	Imidazoles	Imidazoles	Chlorine	Ethanamide	Carboxylate salt		Thione	Nitro	Quinhydrones	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Quinhydrones	Phenol	Amine	Acid amides	N	N	Pyridine	Cyano group	Aldehyde	Quinhydrones	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Quinhydrones	Phenol	Amine	Acid amides	N	N	Pyridine	Cyano group	Aldehyde	Imidazoles	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol

Table II

Cocrystallization forms thing
Cocrystallization forms thing										Chrysin		Alcohol		Ester	Ether	The N-oxide compound	Chlorine	Fluorine	Bromine
Chrysin	Chlorine		Cyano group	Ester	Amine	Nitro	Nitric ether	Bromine	Aldehyde	Chrysin		Alcohol		Ester	Ether	The N-oxide compound	Chlorine	Fluorine	Bromine
Chrysin	Chlorine		Cyano group	Ester	Amine	Nitro	Nitric ether	Bromine	Aldehyde	2, the 5-protocatechuic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
2, the 5-protocatechuic acid		Alcohol		Ester	Ether	The N-oxide compound	Chlorine	Fluorine	Bromine	2, the 5-protocatechuic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
2, the 5-protocatechuic acid		Alcohol		Ester	Ether	The N-oxide compound	Chlorine	Fluorine	Bromine	Glycosamine, the N-methyl	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxilic acid	Metal	Aldehyde	Ester
Glycosamine, the N-methyl	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Glycosamine, the N-methyl	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxilic acid	Metal	Aldehyde	Ester
Glycosamine, the N-methyl	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Glyconic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Glyconic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Glyconic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Glyconic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Glucosamine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Glucuronic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Glucosamine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Glucuronic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Glucuronic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxilic acid	Metal	Aldehyde	Ester
Glucuronic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Fragrance	Carboxilic acid	Metal	Aldehyde	Glucuronic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxilic acid	Metal	Aldehyde	Ester
Glucuronic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Fragrance	Carboxilic acid	Metal	Aldehyde	L-glutamic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
L-glutamic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	L-glutamic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
L-glutamic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Glutamine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Glutamine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde	Glutamine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Glutamine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde	Glutamine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Pentanedioic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Glutamine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Pentanedioic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Glycine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Glycine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Glycine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Glycine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Oxyacetic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Oxyacetic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Oxyacetic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Oxyacetic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Urobenzoic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Urobenzoic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Urobenzoic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Urobenzoic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Urobenzoic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Histidine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Urobenzoic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Histidine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Histidine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Histidine	Cyanamide	Ketone	Cyano group	Carboxylic acid	Alcohol		Mercaptan	Amine	The phosphorous acid semihydrate	Histidine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Histidine	Cyanamide	Ketone	Cyano group	Carboxylic acid	Alcohol		Mercaptan	Amine	The phosphorous acid semihydrate	Quinhydrones	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Quinhydrones		Alcohol		Ester	Ether	The N-oxide compound	Chlorine	Fluorine	Bromine	Quinhydrones	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Quinhydrones		Alcohol		Ester	Ether	The N-oxide compound	Chlorine	Fluorine	Bromine	Imidazoles	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde

Table II

Cocrystallization forms thing
Cocrystallization forms thing									Chrysin	Iodine	Ketone	Sulfonic acid	Sulfuric ester	Phosphoric acid ester	Phosphonic acids	Carboxylic acid	Nitro
Chrysin	Ketone	Superoxide	Epoxide			Heterocycle-S	Iodine	Ester	Chrysin	Iodine	Ketone	Sulfonic acid	Sulfuric ester	Phosphoric acid ester	Phosphonic acids	Carboxylic acid	Nitro
Chrysin	Ketone	Superoxide	Epoxide			Heterocycle-S	Iodine	Ester	2, the 5-protocatechuic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
2, the 5-protocatechuic acid	Iodine	Ketone	Sulfonic acid	Sulfuric ester	Phosphoric acid ester	Phosphonic acids	Carboxylic acid	Nitro	2, the 5-protocatechuic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
2, the 5-protocatechuic acid	Iodine	Ketone	Sulfonic acid	Sulfuric ester	Phosphoric acid ester	Phosphonic acids	Carboxylic acid	Nitro	Glycosamine, the N-methyl	Ester	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Pyridine
Glycosamine, the N-methyl	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Glycosamine, the N-methyl	Ester	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Pyridine
Glycosamine, the N-methyl	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Glyconic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Glyconic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Glyconic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Glyconic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Glucosamine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Glucuronic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Glucosamine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Glucuronic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Glucuronic acid	Ester	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Pyridine
Glucuronic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Glucuronic acid	Ester	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Pyridine
Glucuronic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	L-glutamic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
L-glutamic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	L-glutamic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
L-glutamic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Glutamine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Glutamine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Glutamine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Glutamine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Glutamine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Pentanedioic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Glutamine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Pentanedioic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Glycine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Glycine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Glycine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Glycine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Oxyacetic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Oxyacetic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Oxyacetic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Oxyacetic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Urobenzoic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Urobenzoic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Urobenzoic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Urobenzoic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Urobenzoic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Histidine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Urobenzoic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Histidine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Histidine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Histidine	Chlorine	Alkylsulfonyl	Sulfoxide	Acid amides	Fluorine	Sulphonate	Chlorine	The S-heterocycle	Histidine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Histidine	Chlorine	Alkylsulfonyl	Sulfoxide	Acid amides	Fluorine	Sulphonate	Chlorine	The S-heterocycle	Quinhydrones	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Quinhydrones	Iodine	Ketone	Sulfonic acid	Sulfuric ester	Phosphoric acid ester	Phosphonic acids	Carboxylic acid	Nitro	Quinhydrones	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Quinhydrones	Iodine	Ketone	Sulfonic acid	Sulfuric ester	Phosphoric acid ester	Phosphonic acids	Carboxylic acid	Nitro	Imidazoles	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle

Table II

Cocrystallization forms thing
Cocrystallization forms thing								Chrysin	Sulfone	Aniline
Chrysin	Ether	Carboxylic acid	Sulfuric ester	Sulfone		Alcohol		Chrysin	Sulfone	Aniline
Chrysin	Ether	Carboxylic acid	Sulfuric ester	Sulfone		Alcohol		2, the 5-protocatechuic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
2, the 5-protocatechuic acid	Sulfone	Aniline						2, the 5-protocatechuic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
2, the 5-protocatechuic acid	Sulfone	Aniline						Glycosamine, the N-methyl	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Carbamate
Glycosamine, the N-methyl	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Glycosamine, the N-methyl	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Carbamate
Glycosamine, the N-methyl	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Glyconic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Glyconic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Glyconic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Glyconic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Glucosamine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Glucuronic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Glucosamine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Glucuronic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Glucuronic acid	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Carbamate
Glucuronic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Glucuronic acid	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Carbamate
Glucuronic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	L-glutamic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
L-glutamic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	L-glutamic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
L-glutamic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Glutamine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Glutamine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Glutamine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Glutamine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Glutamine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Pentanedioic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Glutamine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Pentanedioic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Glycine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Glycine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Glycine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Glycine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Oxyacetic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Oxyacetic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Oxyacetic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Oxyacetic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Urobenzoic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Urobenzoic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Urobenzoic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Urobenzoic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Urobenzoic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Histidine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Urobenzoic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Histidine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Histidine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Histidine								Histidine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Histidine								Quinhydrones	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Quinhydrones	Sulfone	Aniline						Quinhydrones	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Quinhydrones	Sulfone	Aniline						Imidazoles	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine

Table II

Cocrystallization forms thing
Cocrystallization forms thing										Chrysin
Chrysin	Phosphoric acid ester	Cyanamide								Chrysin
Chrysin	Phosphoric acid ester	Cyanamide								2, the 5-protocatechuic acid	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine
2, the 5-protocatechuic acid										2, the 5-protocatechuic acid	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine
2, the 5-protocatechuic acid										Glycosamine, the N-methyl	Imidazoles	BF4
Glycosamine, the N-methyl	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Glycosamine, the N-methyl	Imidazoles	BF4
Glycosamine, the N-methyl	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Glyconic acid	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine	Epoxide
Glyconic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Glyconic acid	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine	Epoxide
Glyconic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Glucosamine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine	Epoxide
Glucuronic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Glucosamine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine	Epoxide
Glucuronic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Glucuronic acid	Imidazoles	BF4
Glucuronic acid	Carbamate	Imidazoles	BF4	Alkane	Fragrance	N-SO2	Thiocarbamide	Iodine	Epoxide	Glucuronic acid	Imidazoles	BF4
Glucuronic acid	Carbamate	Imidazoles	BF4	Alkane	Fragrance	N-SO2	Thiocarbamide	Iodine	Epoxide	L-glutamic acid	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine
L-glutamic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		L-glutamic acid	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine
L-glutamic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Glutamine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine
Glutamine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide	Glutamine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine
Glutamine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide	Glutamine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine
Pentanedioic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Glutamine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine
Pentanedioic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Glycine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine
Glycine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Glycine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine
Glycine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Oxyacetic acid	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine	Epoxide
Oxyacetic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Oxyacetic acid	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine	Epoxide
Oxyacetic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Urobenzoic acid	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine	Epoxide
Urobenzoic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Urobenzoic acid	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine	Epoxide
Urobenzoic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Urobenzoic acid	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine
Histidine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Urobenzoic acid	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine
Histidine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Histidine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine
Histidine										Histidine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine
Histidine										Quinhydrones	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine	Epoxide
Quinhydrones										Quinhydrones	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine	Epoxide
Quinhydrones										Imidazoles	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine

Table II

Cocrystallization forms thing
Cocrystallization forms thing		Chrysin
Chrysin		Chrysin
Chrysin
2, the 5-protocatechuic acid
2, the 5-protocatechuic acid	2, the 5-protocatechuic acid
Glycosamine, the N-methyl	2, the 5-protocatechuic acid
Glycosamine, the N-methyl	Glycosamine, the N-methyl
Glyconic acid	Glycosamine, the N-methyl
Glyconic acid	Glyconic acid
Glucosamine	Glyconic acid
Glucosamine	Glucuronic acid
Glucuronic acid	Glucuronic acid
Glucuronic acid	Glucuronic acid
L-glutamic acid	Glucuronic acid
L-glutamic acid	L-glutamic acid
Glutamine	L-glutamic acid
Glutamine	Glutamine	Superoxide
Glutamine	Glutamine	Superoxide
Glutamine	Pentanedioic acid
The sheet propylhomoserin	Pentanedioic acid
The sheet propylhomoserin	Glycine
Oxyacetic acid	Glycine
Oxyacetic acid	Oxyacetic acid
Urobenzoic acid	Oxyacetic acid		Superoxide
Urobenzoic acid	Urobenzoic acid		Superoxide
Urobenzoic acid	Urobenzoic acid
Urobenzoic acid	Histidine
Histidine	Histidine
Histidine	Histidine
Quinhydrones	Histidine
Quinhydrones	Quinhydrones
Imidazoles	Quinhydrones

Table II

Cocrystallization forms thing	Cocrystallization forms thing functional group	Reactive group
Cocrystallization forms thing	Cocrystallization forms thing functional group	Reactive group							Ipriflavone	Ether	Fragrance-N	Acid amides	Amine	Fragrance-S	SP2 amine	Sulfoxide	The chlorate
Ipriflavone	Ketone	Alcohol		Mercaptan	Acid amides	Amine	Aniline	Phenol	Ipriflavone	Ether	Fragrance-N	Acid amides	Amine	Fragrance-S	SP2 amine	Sulfoxide	The chlorate
Ipriflavone	Ketone	Alcohol		Mercaptan	Acid amides	Amine	Aniline	Phenol	Isoleucine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Isoleucine	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Isoleucine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Isoleucine	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Lactobionic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Lactobionic acid	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Lactobionic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Lactobionic acid	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Lactobionic acid	Ether	Fragrance-N	Acid amides	Amine	Fragrance-S	SP2 amine	Sulfoxide	The chlorate
Lauric acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Lactobionic acid	Ether	Fragrance-N	Acid amides	Amine	Fragrance-S	SP2 amine	Sulfoxide	The chlorate
Lauric acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Leucine	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Leucine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Leucine	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Leucine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Methionin	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Methionin	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Methionin	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Methionin	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Toxilic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Oxysuccinic acid	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Toxilic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Oxysuccinic acid	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Oxysuccinic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Propanedioic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Oxysuccinic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Propanedioic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Amygdalic acid	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Amygdalic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Amygdalic acid	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Amygdalic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Methionine(Met)	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Methionine(Met)	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Methionine(Met)	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Methionine(Met)	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Methionine(Met)	Thioether	-N	Acid amides	Amine	-s	SP2 amine	Sulfoxide	The chlorate
Niacinamide	Pyridine	^*Alcohol		^*	^*Acid amides	Nitro	^*Amine	^*Carboxylic acid	Methionine(Met)	Thioether	-N	Acid amides	Amine	-s	SP2 amine	Sulfoxide	The chlorate
Niacinamide	Pyridine	^*Alcohol		^*	^*Acid amides	Nitro	^*Amine	^*Carboxylic acid	Niacinamide	Acid amides	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Nicotinic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Niacinamide	Acid amides	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Nicotinic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Nicotinic acid	Pyridine	^*Alcohol		^*	^*Acid amides	Nitro	^*Amine	^*Carboxylic acid
Vitamin B13	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Nicotinic acid	Pyridine	^*Alcohol		^*	^*Acid amides	Nitro	^*Amine	^*Carboxylic acid
Vitamin B13	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Vitamin B13	Lactan	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Oxalic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Vitamin B13	Lactan	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Oxalic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Palmitinic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Two carbonaphthoic acids	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Palmitinic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Two carbonaphthoic acids	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Two carbonaphthoic acids	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Two carbonaphthoic acids	Phenol	Amine	Ketone	Sulfoxide	N	Pyridine	Cyano group	Aldehyde	Two carbonaphthoic acids	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol

Table II

Cocrystallization forms thing
Cocrystallization forms thing										Ipriflavone	Chlorine		Cyano group	Ester	Amine	Nitro	Nitric ether	Bromine	Aldehyde
Ipriflavone	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Ipriflavone	Chlorine		Cyano group	Ester	Amine	Nitro	Nitric ether	Bromine	Aldehyde
Ipriflavone	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Isoleucine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Isoleucine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Isoleucine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Isoleucine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Lactobionic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Lactobionic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxilic acid	Metal	Aldehyde	Ester	Lactobionic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Lactobionic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxilic acid	Metal	Aldehyde	Ester	Lactobionic acid	Chlorine		Cyano group	Ester	Amine	Nitro	Nitric ether	Bromine	Aldehyde
Lauric acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid		Aldehyde	Lactobionic acid	Chlorine		Cyano group	Ester	Amine	Nitro	Nitric ether	Bromine	Aldehyde
Lauric acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid		Aldehyde	Leucine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Leucine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Leucine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Leucine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Methionin	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Methionin	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Methionin	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Methionin	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Toxilic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Oxysuccinic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde	Toxilic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Oxysuccinic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde	Oxysuccinic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Propanedioic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Oxysuccinic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Propanedioic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Amygdalic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Amygdalic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Amygdalic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Amygdalic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Methionine(Met)	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Methionine(Met)	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Methionine(Met)	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Methionine(Met)	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Methionine(Met)	Chlorine		Cyano group	Ester	Amine	Nitro	Nitric ether	Bromine	Aldehyde
Niacinamide	^*Sulphonamide	^*Ketone	Ether	Triazole		Ammonium	Oxime	^*Chlorine		Methionine(Met)	Chlorine		Cyano group	Ester	Amine	Nitro	Nitric ether	Bromine	Aldehyde
Niacinamide	^*Sulphonamide	^*Ketone	Ether	Triazole		Ammonium	Oxime	^*Chlorine		Niacinamide	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Nicotinic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde	Niacinamide	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Nicotinic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde	Nicotinic acid	^*Sulphonamide	^*Ketone	Ether	Triazole		Ammonium	Oxime	^*Chlorine
Vitamin B13	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid		Aldehyde	Nicotinic acid	^*Sulphonamide	^*Ketone	Ether	Triazole		Ammonium	Oxime	^*Chlorine
Vitamin B13	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid		Aldehyde	Vitamin B13	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Oxalic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid		Aldehyde	Vitamin B13	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Oxalic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid		Aldehyde	Palmitinic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid		Aldehyde
Two carbonaphthoic acids	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid		Aldehyde	Palmitinic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid		Aldehyde
Two carbonaphthoic acids	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid		Aldehyde	Two carbonaphthoic acids	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxilic acid	Metal	Aldehyde	Ester
Two carbonaphthoic acids		Alcohol		Ester	Ether	The N-oxide compound	Chlorine	Fluorine	Bromine	Two carbonaphthoic acids	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxilic acid	Metal	Aldehyde	Ester

Table II

Cocrystallization forms thing
Cocrystallization forms thing									Ipriflavone	Ketone	Superoxide	Epoxide			Heterocycle-S	Iodine	Ester
Ipriflavone	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Ipriflavone	Ketone	Superoxide	Epoxide			Heterocycle-S	Iodine	Ester
Ipriflavone	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Isoleucine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Isoleucine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Isoleucine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Isoleucine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Lactobionic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Lactobionic acid	Ester	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Pyridine	Lactobionic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Lactobionic acid	Ester	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Pyridine	Lactobionic acid	Ketone	Superoxide	Epoxide			Heterocycle-S	Iodine	Ester
Lauric acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Lactobionic acid	Ketone	Superoxide	Epoxide			Heterocycle-S	Iodine	Ester
Lauric acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Leucine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Leucine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Leucine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Leucine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Methionin	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Methionin	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Methionin	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Methionin	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Toxilic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Oxysuccinic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Toxilic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Oxysuccinic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Oxysuccinic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Propanedioic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Oxysuccinic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Propanedioic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Amygdalic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Amygdalic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Amygdalic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Amygdalic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Methionine(Met)	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Methionine(Met)	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Methionine(Met)	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Methionine(Met)	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Methionine(Met)	Ketone	Superoxide	Epoxide	Ag	Se	Heterocycle-S	Iodine	Ester
Niacinamide	Mercaptan	The N-heterocycle	Thionedisulfide	Pyrrolidine-diones	Iodine	Hydrazone	Thiocyanide	^*Bromine	Methionine(Met)	Ketone	Superoxide	Epoxide	Ag	Se	Heterocycle-S	Iodine	Ester
Niacinamide	Mercaptan	The N-heterocycle	Thionedisulfide	Pyrrolidine-diones	Iodine	Hydrazone	Thiocyanide	^*Bromine	Niacinamide	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Nicotinic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Niacinamide	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Nicotinic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Nicotinic acid	Mercaptan	The N-heterocycle	Thionedisulfide	Pyrrolidine-diones	Iodine	Hydrazone	Thiocyanide	^*Bromine
Vitamin B13	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Nicotinic acid	Mercaptan	The N-heterocycle	Thionedisulfide	Pyrrolidine-diones	Iodine	Hydrazone	Thiocyanide	^*Bromine
Vitamin B13	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Vitamin B13	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Oxalic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Vitamin B13	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Oxalic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Palmitinic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Two carbonaphthoic acids	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Palmitinic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Two carbonaphthoic acids	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Two carbonaphthoic acids	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Pyridine
Two carbonaphthoic acids	Iodine	Ketone	Sulfonic acid	Sulfuric ester	Phosphoric acid ester	Phosphonic acids	Carboxylic acid	Nitro	Two carbonaphthoic acids	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Pyridine

Table II

Cocrystallization forms thing
Cocrystallization forms thing								Ipriflavone	Ether	Carboxylic acid	Sulfuric ester	Sulfone		Alcohol
Ipriflavone	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Ipriflavone	Ether	Carboxylic acid	Sulfuric ester	Sulfone		Alcohol
Ipriflavone	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Isoleucine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Isoleucine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Isoleucine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Isoleucine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Lactobionic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Lactobionic acid	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Carbamate	Lactobionic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Lactobionic acid	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Carbamate	Lactobionic acid	Ether	Carboxylic acid	Sulfuric ester	Sulfone		Alcohol
Lauric acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Lactobionic acid	Ether	Carboxylic acid	Sulfuric ester	Sulfone		Alcohol
Lauric acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Leucine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Leucine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Leucine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Leucine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Methionin	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Methionin	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Methionin	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Methionin	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Toxilic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Oxysuccinic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Toxilic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Oxysuccinic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Oxysuccinic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Propanedioic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Oxysuccinic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Propanedioic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Amygdalic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Amygdalic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Amygdalic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Amygdalic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Methionine(Met)	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Methionine(Met)	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Methionine(Met)	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Methionine(Met)	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Methionine(Met)	Ether	Carboxylic acid	Sulfuric ester	Sulfone		Alcohol
Niacinamide		Hydroxamic acid	Cyano group	Carboxylic acid amides	^*Sulfonic acid	^*Phosphoric acid	The N-oxide compound	Methionine(Met)	Ether	Carboxylic acid	Sulfuric ester	Sulfone		Alcohol
Niacinamide		Hydroxamic acid	Cyano group	Carboxylic acid amides	^*Sulfonic acid	^*Phosphoric acid	The N-oxide compound	Niacinamide	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Nicotinic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Niacinamide	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Nicotinic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Nicotinic acid		Hydroxamic acid	Cyano group	Carboxylic acid amides	^*Sulfonic acid	^*Phosphoric acid	The N-oxide compound
Vitamin B13	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Nicotinic acid		Hydroxamic acid	Cyano group	Carboxylic acid amides	^*Sulfonic acid	^*Phosphoric acid	The N-oxide compound
Vitamin B13	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Vitamin B13	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Oxalic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Vitamin B13	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Oxalic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Palmitinic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Two carbonaphthoic acids	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Palmitinic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Two carbonaphthoic acids	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Two carbonaphthoic acids	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Carbamate
Two carbonaphthoic acids	Sulfone	Aniline						Two carbonaphthoic acids	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Carbamate

Table II

Cocrystallization forms thing
Cocrystallization forms thing										Ipriflavone	Phosphoric acid ester	Cyanamide
Ipriflavone	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Ipriflavone	Phosphoric acid ester	Cyanamide
Ipriflavone	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Isoleucine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Isoleucine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Isoleucine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Isoleucine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Lactobionic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Lactobionic acid	Imidazoles	BF4								Lactobionic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Lactobionic acid	Imidazoles	BF4								Lactobionic acid	Phosphoric acid ester	Cyanamide
Lauric acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Lactobionic acid	Phosphoric acid ester	Cyanamide
Lauric acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Leucine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Leucine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Leucine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Leucine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Methionin	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Methionin	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Methionin	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Methionin	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Toxilic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Oxysuccinic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide	Toxilic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Oxysuccinic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide	Oxysuccinic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Propanedioic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Oxysuccinic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Propanedioic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Amygdalic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide
Amygdalic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Amygdalic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide
Amygdalic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Methionine(Met)	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Methionine(Met)	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Methionine(Met)	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Methionine(Met)	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Methionine(Met)	Phosphoric acid ester
Niacinamide	Ester	Ether	Fluorine	Acetate	Thione	Dithio diazacyclo pentadiene base				Methionine(Met)	Phosphoric acid ester
Niacinamide	Ester	Ether	Fluorine	Acetate	Thione	Dithio diazacyclo pentadiene base				Niacinamide	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide
Nicotinic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Niacinamide	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide
Nicotinic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Nicotinic acid	Ester	Ether	Fluorine	Acetate	Thione	Dithio diazacyclo pentadiene base
Vitamin B13	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Nicotinic acid	Ester	Ether	Fluorine	Acetate	Thione	Dithio diazacyclo pentadiene base
Vitamin B13	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Vitamin B13	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide
Oxalic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Vitamin B13	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide
Oxalic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Palmitinic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Two carbonaphthoic acids	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Palmitinic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Two carbonaphthoic acids	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Two carbonaphthoic acids	Imidazoles	BF4
Two carbonaphthoic acids										Two carbonaphthoic acids	Imidazoles	BF4

Table II

Cocrystallization forms thing
Cocrystallization forms thing	Ipriflavone
Ipriflavone	Ipriflavone
Ipriflavone	Isoleucine
Isoleucine	Isoleucine
Isoleucine	Lactobionic acid
Lactobionic acid	Lactobionic acid
Lactobionic acid	Lactobionic acid
Lauric acid	Lactobionic acid
Lauric acid	Leucine
Leucine	Leucine
Leucine	Methionin
Methionin	Methionin
Methionin	Toxilic acid
Oxysuccinic acid	Toxilic acid
Oxysuccinic acid	Oxysuccinic acid
Propanedioic acid	Oxysuccinic acid
Propanedioic acid	Amygdalic acid
Amygdalic acid	Amygdalic acid
Amygdalic acid	Methionine(Met)
Methionine(Met)	Methionine(Met)
Methionine(Met)	Methionine(Met)
Niacinamide	Methionine(Met)
Niacinamide	Niacinamide	Superoxide
Nicotinic acid	Niacinamide	Superoxide
Nicotinic acid	Nicotinic acid
Vitamin B13	Nicotinic acid
Vitamin B13	Vitamin B13	Superoxide
Oxalic acid	Vitamin B13	Superoxide
Oxalic acid	Palmitinic acid
Two carbonaphthoic acids	Palmitinic acid
Two carbonaphthoic acids	Two carbonaphthoic acids
Two carbonaphthoic acids	Two carbonaphthoic acids

Table II

Cocrystallization forms thing	Cocrystallization forms thing functional group	Reactive group
Cocrystallization forms thing	Cocrystallization forms thing functional group	Reactive group							Phenylalanine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Phenylalanine	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Phenylalanine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Phenylalanine	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Piperazine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
PROCAINE HCL, PHARMA GRADE	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Piperazine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
PROCAINE HCL, PHARMA GRADE	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	PROCAINE HCL, PHARMA GRADE	Ketone	Alcohol		Mercaptan	Acid amides	Amine	Aniline	Phenol
Proline(Pro)	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	PROCAINE HCL, PHARMA GRADE	Ketone	Alcohol		Mercaptan	Acid amides	Amine	Aniline	Phenol
Proline(Pro)	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Proline(Pro)	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Tosic acid	Sulfonic acid	Pyridine	Ketone	Aldehyde	Ether	Ester	Acid amides	Carboxylic acid	Proline(Pro)	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Tosic acid	Sulfonic acid	Pyridine	Ketone	Aldehyde	Ether	Ester	Acid amides	Carboxylic acid	Pyridoxylamine	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Pyridoxylamine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Pyridoxylamine	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Pyridoxylamine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Pyridoxylamine	Pyridine	^*Alcohol		*	^*Acid amides	Nitro	^*Amine	^*Carboxylic acid
Pyridoxol (4-Pvridoxic Acid)	Pyridine	^*Alcohol	Pyridine _		^*Acid amides	Nitro	^*Amine	^*Carboxylic acid	Pyridoxylamine	Pyridine	^*Alcohol		*	^*Acid amides	Nitro	^*Amine	^*Carboxylic acid
Pyridoxol (4-Pvridoxic Acid)	Pyridine	^*Alcohol	Pyridine _		^*Acid amides	Nitro	^*Amine	^*Carboxylic acid	Pyridoxol (4-Pvridoxic Acid)	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Pyrrolidonecarboxylic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Pyridoxol (4-Pvridoxic Acid)	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Pyrrolidonecarboxylic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Pyrrolidonecarboxylic acid	Lactan	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Quercetin	Ketone	Alcohol		Mercaptan	Acid amides	Amine	Aniline	Phenol	Pyrrolidonecarboxylic acid	Lactan	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Quercetin	Ketone	Alcohol		Mercaptan	Acid amides	Amine	Aniline	Phenol	Quercetin	Phenol	Amine	Acid amides	Sulfoxide	N	Pyridine	Cyano group	Aldehyde
Quercetin	Ether	Fragrance-N	Acid amides	Amine	Fragrance-S	SP2 amine	Sulfoxide	The chlorate	Quercetin	Phenol	Amine	Acid amides	Sulfoxide	N	Pyridine	Cyano group	Aldehyde
Quercetin	Ether	Fragrance-N	Acid amides	Amine	Fragrance-S	SP2 amine	Sulfoxide	The chlorate	Trans-resveratrol	Ketone	Alcohol		Mercaptan	Acid amides	Amine	Aniline	Phenol
Trans-resveratrol	Phenol	Amine	Acid amides	Sulfoxide	N	Pyridine	Cyano group	Aldehyde	Trans-resveratrol	Ketone	Alcohol		Mercaptan	Acid amides	Amine	Aniline	Phenol
Trans-resveratrol	Phenol	Amine	Acid amides	Sulfoxide	N	Pyridine	Cyano group	Aldehyde	Asccharin	Acid amides	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Asccharin	Ketone	Alcohol		Mercaptan	Acid amides	Amine	Aniline	Phenol	Asccharin	Acid amides	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Asccharin	Ketone	Alcohol		Mercaptan	Acid amides	Amine	Aniline	Phenol	Asccharin	Sulfoxide	Pyridine	Ketone	Aldehyde	Ether	Ester	Acid amides	Carboxylic acid
Asccharin	Amine	Alcohol	Ketone	Mercaptan	Acid amides		Aniline	Phenol	Asccharin	Sulfoxide	Pyridine	Ketone	Aldehyde	Ether	Ester	Acid amides	Carboxylic acid
Asccharin	Amine	Alcohol	Ketone	Mercaptan	Acid amides		Aniline	Phenol	Whitfield's ointment	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Whitfield's ointment	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Whitfield's ointment	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Whitfield's ointment	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Whitfield's ointment, 4-amino	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Whitfield's ointment, 4-amino	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Whitfield's ointment, 4-amino	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Whitfield's ointment, 4-amino	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Whitfield's ointment, 4-amino	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol

Table II

Cocrystallization forms thing
Cocrystallization forms thing										Phenylalanine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Phenylalanine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Phenylalanine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Phenylalanine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Piperazine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
PROCAINE HCL, PHARMA GRADE	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Piperazine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
PROCAINE HCL, PHARMA GRADE	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	PROCAINE HCL, PHARMA GRADE	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Proline(Pro)	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	PROCAINE HCL, PHARMA GRADE	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Proline(Pro)	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Proline(Pro)	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Tosic acid	Amine	Metal	Thioether		Sulfuric ester	Alcohol				Proline(Pro)	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Tosic acid	Amine	Metal	Thioether		Sulfuric ester	Alcohol				Pyridoxylamine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Pyridoxylamine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Pyridoxylamine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Pyridoxylamine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Pyridoxylamine	^*Sulphonamide	^*Ketone	Ether	Triazole		Ammonium	Oxime	^*Chlorine
Pyridoxol (4-Pvridoxic Acid)	^*Sulphonamide	^*Ketone	Ether	Triazole		Ammonium	Oxime	^*Chlorine		Pyridoxylamine	^*Sulphonamide	^*Ketone	Ether	Triazole		Ammonium	Oxime	^*Chlorine
Pyridoxol (4-Pvridoxic Acid)	^*Sulphonamide	^*Ketone	Ether	Triazole		Ammonium	Oxime	^*Chlorine		Pyridoxol (4-Pvridoxic Acid)	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Pyrrolidonecarboxylic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Pyridoxol (4-Pvridoxic Acid)	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Pyrrolidonecarboxylic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde	Pyrrolidonecarboxylic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Quercetin	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde	Pyrrolidonecarboxylic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Quercetin	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde	Quercetin		Alcohol		Ester	Ether	The N-oxide compound	Chlorine	Fluorine	Bromine
Quercetin	Chlorine		Cyano group	Ester	Amine	Nitro	Nitric ether	Bromine	Aldehyde	Quercetin		Alcohol		Ester	Ether	The N-oxide compound	Chlorine	Fluorine	Bromine
Quercetin	Chlorine		Cyano group	Ester	Amine	Nitro	Nitric ether	Bromine	Aldehyde	Trans-resveratrol	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Trans-resveratrol		Alcohol		Ester	Ether	The N-oxide compound	Chlorine	Fluorine	Bromine	Trans-resveratrol	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Trans-resveratrol		Alcohol		Ester	Ether	The N-oxide compound	Chlorine	Fluorine	Bromine	Asccharin	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Asccharin	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde	Asccharin	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Asccharin	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde	Asccharin	Amine	Metal	Thioether		Sulfuric ester	Alcohol
Asccharin	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde	Asccharin	Amine	Metal	Thioether		Sulfuric ester	Alcohol
Asccharin	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde	Whitfield's ointment	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Whitfield's ointment	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde	Whitfield's ointment	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Whitfield's ointment	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde	Whitfield's ointment, 4-amino	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Whitfield's ointment, 4-amino	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxilic acid	Metal	Aldehyde	Ester	Whitfield's ointment, 4-amino	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Whitfield's ointment, 4-amino	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxilic acid	Metal	Aldehyde	Ester	Whitfield's ointment, 4-amino	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde

Table II

Cocrystallization forms thing
Cocrystallization forms thing									Phenylalanine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Phenylalanine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Phenylalanine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Phenylalanine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Piperazine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
PROCAINE HCL, PHARMA GRADE	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Piperazine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
PROCAINE HCL, PHARMA GRADE	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	PROCAINE HCL, PHARMA GRADE	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Proline(Pro)	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	PROCAINE HCL, PHARMA GRADE	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Proline(Pro)	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Proline(Pro)	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Tosic acid									Proline(Pro)	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Tosic acid									Pyridoxylamine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Pyridoxylamine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Pyridoxylamine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Pyridoxylamine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Pyridoxylamine	Mercaptan	The N-heterocycle	thionedisulfide		Iodine	Hydrazone	Thiocyanide	^*Bromine
Pyridoxol (4-Pvridoxic Acid)	Mercaptan	The N-heterocycle	Thionedisulfide	Pyrrolidine-diones	Iodine	Hydrazone	Thiocyanide	^*Bromine	Pyridoxylamine	Mercaptan	The N-heterocycle	thionedisulfide		Iodine	Hydrazone	Thiocyanide	^*Bromine
Pyridoxol (4-Pvridoxic Acid)	Mercaptan	The N-heterocycle	Thionedisulfide	Pyrrolidine-diones	Iodine	Hydrazone	Thiocyanide	^*Bromine	Pyridoxol (4-Pvridoxic Acid)	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Pyrrolidonecarboxylic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Pyridoxol (4-Pvridoxic Acid)	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Pyrrolidonecarboxylic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Pyrrolidonecarboxylic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Quercetin	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Pyrrolidonecarboxylic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Quercetin	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Quercetin	Iodine	Ketone	Sulfonic acid	Sulfuric ester	Phosphoric acid ester	Phosphonic acids	Carboxylic acid	Nitro
Quercetin	Ketone	Superoxide	Epoxide			Heterocycle-S	Iodine	Ester	Quercetin	Iodine	Ketone	Sulfonic acid	Sulfuric ester	Phosphoric acid ester	Phosphonic acids	Carboxylic acid	Nitro
Quercetin	Ketone	Superoxide	Epoxide			Heterocycle-S	Iodine	Ester	Trans-resveratrol	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Resveratrol	Iodine	Ketone	Sulfonic acid	Sulfuric ester	Phosphoric acid ester	Phosphonic acids	Carboxylic acid	Nitro	Trans-resveratrol	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Resveratrol	Iodine	Ketone	Sulfonic acid	Sulfuric ester	Phosphoric acid ester	Phosphonic acids	Carboxylic acid	Nitro	Asccharin	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Asccharin	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Asccharin	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Asccharin	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Asccharin
Asccharin	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Asccharin
Asccharin	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Whitfield's ointment	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Whitfield's ointment	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Whitfield's ointment	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Whitfield's ointment	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Whitfield's ointment, 4-amino	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Whitfield's ointment, 4-amino	Ester	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Pyridine	Whitfield's ointment, 4-amino	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Whitfield's ointment, 4-amino	Ester	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle	Pyridine	Whitfield's ointment, 4-amino	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle

Table II

Cocrystallization forms thing
Cocrystallization forms thing								Phenylalanine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Phenylalanine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Phenylalanine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Phenylalanine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Piperazine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
PROCAINE HCL, PHARMA GRADE	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Piperazine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
PROCAINE HCL, PHARMA GRADE	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	PROCAINE HCL, PHARMA GRADE	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Proline(Pro)	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	PROCAINE HCL, PHARMA GRADE	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Proline(Pro)	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Proline(Pro)	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Tosic acid								Proline(Pro)	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Tosic acid								Pyridoxylamine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Pyridoxylamine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Pyridoxylamine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Pyridoxylamine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Pyridoxylamine		Hydroxamic acid	Cyano group	Carboxylic acid amides	^*Sulfonic acid	^*Phosphonic acids	The N-oxide compound
Pyridoxol (4-Pvridoxic Acid)		Hydroxamic acid	Cyano group	Carboxylic acid amides	^*Sulfonic acid	^*Phosphonic acids	The N-oxide compound	Pyridoxylamine		Hydroxamic acid	Cyano group	Carboxylic acid amides	^*Sulfonic acid	^*Phosphonic acids	The N-oxide compound
Pyridoxol (4-Pvridoxic Acid)		Hydroxamic acid	Cyano group	Carboxylic acid amides	^*Sulfonic acid	^*Phosphonic acids	The N-oxide compound	Pyridoxol (4-Pvridoxic Acid)	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Pyrrolidonecarboxylic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Pyridoxol (4-Pvridoxic Acid)	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Pyrrolidonecarboxylic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Pyrrolidonecarboxylic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Quercetin	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Pyrrolidonecarboxylic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Quercetin	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Quercetin	Sulfone	Aniline
Quercetin	Ether	Carboxylic acid	Sulfuric ester	Sulfone		Alcohol		Quercetin	Sulfone	Aniline
Quercetin	Ether	Carboxylic acid	Sulfuric ester	Sulfone		Alcohol		Trans-resveratrol	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Trans-resveratrol	Sulfone	Aniline						Trans-resveratrol	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Trans-resveratrol	Sulfone	Aniline						Asccharin	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Asccharin	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Asccharin	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Asccharin	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Asccharin
Asccharin	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Asccharin
Asccharin	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Whitfield's ointment	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Whitfield's ointment	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Whitfield's ointment	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Whitfield's ointment	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Whitfield's ointment, 4-amino	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Whitfield's ointment, 4-amino	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Carbamate	Whitfield's ointment, 4-amino	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Whitfield's ointment, 4-amino	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine	Carbamate	Whitfield's ointment, 4-amino	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine

Table II

Cocrystallization forms thing
Cocrystallization forms thing										Phenylalanine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Phenylalanine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Phenylalanine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Phenylalanine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Piperazine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
PROCAINE HCL, PHARMA GRADE	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Piperazine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
PROCAINE HCL, PHARMA GRADE	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		PROCAINE HCL, PHARMA GRADE	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Proline(Pro)	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		PROCAINE HCL, PHARMA GRADE	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Proline(Pro)	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Proline(Pro)	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Tosic acid										Proline(Pro)	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Tosic acid										Pyridoxylamine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide
Pyridoxylamine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Pyridoxylamine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide
Pyridoxylamine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Pyridoxylamine	Ester	Ether	Fluorine	Acetate	Thione	Dithia diazacyclo pentadiene base
Pyridoxol (4-Pvridoxic Acid)	Ester	Ether	Fluorine	Acetate	Thione	Dithia diazacyclo pentadiene base				Pyridoxylamine	Ester	Ether	Fluorine	Acetate	Thione	Dithia diazacyclo pentadiene base
Pyridoxol (4-Pvridoxic Acid)	Ester	Ether	Fluorine	Acetate	Thione	Dithia diazacyclo pentadiene base				Pyridoxol (4-Pvridoxic Acid)	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide
Pyrrolidonecarboxylic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Pyridoxol (4-Pvridoxic Acid)	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide
Pyrrolidonecarboxylic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Pyrrolidonecarboxylic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide
Quercetin	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Pyrrolidonecarboxylic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide
Quercetin	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Quercetin
Quercetin	Phosphoric acid ester	Cyanamide								Quercetin
Quercetin	Phosphoric acid ester	Cyanamide								Trans-resveratrol	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Trans-resveratrol										Trans-resveratrol	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Trans-resveratrol										Asccharin	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide
Asccharin	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Asccharin	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide
Asccharin	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Asccharin
Asccharin	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Asccharin
Asccharin	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine		Whitfield's ointment	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Whitfield's ointment	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide	Whitfield's ointment	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Whitfield's ointment	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide	Whitfield's ointment, 4-amino	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Whitfield's ointment, 4-amino	Imidazoles	BF4								Whitfield's ointment, 4-amino	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Whitfield's ointment, 4-amino	Imidazoles	BF4								Whitfield's ointment, 4-amino	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine

Table II

Cocrystallization forms thing
Cocrystallization forms thing	Phenylalanine
Phenylalanine	Phenylalanine
Phenylalanine	Piperazine
PROCAINE HCL, PHARMA GRADE	Piperazine
PROCAINE HCL, PHARMA GRADE	PROCAINE HCL, PHARMA GRADE
Proline(Pro)	PROCAINE HCL, PHARMA GRADE
Proline(Pro)	Proline(Pro)
Tosic acid	Proline(Pro)
Tosic acid	Pyridoxylamine
Pyridoxylamine	Pyridoxylamine
Pyridoxylamine	Pyridoxylamine
Pyridoxol (4-Pvridoxic Acid)	Pyridoxylamine
Pyridoxol (4-Pvridoxic Acid)	Pyridoxol (4-Pvridoxic Acid)
Pyrrolidonecarboxylic acid	Pyridoxol (4-Pvridoxic Acid)
Pyrrolidonecarboxylic acid	Pyrrolidonecarboxylic acid	Superoxide
Quercetin	Pyrrolidonecarboxylic acid	Superoxide
Quercetin	Quercetin
Quercetin	Quercetin
Quercetin	Trans-resveratrol
Trans-resveratrol	Trans-resveratrol
Trans-resveratrol	Asccharin	Superoxide
Asccharin	Asccharin	Superoxide
Asccharin	Asccharin
Asccharin	Asccharin
Asccharin	Whitfield's ointment
Whitfield's ointment	Whitfield's ointment
Whitfield's ointment	Whitfield's ointment, 4-amino
Whitfield's ointment, 4-amino	Whitfield's ointment, 4-amino
Whitfield's ointment, 4-amino	Whitfield's ointment, 4-amino

Table II

Cocrystallization forms thing	Cocrystallization forms thing functional group	Reactive group
Cocrystallization forms thing	Cocrystallization forms thing functional group	Reactive group							Sebacic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Serine	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Sebacic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Serine	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Serine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Serine	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Serine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Serine	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Stearic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Succsinic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Stearic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Succsinic acid	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Tartrate	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Threonine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Tartrate	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Threonine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Threonine	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Threonine	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Threonine	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Threonine	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Tris	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Tris	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Tris	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Tris	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Tryptophane	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Tryptophane	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Tryptophane	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Tryptophane	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Tryptophane	Indoles	^*Alcohol	Pyridine _	^*	^*Acid amides	Nitro	^*Amine	^*carboxilic acid
Tyrosine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Tryptophane	Indoles	^*Alcohol	Pyridine _	^*	^*Acid amides	Nitro	^*Amine	^*carboxilic acid
Tyrosine	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Tyrosine	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Tyrosine	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Tyrosine	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Tyrosine	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Urea	Ketone	Alcohol		Mercaptan	Acid amides	Amine	Aniline	Phenol
Urea	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Urea	Ketone	Alcohol		Mercaptan	Acid amides	Amine	Aniline	Phenol
Urea	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Urea	Acid amides	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Xie Ansuan	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Urea	Acid amides	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Xie Ansuan	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Xie Ansuan	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Vitamin K5	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Xie Ansuan	Carboxylic acid	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Vitamin K5	Amine	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Vitamin K5	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Xylitol	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol	Vitamin K5	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol
Xylitol	Alcohol	Alcohol	Ketone	Mercaptan	Acid amides	Amine	Aniline	Phenol

Table II

Cocrystallization forms thing
Cocrystallization forms thing									Sebacic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Serine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxylic acid	Metal	Aldehyde	Sebacic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Serine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxylic acid	Metal	Aldehyde	Serine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Serine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxylic acid	Metal	Aldehyde	Serine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Serine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxylic acid	Metal	Aldehyde	Stearic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Succsinic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxylic acid	Metal	Aldehyde	Stearic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Succsinic acid	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxylic acid	Metal	Aldehyde	Tartrate	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Threonine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxilic acid	Metal	Aldehyde	Tartrate	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Threonine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxilic acid	Metal	Aldehyde	Threonine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Threonine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxylic acid	Metal	Aldehyde	Threonine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Threonine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxylic acid	Metal	Aldehyde	Tris	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Tris	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxylic acid	Metal	Aldehyde	Tris	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Tris	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxylic acid	Metal	Aldehyde	Tryptophane	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Tryptophane	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxilic acid	Metal	Aldehyde	Tryptophane	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Tryptophane	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxilic acid	Metal	Aldehyde	Tryptophane	^*Sulphonamide	^*Ketone	Ether	Triazole		Ammonium	Oxime	^*Chlorine
Tyrosine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxilic acid	Metal	Aldehyde	Tryptophane	^*Sulphonamide	^*Ketone	Ether	Triazole		Ammonium	Oxime	^*Chlorine
Tyrosine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxilic acid	Metal	Aldehyde	Tyrosine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Tyrosine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxylic acid	Metal	Aldehyde	Tyrosine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Tyrosine	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxylic acid	Metal	Aldehyde	Urea	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Urea	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxilic acid	Metal	Aldehyde	Urea	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Urea	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxilic acid	Metal	Aldehyde	Urea	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Xie Ansuan	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxilic acid	Metal	Aldehyde	Urea	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Xie Ansuan	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxilic acid	Metal	Aldehyde	Xie Ansuan	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Vitamin K5	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxilic acid	Metal	Aldehyde	Xie Ansuan	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxilic acid	Metal	Aldehyde
Vitamin K5	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxilic acid	Metal	Aldehyde	Vitamin K5	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Xylitol	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxylic acid	Metal	Aldehyde	Vitamin K5	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine		Carboxylic acid	Metal	Aldehyde
Xylitol	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Carboxylic acid	Metal	Aldehyde

Table II

Cocrystallization forms thing
Cocrystallization forms thing								Sebacic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Serine	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocycle	Sebacic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Serine	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocycle	Serine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Serine	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocycle	Serine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Serine	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocycle	Stearic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Succsinic acid	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocycle	Stearic acid	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Succsinic acid	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocycle	Tartrate	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Threonine	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocycle	Tartrate	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Threonine	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocycle	Threonine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Threonine	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocycle	Threonine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Threonine	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocycle	Tris	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Tris	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocycle	Tris	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Tris	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocycle	Tryptophane	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Tryptophane	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocycle	Tryptophane	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Tryptophane	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocycle	Tryptophane	Mercaptan	The N-heterocycle	thionedisulfide	Pyrrolidine-diones	Iodine	Hydrazone	Thiocyanide	^*Bromine
Tyrosine	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocycle	Tryptophane	Mercaptan	The N-heterocycle	thionedisulfide	Pyrrolidine-diones	Iodine	Hydrazone	Thiocyanide	^*Bromine
Tyrosine	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocycle	Tyrosine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Tyrosine	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocycle	Tyrosine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Tyrosine	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocycle	Urea	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Urea	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocycle	Urea	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Urea	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocycle	Urea	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Xie Ansuan	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocycle	Urea	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Xie Ansuan	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocycle	Xie Ansuan	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Vitamin K5	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocycle	Xie Ansuan	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Vitamin K5	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocycle	Vitamin K5	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Xylitol	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocycle	Vitamin K5	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocycle
Xylitol	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocycle

Table II

Cocrystallization forms thing
Cocrystallization forms thing							Sebacic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Serine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Sebacic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Serine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Serine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Serine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Serine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Serine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Stearic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Succsinic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Stearic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Succsinic acid	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Tartrate	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Threonine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Tartrate	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Threonine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Threonine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Threonine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Threonine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Threonine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Tris	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Tris	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Tris	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Tris	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Tryptophane	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Tryptophane	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Tryptophane	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Tryptophane	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Tryptophane		Hydroxamic acid	Cyano group	Carboxamide	^*Sulfonic acid	^*Phosphonic acids	The N-oxide compound
Tyrosine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Tryptophane		Hydroxamic acid	Cyano group	Carboxamide	^*Sulfonic acid	^*Phosphonic acids	The N-oxide compound
Tyrosine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Tyrosine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Tyrosine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Tyrosine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Tyrosine	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Urea	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Urea	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Urea	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Urea	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Urea	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Xie Ansuan	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Urea	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Xie Ansuan	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Xie Ansuan	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Vitamin K5	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Xie Ansuan	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Vitamin K5	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Vitamin K5	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Xylitol	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine	Vitamin K5	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester		Fluorine
Xylitol	Pyridine	Cyano group	The N-heterocycle	Ketone	Phosphoric acid ester	Fluorine

Table II

Cocrystallization forms thing
Cocrystallization forms thing								Sebacic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Serine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Sebacic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Serine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Serine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Serine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine	Epoxide	Serine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Serine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine	Epoxide	Stearic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Succsinic acid	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Stearic acid	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Succsinic acid	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Tartrate	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Threonine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Tartrate	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Threonine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Threonine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Threonine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine	Epoxide	Threonine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Threonine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine	Epoxide	Tris	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Tris	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine	Epoxide	Tris	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Tris	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine	Epoxide	Tryptophane	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Tryptophane	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Tryptophane	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Tryptophane	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Tryptophane	Ester	Ether	Fluorine	Acetate	thione	Dithia diazacyclo pentadiene base
Tyrosine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Tryptophane	Ester	Ether	Fluorine	Acetate	thione	Dithia diazacyclo pentadiene base
Tyrosine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Tyrosine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Tyrosine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine	Epoxide	Tyrosine	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Tyrosine	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine	Epoxide	Urea	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Urea	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Urea	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Urea	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Urea	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide
Xie Ansuan	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Urea	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide
Xie Ansuan	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Xie Ansuan	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Vitamin K5	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Xie Ansuan	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine
Vitamin K5	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine		Vitamin K5	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide
Xylitol	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine	Epoxide	Vitamin K5	Carbamate	Imidazoles	BF4			N-SO2	Thiocarbamide	Iodine	Epoxide
Xylitol	Carbamate	Imidazoles	BF4	N-SO2	Thiocarbamide	Iodine	Epoxide

Table II

Cocrystallization forms thing
Cocrystallization forms thing	Sebacic acid
Serine	Sebacic acid
Serine	Serine
Serine	Serine
Serine	Stearic acid
Succsinic acid	Stearic acid
Succsinic acid	Tartrate
Threonine	Tartrate
Threonine	Threonine
Threonine	Threonine
Threonine	Tris
Tris	Tris
Tris	Tryptophane
Tryptophane	Tryptophane
Tryptophane	Tryptophane
Tyrosine	Tryptophane
Tyrosine	Tyrosine
Tyrosine	Tyrosine
Tyrosine	Urea
Urea	Urea
Urea	Urea	Superoxide
Xie Ansuan	Urea	Superoxide
Xie Ansuan	Xie Ansuan
Vitamin K5	Xie Ansuan
Vitamin K5	Vitamin K5
Xylitol	Vitamin K5
Xylitol

Table III

Table III

Functional group
Functional group											Pyridine	^*Sulphonamide	^*Ketone	Ether	Triazole	Alkane	Ammonium	Oxime	^*Chlorine	Alkynes	Mercaptan
Imidazoles	Cyanamide	Ketone	Cyano group	Carboxilic acid	Alcohol	Alkane	Mercaptan	Amine	The Hypophosporous Acid, 50 semihydrate	Chlorine	Pyridine	^*Sulphonamide	^*Ketone	Ether	Triazole	Alkane	Ammonium	Oxime	^*Chlorine	Alkynes	Mercaptan
Imidazoles	Cyanamide	Ketone	Cyano group	Carboxilic acid	Alcohol	Alkane	Mercaptan	Amine	The Hypophosporous Acid, 50 semihydrate	Chlorine	Hydroxamic acid	Sulphonamide	Carboxylicesters	Phosphine	Amine	Fragrance
Superoxide	Fragrance	Alcohol	Pyrimidine dione	Aniline	Thiazole	Peroxy acid	Ketone	Carboxilic acid	Nitrine	Phosphine oxide	Hydroxamic acid	Sulphonamide	Carboxylicesters	Phosphine	Amine	Fragrance
Superoxide	Fragrance	Alcohol	Pyrimidine dione	Aniline	Thiazole	Peroxy acid	Ketone	Carboxilic acid	Nitrine	Phosphine oxide	Epoxide	Alkene	Hydrazone	Fragrance	Thioether	Ketone	Aldehyde	Chlorine	Carboxilic acid	Alkynes
Thioesters	Iodine	Amine	Cyano group	Thioketones	Acid amides		Chlorine	Nitro			Epoxide	Alkene	Hydrazone	Fragrance	Thioether	Ketone	Aldehyde	Chlorine	Carboxilic acid	Alkynes
Thioesters	Iodine	Amine	Cyano group	Thioketones	Acid amides		Chlorine	Nitro			Thioketones	Sulfoxide	Oxo	Chlorine	Bromine	Fragrance	Alkene	Sulfone	Iodine	Azoxy	Potassium

Table III

Functional group
Functional group						Pyridine	The N-heterocycle	Thionedisulfide	Pyrrolidine-diones	Iodine	Hydrazone	Thiocyanic ester	^*Bromine	Fragrance	Hydroxamic acid	Cyano group
Imidazoles	Alkylsulfonyl	Sulfoxide	Acid amides	Fluorine	Sulphonate	Pyridine	The N-heterocycle	Thionedisulfide	Pyrrolidine-diones	Iodine	Hydrazone	Thiocyanic ester	^*Bromine	Fragrance	Hydroxamic acid	Cyano group
Imidazoles	Alkylsulfonyl	Sulfoxide	Acid amides	Fluorine	Sulphonate	Hydroxamic acid
Superoxide	Sulphonamide	Aniline				Hydroxamic acid
Superoxide	Sulphonamide	Aniline				Epoxide	Ammonium	Fluorine	Nitro	Amine	Cyano group
Thioesters						Epoxide	Ammonium	Fluorine	Nitro	Amine	Cyano group
Thioesters						Thioketones	Epoxide	The N-oxide compound	Cyano group	Iron	Cobalt	Amine	Sulfuric ester

Table III

Functional group
Functional group	Pyridine	Carboxylic acid amides	^*Sulfonic acid	^*Phosphoric acid	The N-oxide compound	Ester	Ether	Fluorine	Acetic ester	Thione	The dithia diazacyclo pentadiene
Imidazoles	Pyridine	Carboxylic acid amides	^*Sulfonic acid	^*Phosphoric acid	The N-oxide compound	Ester	Ether	Fluorine	Acetic ester	Thione	The dithia diazacyclo pentadiene
Imidazoles	Hydroxamic acid
Superoxide	Hydroxamic acid
Superoxide	Epoxide
Thioesters	Epoxide
Thioesters	Thioketones

Table III

Functional group
Functional group					Pyridine
Imidazoles					Pyridine
Imidazoles					Hydroxamic acid
Superoxide					Hydroxamic acid
Superoxide					Epoxide
Thioesters					Epoxide
Thioesters					Thioketones

Table III

Table III

Functional group
Functional group											Nitric ether	Alcohol	Ether	Acetic ester
Thiophosphatephosphorothioate-O											Nitric ether	Alcohol	Ether	Acetic ester
Thiophosphatephosphorothioate-O											Phosphoric acid ester	Amine		Sodium	Potassium	Lithium	Carboxylic acid	Acid amides	Alkane
Ketone	Phenol	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Fragrance	Carboxilic acid	Metal	Aldehyde	Phosphoric acid ester	Amine		Sodium	Potassium	Lithium	Carboxylic acid	Acid amides	Alkane
Ketone	Phenol	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Fragrance	Carboxilic acid	Metal	Aldehyde	Aldehyde	Phenol	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Fragrance	Carboxilic acid	Metal	Aldehyde
Mercaptan	Alkane	Arsenic	Chlorine	Alcohol	Potassium	Ru	Fragrance	Rb	Sb		Aldehyde	Phenol	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Fragrance	Carboxilic acid	Metal	Aldehyde
Mercaptan	Alkane	Arsenic	Chlorine	Alcohol	Potassium	Ru	Fragrance	Rb	Sb		Alcohol	Phenol	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Fragrance	Carboxilic acid	Metal	Aldehyde

Table III

Functional group
Functional group										Nitric ether
Thiophosphatephosphorothioate-O										Nitric ether
Thiophosphatephosphorothioate-O										Phosphoric acid ester
Ketone	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocyclic radical	Pyridine	Cyano group	Phosphoric acid ester
Ketone	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocyclic radical	Pyridine	Cyano group	Aldehyde	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocyclic radical	Pyridine	Cyano group
Mercaptan										Aldehyde	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocyclic radical	Pyridine	Cyano group
Mercaptan										Alcohol	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocyclic radical	Pyridine	Cyano group

Table III

Functional group
Functional group											Nitric ether
Thiophosphatephosphorothioate-O											Nitric ether
Thiophosphatephosphorothioate-O											Phosphoric acid ester
Ketone	The N-heterocyclic radical	Ketone	Phosphoric acid ester	Fluorine	Carbamate	Imidazoles	BF4	Alkane	Fragrance	N-SO2	Phosphoric acid ester
Ketone	The N-heterocyclic radical	Ketone	Phosphoric acid ester	Fluorine	Carbamate	Imidazoles	BF4	Alkane	Fragrance	N-SO2	Aldehyde	The N-heterocyclic radical	Ketone	Phosphoric acid ester	Fluorine	Carbamate	Imidazoles	BF4	Alkane	Fragrance	N-SO2
Mercaptan											Aldehyde	The N-heterocyclic radical	Ketone	Phosphoric acid ester	Fluorine	Carbamate	Imidazoles	BF4	Alkane	Fragrance	N-SO2
Mercaptan											Alcohol	The N-heterocyclic radical	Ketone	Phosphoric acid ester	Fluorine	Carbamate	Imidazoles	BF4	Alkane	Fragrance	N-SO2

Table III

Functional group
Functional group			Nitric ether
Thiophosphatephosphorothioate-O			Nitric ether
Thiophosphatephosphorothioate-O			Phosphoric acid ester
Ketone	Thiocarbamide	Iodine	Phosphoric acid ester
Ketone	Thiocarbamide	Iodine	Aldehyde	Thiocarbamide	Iodine	Epoxide
Mercaptan			Aldehyde	Thiocarbamide	Iodine	Epoxide
Mercaptan			Alcohol	Thiocarbamide	Iodine	Epoxide

Table III

Table III

Functional group
Functional group											Thioether	The chlorate	Chlorine	Alkynes	Cyano group	Ester	Amine	Nitro	Nitric ether	Bromine	Aldehyde
Ether	The chlorate	Chlorine	Alkynes	Cyano group	Ester	Amine	Nitro	Nitric ether	Bromine	Aldehyde	Thioether	The chlorate	Chlorine	Alkynes	Cyano group	Ester	Amine	Nitro	Nitric ether	Bromine	Aldehyde
Ether	The chlorate	Chlorine	Alkynes	Cyano group	Ester	Amine	Nitro	Nitric ether	Bromine	Aldehyde	Cyanamide	Imidazoles	Ether	The N-heterocyclic radical	Alcohol	Caesium	Ag
Thiocyanic ester											Cyanamide	Imidazoles	Ether	The N-heterocyclic radical	Alcohol	Caesium	Ag
Thiocyanic ester											SP2 amine	Chlorine		Sp2 amine	Sulfuric ester	Osmium
Primary amine	Phenol	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Fragrance	Carboxylic acid	Metal	Aldehyde	SP2 amine	Chlorine		Sp2 amine	Sulfuric ester	Osmium
Primary amine	Phenol	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Fragrance	Carboxylic acid	Metal	Aldehyde	Secondary amine	Phenol	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Fragrance	Carboxylic acid	Metal	Aldehyde

Table III

Functional group
Functional group											Thioether	Ketone	Superoxide	Epoxide	Ag	Se	Heterocycle-S	Iodine	Ester	Ether	Carboxylic acid
Ether	Ketone	Superoxide	Epoxide	Ag	Se	Heterocycle-S	Iodine	Ester	Ether	Carboxylic acid	Thioether	Ketone	Superoxide	Epoxide	Ag	Se	Heterocycle-S	Iodine	Ester	Ether	Carboxylic acid
Ether	Ketone	Superoxide	Epoxide	Ag	Se	Heterocycle-S	Iodine	Ester	Ether	Carboxylic acid	Cyanamide
Thiocyanic ester											Cyanamide
Thiocyanic ester											SP2 amine
Primary amine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocyclic radical	Pyridine	Cyano group	SP2 amine
Primary amine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocyclic radical	Pyridine	Cyano group	Secondary amine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocyclic radical	Pyridine	Cyano group

Table III

Functional group
Functional group												Thioether	Sulfuric ester	Sulfone	Alkane	Alcohol		Phosphoric acid ester
Ether	Sulfuric ester	Sulfone	Alkane	Alcohol		Phosphoric acid ester	Cyanamide					Thioether	Sulfuric ester	Sulfone	Alkane	Alcohol		Phosphoric acid ester
Ether	Sulfuric ester	Sulfone	Alkane	Alcohol		Phosphoric acid ester	Cyanamide					Cyanamide
Thiocyanic ester												Cyanamide
Thiocyanic ester												SP2 amine
Primary amine	The N-heterocyclic radical	Ketone	Sulfuric ester		Fluorine	Carbamate	Imidazoles	BF4	Alkane	Fragrance	N-SO2	SP2 amine
Primary amine	The N-heterocyclic radical	Ketone	Sulfuric ester		Fluorine	Carbamate	Imidazoles	BF4	Alkane	Fragrance	N-SO2	Secondary amine	The N-heterocyclic radical	Ketone	Sulfuric ester		Fluorine	Carbamate	Imidazoles	BF4	Alkane	Fragrance	N-SO2

Table III

Functional group
Functional group			Thioether
Ether			Thioether
Ether			Cyanamide
Thiocyanic ester			Cyanamide
Thiocyanic ester			SP2 amine
Primary amine	Thiocarbamide	Iodine	SP2 amine
Primary amine	Thiocarbamide	Iodine	Secondary amine	Thiocarbamide	Iodine

Table III

Functional group
Functional group											Tertiary amine	Phenol	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Fragrance	Carboxilica acid	Metal	Aldehyde
Acid amides	Phenol	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Fragrance	Carboxilica acid	Metal	Aldehyde	Tertiary amine	Phenol	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Fragrance	Carboxilica acid	Metal	Aldehyde
Acid amides	Phenol	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Fragrance	Carboxilica acid	Metal	Aldehyde	Sulfonic acid	Carboxilica acid	Amine	Metal	Thioether		Sulfuric ester	Alcohol
Phospho acid	Phenol	Fragrance	Amine	Alcohol		Metal					Sulfonic acid	Carboxilica acid	Amine	Metal	Thioether		Sulfuric ester	Alcohol
Phospho acid	Phenol	Fragrance	Amine	Alcohol		Metal					Phosphonic acids	Phenol	Fragrance	Amine	Alcohol		Metal	Carboxylic acid	SP2 amine	Aniline	Ether
Carboxylic acid	Phenol	Phosphoric acid ester	Sulfuric ester	Sulfone	Nitric ether	Pyridine	Fragrance	Carboxilica acid	Metal	Aldehyde	Phosphonic acids	Phenol	Fragrance	Amine	Alcohol		Metal	Carboxylic acid	SP2 amine	Aniline	Ether

Table III

Functional group
Functional group										Tertiary amine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocyclic radical	Pyridine	Cyano group
Acid amides	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocyclic radical	Pyridine	Cyano group	Tertiary amine	Ester	Ether	Cyano group		Furans	Bromine	Chlorine	The S-heterocyclic radical	Pyridine	Cyano group
Acid amides	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocyclic radical	Pyridine	Cyano group	Sulfonic acid
Phospho acid										Sulfonic acid
Phospho acid										Phosphonic acids	Phosphonic acids	Fragrance-N	Ketone	Aldehyde	Imidazoles
Carboxylic acid	Ester	Ether	Cyano group	Furans	Bromine	Chlorine	The S-heterocyclic radical	Pyridine	Cyano group	Phosphonic acids	Phosphonic acids	Fragrance-N	Ketone	Aldehyde	Imidazoles

Table III

Functional group
Functional group											Tertiary amine	The N-heterocyclic radical	Ketone	Phosphoric acid ester	Fluorine	Carbamate	Imidazoles	BF4	Alkane	Fragrance	N-SO2
Acid amides	The N-heterocyclic radical	Ketone	Phosphoric acid ester	Fluorine	Carbamate	Imidazoles	BF4	Alkane	Fragrance	N-SO2	Tertiary amine	The N-heterocyclic radical	Ketone	Phosphoric acid ester	Fluorine	Carbamate	Imidazoles	BF4	Alkane	Fragrance	N-SO2
Acid amides	The N-heterocyclic radical	Ketone	Phosphoric acid ester	Fluorine	Carbamate	Imidazoles	BF4	Alkane	Fragrance	N-SO2	Sulfonic acid
Phospho acid											Sulfonic acid
Phospho acid											Phosphonic acids
Carboxylic acid	The N-heterocyclic radical	Ketone	Phosphoric acid ester	Fluorine	Carbamate	Imidazoles	BF4	Alkane	Fragrance	N-SO2	Phosphonic acids

Table III

Functional group
Functional group					Tertiary amine	Thiocarbamide	Iodine
Acid amides	Thiocarbamide	Iodine	Epoxide	Superoxide	Tertiary amine	Thiocarbamide	Iodine
Acid amides	Thiocarbamide	Iodine	Epoxide	Superoxide	Sulfonic acid
Phospho acid					Sulfonic acid
Phospho acid					Phosphonic acids
Carboxylic acid	Thiocarbamide	Iodine			Phosphonic acids

Table III

Table III

Functional group
Functional group											Sulfuric ester	Carboxilic acid	Amine	Metal	Thioether	Sulfuric ester	Alcohol
Oxime	Pyridine	N-fragrance	The chlorate	Chlorine	Sp2-N	Diazonium	Thioketones	Cyano group	The N-oxide compound	Ketone	Sulfuric ester	Carboxilic acid	Amine	Metal	Thioether	Sulfuric ester	Alcohol
Oxime	Pyridine	N-fragrance	The chlorate	Chlorine	Sp2-N	Diazonium	Thioketones	Cyano group	The N-oxide compound	Ketone	Nitrile	Amine	Aniline	Bromine	Acid amides	Alkane	Carboxylic acid	Chlorine	The N-heterocyclic radical	Fragrance	Potassium
Diazonium											Nitrile	Amine	Aniline	Bromine	Acid amides	Alkane	Carboxylic acid	Chlorine	The N-heterocyclic radical	Fragrance	Potassium
Diazonium											Nitro	Carboxylic acid	Amine	Metal	Thioether	Sulfuric ester	Alcohol
The S-heterocycle	Alkene	Amine	Chlorine	BF4	Sulfuric ester	Ester	NO	Ether	Acid amides	Iodine	Nitro	Carboxylic acid	Amine	Metal	Thioether	Sulfuric ester	Alcohol
The S-heterocycle	Alkene	Amine	Chlorine	BF4	Sulfuric ester	Ester	NO	Ether	Acid amides	Iodine	Thiophene	CO

Table III

Functional group
Functional group							Sulfuric ester
Oxime	Aldehyde	Carboxylic acid	Bromine	Fragrance	Pyridine	BF4	Sulfuric ester
Oxime	Aldehyde	Carboxylic acid	Bromine	Fragrance	Pyridine	BF4	Nitrile	Aldehyde	Thioether	Pyridine	N-fragrance	Bromine	Ether	S-fragrance	Thiophene
Diazonium							Nitrile	Aldehyde	Thioether	Pyridine	N-fragrance	Bromine	Ether	S-fragrance	Thiophene
Diazonium							Nitro
The S-heterocycle	Carboxylic acid	Sodium	Cyano group	Chlorine	Furans		Nitro
The S-heterocycle	Carboxylic acid	Sodium	Cyano group	Chlorine	Furans		Thiophene

Table III

Functional group
Functional group											Sulfuric ester
Oxime											Sulfuric ester
Oxime											Nitrile
Diazonium											Nitrile
Diazonium											Nitro
The S-heterocycle											Nitro
The S-heterocycle											Thiophene

Table III

Table III

Functional group
Functional group											The N-heterocycle	Alkene	Amine	Chlorine	BF4	Sulfuric ester	Ester	NO	Ether	Acid amides	Iodine
The O-heterocycle	Alkene	Amine	Chlorine	BF4	Sulfuric ester	Ester	NO	Ether	Acid amides	Iodine	The N-heterocycle	Alkene	Amine	Chlorine	BF4	Sulfuric ester	Ester	NO	Ether	Acid amides	Iodine
The O-heterocycle	Alkene	Amine	Chlorine	BF4	Sulfuric ester	Ester	NO	Ether	Acid amides	Iodine	The pyrroles	CO	Imidazoles	Pyridine	N-fragrance	Aldehyde	Carboxylic acid	Sulfuric ester	Chlorine	Bromine	Oxime
Furans											The pyrroles	CO	Imidazoles	Pyridine	N-fragrance	Aldehyde	Carboxylic acid	Sulfuric ester	Chlorine	Bromine	Oxime

Table III

Functional group
Functional group						The N-heterocycle	Carboxylic acid	Sodium	Cyano group	Chlorine	Aldehyde
The O-heterocycle	Carboxylic acid	Sodium	Cyano group	Chlorine	Aldehyde	The N-heterocycle	Carboxylic acid	Sodium	Cyano group	Chlorine	Aldehyde
The O-heterocycle	Carboxylic acid	Sodium	Cyano group	Chlorine	Aldehyde	The pyrroles	Alcohol	Phenol	Ester	Ether
Furans						The pyrroles	Alcohol	Phenol	Ester	Ether

Table III

Functional group
Functional group											The N-heterocycle
The O-heterocycle											The N-heterocycle
The O-heterocycle											The pyrroles
Furans											The pyrroles

Table III

Claims

1. cocrystallization composition, it comprises: Provigil and cocrystallization form thing, and wherein to form thing at room temperature be solid to cocrystallization, and Provigil and cocrystallization formation thing hydrogen bonding each other wherein.

2. the cocrystallization composition of claim 1, wherein:

(a) cocrystallization forms the cocrystallization formation thing that thing is selected from Table I or Table II;

(b) cocrystallization formation thing has at least a ether that is selected from, thioether, alcohol, mercaptan, aldehyde, ketone, thioketones, nitric ether, phosphoric acid ester, thiophosphatephosphorothioate, ester, thioesters, sulfuric ester, carboxylic acid, phosphonic acids, phospho acid, sulfonic acid, acid amides, primary amine, secondary amine, ammonia, tertiary amine, sp2 amine, thiocyanic ester, cyanamide, oxime, nitrile, diazonium, Organohalogen compounds, nitro, the S-heterocycle, thiophene, the N-heterocycle, the pyrroles, the O-heterocycle, furans, epoxide, hydroxamic acid, the functional group of imidazoles and pyridine;

(c) compare with Provigil, the solubleness of cocrystallization increases;

(d) compare with Provigil, the dose response of cocrystallization increases;

(e) compare with Provigil, the stripping of cocrystallization increases;

(f) compare with Provigil, the bioavailability of cocrystallization increases; Or

(g) compare with Provigil, the stability of cocrystallization increases.

3. cocrystallization composition, it comprises that Provigil, cocrystallization form thing and the 3rd molecule; Wherein to form thing at room temperature be solid to cocrystallization, and Provigil and the 3rd molecule bonding each other wherein, and cocrystallization formation thing and the 3rd molecule hydrogen bonding each other wherein in addition.

4. the cocrystallization composition of claim 3, wherein:

(b) cocrystallization formation thing has at least a ether that is selected from, thioether, alcohol, mercaptan, aldehyde, ketone, thioketones, nitric ether, phosphoric acid ester, thiophosphatephosphorothioate, ester, thioesters, sulfuric ester, carboxylic acid, phosphonic acids, phospho acid, sulfonic acid, acid amides, primary amine, secondary amine, ammonia, tertiary amine, sp2 amine, thiocyanic ester, cyanamide, oxime, nitrile, diazonium, Organohalogen compounds, nitro, the S-heterocycle, thiophene, the N-heterocycle, the pyrroles, the O-heterocycle, furans, epoxide, hydroxamic acid, the functional group of imidazoles and pyridine; Or

(c) compare with Provigil, the solubleness of cocrystallization increases;

(d) compare with Provigil, the dose response of cocrystallization increases;

(e) compare with Provigil, the stripping of cocrystallization increases;

(g) compare with Provigil, the stability of cocrystallization increases.

5. cocrystallization composition, it comprises: Provigil and the 2nd API, wherein the 2nd API at room temperature is a liquid or solid, and wherein Provigil and the 2nd API hydrogen bonding to molecule.

6. the cocrystallization composition of claim 5, wherein:

(a) on Provigil hydrogen bonding to the two API;

(b) the 2nd API at room temperature is a liquid;

(c) the 2nd API at room temperature is a solid;

(d) the 2nd API has at least a functional group that is selected from ether, thioether, alcohol, mercaptan, aldehyde, ketone, thioketones, nitric ether, phosphoric acid ester, thiophosphatephosphorothioate, ester, thioesters, sulfuric ester, carboxylic acid, phosphonic acids, phospho acid, sulfonic acid, acid amides, primary amine, secondary amine, ammonia, tertiary amine, sp2 amine, thiocyanic ester, cyanamide, oxime, nitrile, diazonium, Organohalogen compounds, nitro, S-heterocycle, thiophene, N-heterocycle, pyrroles, O-heterocycle, furans, epoxide, hydroxamic acid, imidazoles and pyridine;

(e) compare with Provigil, the solubleness of cocrystallization increases;

(f) compare with Provigil, the dose response of cocrystallization increases;

(g) compare with Provigil, the stripping of cocrystallization increases;

(h) compare with Provigil, the bioavailability of cocrystallization increases; Or

(i) compare with Provigil, the stability of cocrystallization increases.

7. the cocrystallization composition of claim 1,

(a) wherein the cocrystallization composition is medicinal cocrystallization composition; Or

(b) further comprise acceptable diluents, vehicle or carrier.

8. comprise that Provigil and cocrystallization form the cocrystallization of thing, described cocrystallization forms thing and is selected from: propanedioic acid, oxyacetic acid, fumaric acid, tartrate, citric acid, succsinic acid, 2,5-resorcylic acid, oxalic acid, 1-hydroxyl-2-naphthoic acid, vitamin B13, pentanedioic acid, L-tartrate, palmitinic acid, L-proline(Pro), Whitfield's ointment, lauric acid, L MALIC ACID and toxilic acid.

9. the cocrystallization of claim 8, wherein:

(a) cocrystallization characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(i) described cocrystallization is a Provigil: propanedioic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.08,9.28 and 16.81 degree;

(ii) described cocrystallization is a Provigil: propanedioic acid cocrystallization and described X-ray diffractogram are included in the peak of 16.81,18.27 and 19.45 degree;

(iii) described cocrystallization is a Provigil: propanedioic acid cocrystallization and described X-ray diffractogram are included in the peak of 9.28,19.45 and 22.83 degree;

(iv) described cocrystallization is a Provigil: propanedioic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.08 and 9.28 degree;

(v) described cocrystallization is a Provigil: propanedioic acid cocrystallization and described X-ray diffractogram are included in the peak of 16.81 and 19.45 degree;

(vi) described cocrystallization is a Provigil: propanedioic acid cocrystallization and described X-ray diffractogram are included in the peak of 18.27 and 22.83 degree;

(vii) described cocrystallization is a Provigil: propanedioic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.08 degree;

(viii) described cocrystallization is a Provigil: propanedioic acid cocrystallization and described X-ray diffractogram are included in the peak of 9.28 degree; Or

(ix) described cocrystallization is a Provigil: propanedioic acid cocrystallization and described X-ray diffractogram are included in the peak of 16.81 degree;

(b) cocrystallization characterizes by the DSC differential thermogram, and wherein said cocrystallization is a Provigil: propanedioic acid cocrystallization and described DSC differential thermogram are included in about 116 ℃ endothermic transition; Or

(c) cocrystallization is by comprising with cm ^-1The Raman spectrum at the peak of expression characterizes, wherein:

(i) described cocrystallization is a Provigil: propanedioic acid cocrystallization and described Raman spectrum are included in 1004,633 and 265 peak;

(ii) described cocrystallization is a Provigil: propanedioic acid cocrystallization and described Raman spectrum are included in 1032,1601 and 767 peak;

(iii) described cocrystallization is a Provigil: propanedioic acid cocrystallization and described Raman spectrum are included in 1004 and 633 peak;

(iv) described cocrystallization is a Provigil: propanedioic acid cocrystallization and described Raman spectrum are included in 1183 and 767 peak; Or

(v) described cocrystallization is a Provigil: propanedioic acid cocrystallization and described Raman spectrum are included in 1601 and 718 peak.

10. the cocrystallization of claim 8, wherein cocrystallization characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described cocrystallization is a Provigil: oxyacetic acid cocrystallization and described X-ray diffractogram are included in the peak of 9.51,15.97 and 20.03 degree;

(b) described cocrystallization is a Provigil: oxyacetic acid cocrystallization and described X-ray diffractogram are included in the peak of 14.91,19.01 and 22.75 degree;

(c) described cocrystallization is a Provigil: oxyacetic acid cocrystallization and described X-ray diffractogram are included in the peak of 15.97,25.03 and 25.71 degree;

(d) described cocrystallization is a Provigil: oxyacetic acid cocrystallization and described X-ray diffractogram are included in the peak of 9.51 and 15.97 degree;

(e) described cocrystallization is a Provigil: oxyacetic acid cocrystallization and described X-ray diffractogram are included in the peak of 20.03 and 25.03 degree;

(f) described cocrystallization is a Provigil: oxyacetic acid cocrystallization and described X-ray diffractogram are included in the peak of 15.97 and 25.03 degree;

(g) described cocrystallization is a Provigil: oxyacetic acid cocrystallization and described X-ray diffractogram are included in the peak of 9.51 degree;

(h) described cocrystallization is a Provigil: oxyacetic acid cocrystallization and described X-ray diffractogram are included in the peak of 15.97 degree; Or

(i) described cocrystallization is a Provigil: oxyacetic acid cocrystallization and described X-ray diffractogram are included in the peak of 20.03 degree.

11. the cocrystallization of claim 8, wherein:

(i) described cocrystallization is a Provigil: toxilic acid cocrystallization and described X-ray diffractogram are included in the peak of 4.69,6.15 and 9.61 degree;

(ii) described cocrystallization is a Provigil: toxilic acid cocrystallization and described X-ray diffractogram are included in the peak of 10.23,19.97 and 21.83 degree;

(iii) described cocrystallization is a Provigil: toxilic acid cocrystallization and described X-ray diffractogram are included in the peak of 4.69,10.23 and 21.83 degree;

(iv) described cocrystallization is a Provigil: toxilic acid cocrystallization and described X-ray diffractogram are included in the peak of 4.69 and 19.97 degree;

(v) described cocrystallization is a Provigil: toxilic acid cocrystallization and described X-ray diffractogram are included in the peak of 6.15 and 9.61 degree;

(vi) described cocrystallization is a Provigil: toxilic acid cocrystallization and described X-ray diffractogram are included in the peak of 4.69 and 6.15 degree;

(vii) described cocrystallization is a Provigil: toxilic acid cocrystallization and described X-ray diffractogram are included in the peak of 4.69 degree;

(viii) described cocrystallization is a Provigil: toxilic acid cocrystallization and described X-ray diffractogram are included in the peak of 9.61 degree; Or

(x) described cocrystallization is a Provigil: toxilic acid cocrystallization and described X-ray diffractogram are included in the peak of 19.97 degree; Or

(b) cocrystallization characterizes by the DSC differential thermogram, and wherein said cocrystallization is a Provigil: toxilic acid cocrystallization and described DSC differential thermogram are included in about 168 ℃ endothermic transition.

12. the cocrystallization of claim 8, wherein cocrystallization characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described cocrystallization is a Provigil: L-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 6.10,14.33 and 20.71 degree;

(b) described cocrystallization is a Provigil: L-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 16.93,20.15 and 22.49 degree;

(c) described cocrystallization is a Provigil: L-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 16.93,20.71 and 29.72 degree;

(d) described cocrystallization is a Provigil: L-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 6.10 and 20.15 degree;

(e) described cocrystallization is a Provigil: L-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 14.33 and 20.71 degree;

(f) described cocrystallization is a Provigil: L-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 7.36 and 25.04 degree;

(g) described cocrystallization is a Provigil: L-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 6.10 degree;

(h) described cocrystallization is a Provigil: L-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 16.93 degree; Or

(i) described cocrystallization is a Provigil: L-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 20.71 degree.

13. the cocrystallization of claim 8, wherein cocrystallization characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described cocrystallization is a Provigil: citric acid cocrystallization and described X-ray diffractogram are included in the peak of 5.29,7.29 and 9.31 degree;

(b) described cocrystallization is a Provigil: citric acid cocrystallization and described X-ray diffractogram are included in the peak of 12.41,13.29 and 14.61 degree;

(c) described cocrystallization is a Provigil: citric acid cocrystallization and described X-ray diffractogram are included in the peak of 17.29,17.97 and 21.37 degree;

(d) described cocrystallization is a Provigil: citric acid cocrystallization and described X-ray diffractogram are included in the peak of 5.29 and 17.29 degree;

(e) described cocrystallization is a Provigil: citric acid cocrystallization and described X-ray diffractogram are included in the peak of 7.29 and 9.31 degree;

(f) described cocrystallization is a Provigil: citric acid cocrystallization and described X-ray diffractogram are included in the peak of 12.41 and 21.37 degree;

(g) described cocrystallization is a Provigil: citric acid cocrystallization and described X-ray diffractogram are included in the peak of 5.29 degree;

(h) described cocrystallization is a Provigil: citric acid cocrystallization and described X-ray diffractogram are included in the peak of 7.29 degree; Or

(i) described cocrystallization is a Provigil: citric acid cocrystallization and described X-ray diffractogram are included in the peak of 12.41 degree.

14. the cocrystallization of claim 8, wherein:

(i) described cocrystallization is a Provigil: succsinic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.45,9.93 and 17.99 degree;

(ii) described cocrystallization is a Provigil: succsinic acid cocrystallization and described X-ray diffractogram are included in the peak of 19.95,21.95 and 25.07 degree;

(iii) described cocrystallization is a Provigil: succsinic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.45,17.99 and 21.35 degree;

(iv) described cocrystallization is a Provigil: succsinic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.45 and 9.93 degree;

(v) described cocrystallization is a Provigil: succsinic acid cocrystallization and described X-ray diffractogram are included in the peak of 17.99 and 21.95 degree;

(vi) described cocrystallization is a Provigil: succsinic acid cocrystallization and described X-ray diffractogram are included in the peak of 9.93 and 19.95 degree;

(vii) described cocrystallization is a Provigil: succsinic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.45 degree;

(viii) described cocrystallization is a Provigil: succsinic acid cocrystallization and described X-ray diffractogram are included in the peak of 9.93 degree; Or

(xi) described cocrystallization is a Provigil: succsinic acid cocrystallization and described X-ray diffractogram are included in the peak of 17.99 degree; Or

(b) cocrystallization characterizes by the DSC differential thermogram, and wherein said cocrystallization is a Provigil: succsinic acid cocrystallization and described DSC differential thermogram are included in about 149 ℃ endothermic transition.

15. the cocrystallization of claim 8, wherein cocrystallization characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described cocrystallization is a Provigil: DL-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 4.75,9.53 and 15.83 degree;

(b) described cocrystallization is a Provigil: DL-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 17.61,20.25 and 22.55 degree;

(c) described cocrystallization is a Provigil: DL-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 10.07,17.61 and 21.53 degree;

(d) described cocrystallization is a Provigil: DL-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 4.75 and 15.83 degree;

(e) described cocrystallization is a Provigil: DL-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 9.53 and 17.61 degree;

(f) described cocrystallization is a Provigil: DL-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 21.53 and 22.55 degree;

(g) described cocrystallization is a Provigil: DL-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 4.75 degree;

(h) described cocrystallization is a Provigil: DL-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 9.53 degree; Or

(i) described cocrystallization is a Provigil: DL-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 15.83 degree.

16. the cocrystallization of claim 8, wherein cocrystallization characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described cocrystallization is a Provigil: fumaric acid cocrystallization and described X-ray diffractogram are included in the peak of 5.45,9.95 and 18.03 degree;

(b) described cocrystallization is a Provigil: fumaric acid cocrystallization and described X-ray diffractogram are included in the peak of 15.93,18.81 and 21.95 degree;

(c) described cocrystallization is a Provigil: fumaric acid cocrystallization and described X-ray diffractogram are included in the peak of 9.95,19.93 and 23.09 degree;

(d) described cocrystallization is a Provigil: fumaric acid cocrystallization and described X-ray diffractogram are included in the peak of 5.45 and 9.95 degree;

(e) described cocrystallization is a Provigil: fumaric acid cocrystallization and described X-ray diffractogram are included in the peak of 5.45 and 18.03 degree;

(f) described cocrystallization is a Provigil: fumaric acid cocrystallization and described X-ray diffractogram are included in the peak of 15.93 and 21.95 degree;

(g) described cocrystallization is a Provigil: fumaric acid cocrystallization and described X-ray diffractogram are included in the peak of 5.45 degree;

(h) described cocrystallization is a Provigil: fumaric acid cocrystallization and described X-ray diffractogram are included in the peak of 9.95 degree; Or

(i) described cocrystallization is a Provigil: fumaric acid cocrystallization and described X-ray diffractogram are included in the peak of 18.03 degree.

17. the cocrystallization of claim 6, wherein cocrystallization is a Provigil: fumaric acid I type.

18. the cocrystallization of claim 8, wherein cocrystallization characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described cocrystallization is a Provigil: fumaric acid cocrystallization and described X-ray diffractogram are included in the peak of 6.47,8.57 and 9.99 degree;

(b) described cocrystallization is a Provigil: fumaric acid cocrystallization and described X-ray diffractogram are included in the peak of 13.89,14.53 and 20.79 degree;

(c) described cocrystallization is a Provigil: fumaric acid cocrystallization and described X-ray diffractogram are included in the peak of 16.45,18.39 and 20.05 degree;

(d) described cocrystallization is a Provigil: fumaric acid cocrystallization and described X-ray diffractogram are included in the peak of 6.47 and 20.79 degree;

(e) described cocrystallization is a Provigil: fumaric acid cocrystallization and described X-ray diffractogram are included in the peak of 9.99 and 14.53 degree;

(f) described cocrystallization is a Provigil: fumaric acid cocrystallization and described X-ray diffractogram are included in the peak of 13.89 and 20.05 degree;

(g) described cocrystallization is a Provigil: fumaric acid cocrystallization and described X-ray diffractogram are included in the peak of 6.47 degree;

(h) described cocrystallization is a Provigil: fumaric acid cocrystallization and described X-ray diffractogram are included in the peak of 13.89 degree; Or

(i) described cocrystallization is a Provigil: fumaric acid cocrystallization and described X-ray diffractogram are included in the peak of 20.79 degree.

19. the cocrystallization of claim 18, wherein cocrystallization is a Provigil: fumaric acid II type.

20. the cocrystallization of claim 8, wherein cocrystallization characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described cocrystallization is a Provigil: 2, and 5-resorcylic acid cocrystallization and described X-ray diffractogram are included in the peak of 6.96,12.92 and 14.76 degree;

(b) described cocrystallization is a Provigil: 2, and 5-resorcylic acid cocrystallization and described X-ray diffractogram are included in the peak of 14.76,18.26 and 20.10 degree;

(c) described cocrystallization is a Provigil: 2, and 5-resorcylic acid cocrystallization and described X-ray diffractogram are included in the peak of 6.96,17.40 and 20.94 degree;

(d) described cocrystallization is a Provigil: 2, and 5-resorcylic acid cocrystallization and described X-ray diffractogram are included in the peak of 6.96 and 14.76 degree;

(e) described cocrystallization is a Provigil: 2, and 5-resorcylic acid cocrystallization and described X-ray diffractogram are included in the peak of 12.92 and 17.40 degree;

(f) described cocrystallization is a Provigil: 2, and 5-resorcylic acid cocrystallization and described X-ray diffractogram are included in the peak of 6.96 and 18.26 degree;

(g) described cocrystallization is a Provigil: 2, and 5-resorcylic acid cocrystallization and described X-ray diffractogram are included in the peak of 6.96 degree;

(h) described cocrystallization is a Provigil: 2, and 5-resorcylic acid cocrystallization and described X-ray diffractogram are included in the peak of 14.76 degree; Or

(i) described cocrystallization is a Provigil: 2, and 5-resorcylic acid cocrystallization and described X-ray diffractogram are included in the peak of 18.26 degree.

21. the cocrystallization of claim 8, wherein cocrystallization characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described cocrystallization is a Provigil: oxalic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.98,17.54 and 19.68 degree;

(b) described cocrystallization is a Provigil: oxalic acid cocrystallization and described X-ray diffractogram are included in the peak of 13.68,14.80 and 21.12 degree;

(c) described cocrystallization is a Provigil: oxalic acid cocrystallization and described X-ray diffractogram are included in the peak of 17.54,19.68 and 21.86 degree;

(d) described cocrystallization is a Provigil: oxalic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.98 and 19.68 degree;

(e) described cocrystallization is a Provigil: oxalic acid cocrystallization and described X-ray diffractogram are included in the peak of 13.68 and 14.80 degree;

(f) described cocrystallization is a Provigil: oxalic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.98 and 17.54 degree;

(g) described cocrystallization is a Provigil: oxalic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.98 degree;

(h) described cocrystallization is a Provigil: oxalic acid cocrystallization and described X-ray diffractogram are included in the peak of 19.68 degree; Or

(i) described cocrystallization is a Provigil: oxalic acid cocrystallization and described X-ray diffractogram are included in the peak of 17.54 degree.

22. the cocrystallization of claim 8, wherein cocrystallization characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described cocrystallization is a Provigil: 1-hydroxyl-2-naphthoic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.72,7.10 and 14.16 degree;

(b) described cocrystallization is a Provigil: 1-hydroxyl-2-naphthoic acid cocrystallization and described X-ray diffractogram are included in the peak of 11.48,15.66 and 20.26 degree;

(c) described cocrystallization is a Provigil: 1-hydroxyl-2-naphthoic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.72,7.10 and 20.26 degree;

(d) described cocrystallization is a Provigil: 1-hydroxyl-2-naphthoic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.72 and 7.10 degree;

(e) described cocrystallization is a Provigil: 1-hydroxyl-2-naphthoic acid cocrystallization and described X-ray diffractogram are included in the peak of 14.16 and 20.26 degree;

(f) described cocrystallization is a Provigil: 1-hydroxyl-2-naphthoic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.72 and 14.16 degree;

(g) described cocrystallization is a Provigil: 1-hydroxyl-2-naphthoic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.72 degree;

(h) described cocrystallization is a Provigil: 1-hydroxyl-2-naphthoic acid cocrystallization and described X-ray diffractogram are included in the peak of 7.10 degree; Or

(i) described cocrystallization is a Provigil: 1-hydroxyl-2-naphthoic acid cocrystallization and described X-ray diffractogram are included in the peak of 14.16 degree.

23. the cocrystallization of claim 8, wherein:

(i) described cocrystallization is a Provigil: propanedioic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.04,9.26 and 16.73 degree;

(ii) described cocrystallization is a Provigil: propanedioic acid cocrystallization and described X-ray diffractogram are included in the peak of 18.23,19.37 and 22.74 degree;

(iii) described cocrystallization is a Provigil: propanedioic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.04,16.73 and 19.37 degree;

(iv) described cocrystallization is a Provigil: propanedioic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.04 and 9.26 degree;

(v) described cocrystallization is a Provigil: propanedioic acid cocrystallization and described X-ray diffractogram are included in the peak of 16.73 and 19.37 degree;

(vi) described cocrystallization is a Provigil: propanedioic acid cocrystallization and described X-ray diffractogram are included in the peak of 9.26 and 18.23 degree;

(vii) described cocrystallization is a Provigil: propanedioic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.04 degree;

(viii) described cocrystallization is a Provigil: propanedioic acid cocrystallization and described X-ray diffractogram are included in the peak of 9.26 degree; Or

(ix) described cocrystallization is a Provigil: propanedioic acid cocrystallization and described X-ray diffractogram are included in the peak of 19.37 degree; Or

(b) cocrystallization characterizes by the DSC differential thermogram, and wherein said cocrystallization is a Provigil: propanedioic acid cocrystallization and described DSC differential thermogram are included in about 115 ℃ endothermic transition.

24. the cocrystallization of claim 23, wherein Provigil is R-(-)-Provigil.

25. the cocrystallization of claim 8, wherein:

(i) described cocrystallization is a Provigil: succsinic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.36,9.83 and 17.88 degree;

(ii) described cocrystallization is a Provigil: succsinic acid cocrystallization and described X-ray diffractogram are included in the peak of 15.80,19.87 and 21.85 degree;

(iii) described cocrystallization is a Provigil: succsinic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.36,9.83 and 21.85 degree;

(iv) described cocrystallization is a Provigil: succsinic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.36 and 9.83 degree;

(v) described cocrystallization is a Provigil: succsinic acid cocrystallization and described X-ray diffractogram are included in the peak of 17.88 and 19.87 degree;

(vi) described cocrystallization is a Provigil: succsinic acid cocrystallization and described X-ray diffractogram are included in the peak of 9.83 and 15.80 degree;

(vii) described cocrystallization is a Provigil: succsinic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.36 degree;

(viii) described cocrystallization is a Provigil: succsinic acid cocrystallization and described X-ray diffractogram are included in the peak of 9.83 degree; Or

(ix) described cocrystallization is a Provigil: succsinic acid cocrystallization and described X-ray diffractogram are included in the peak of 17.88 degree; Or

(b) cocrystallization characterizes by the DSC differential thermogram, and wherein said cocrystallization is a Provigil: succsinic acid cocrystallization and described DSC differential thermogram are included in about 145 ℃ endothermic transition.

26. the cocrystallization of claim 25, wherein Provigil is R-(-)-Provigil.

27. the cocrystallization of claim 8, wherein:

(i) described cocrystallization is a Provigil: citric acid cocrystallization and described X-ray diffractogram are included in the peak of 5.18,7.23 and 9.23 degree;

(ii) described cocrystallization is a Provigil: citric acid cocrystallization and described X-ray diffractogram are included in the peak of 12.32,13.23 and 17.25 degree;

(iii) described cocrystallization is a Provigil: citric acid cocrystallization and described X-ray diffractogram are included in the peak of 9.23,17.92 and 21.30 degree;

(iv) described cocrystallization is a Provigil: citric acid cocrystallization and described X-ray diffractogram are included in the peak of 5.18 and 9.23 degree;

(v) described cocrystallization is a Provigil: citric acid cocrystallization and described X-ray diffractogram are included in the peak of 7.23 and 13.23 degree;

(vi) described cocrystallization is a Provigil: citric acid cocrystallization and described X-ray diffractogram are included in the peak of 17.25 and 17.92 degree;

(vii) described cocrystallization is a Provigil: citric acid cocrystallization and described X-ray diffractogram are included in the peak of 5.18 degree;

(viii) described cocrystallization is a Provigil: citric acid cocrystallization and described X-ray diffractogram are included in the peak of 7.23 degree; Or

(ix) described cocrystallization is a Provigil: citric acid cocrystallization and described X-ray diffractogram are included in the peak of 9.23 degree; Or

(b) cocrystallization characterizes by the DSC differential thermogram, and wherein said cocrystallization is a Provigil: citric acid cocrystallization and described DSC differential thermogram are included in about 89 ℃ endothermic transition.

28. the cocrystallization of claim 27, wherein Provigil R-(-)-Provigil.

29. the cocrystallization of claim 8, wherein cocrystallization characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described cocrystallization is a Provigil: 1-hydroxyl-2-naphthoic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.27,8.85 and 10.60 degree;

(b) described cocrystallization is a Provigil: 1-hydroxyl-2-naphthoic acid cocrystallization and described X-ray diffractogram are included in the peak of 10.60,14.47 and 21.20 degree;

(c) described cocrystallization is a Provigil: 1-hydroxyl-2-naphthoic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.27,14.47 and 23.03 degree;

(d) described cocrystallization is a Provigil: 1-hydroxyl-2-naphthoic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.27 and 8.85 degree;

(e) described cocrystallization is a Provigil: 1-hydroxyl-2-naphthoic acid cocrystallization and described X-ray diffractogram are included in the peak of 10.60 and 23.03 degree;

(f) described cocrystallization is a Provigil: 1-hydroxyl-2-naphthoic acid cocrystallization and described X-ray diffractogram are included in the peak of 14.47 and 21.20 degree;

(g) described cocrystallization is a Provigil: 1-hydroxyl-2-naphthoic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.27 degree;

(h) described cocrystallization is a Provigil: 1-hydroxyl-2-naphthoic acid cocrystallization and described X-ray diffractogram are included in the peak of 8.85 degree; Or

(i) described cocrystallization is a Provigil: 1-hydroxyl-2-naphthoic acid cocrystallization and described X-ray diffractogram are included in the peak of 14.47 degree.

30. the cocrystallization of claim 29, wherein Provigil R-(-)-Provigil.

31. the cocrystallization of claim 8, wherein cocrystallization characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described cocrystallization is a Provigil: DL-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 4.67,15.41 and 19.46 degree;

(b) described cocrystallization is a Provigil: DL-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 17.97,19.46 and 22.91 degree;

(c) described cocrystallization is a Provigil: DL-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 4.67,22.91 and 24.63 degree;

(d) described cocrystallization is a Provigil: DL-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 4.67 and 19.46 degree;

(e) described cocrystallization is a Provigil: DL-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 17.97 and 22.91 degree;

(f) described cocrystallization is a Provigil: DL-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 15.41 and 24.63 degree;

(g) described cocrystallization is a Provigil: DL-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 4.67 degree;

(h) described cocrystallization is a Provigil: DL-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 19.46 degree; Or

(i) described cocrystallization is a Provigil: DL-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 22.91 degree.

32. the cocrystallization of claim 31, wherein Provigil R-(-)-Provigil.

33. the cocrystallization of claim 8, wherein cocrystallization characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described cocrystallization is a Provigil: vitamin B13 cocrystallization and described X-ray diffractogram are included in the peak of 9.77,17.85 and 20.52 degree;

(b) described cocrystallization is a Provigil: vitamin B13 cocrystallization and described X-ray diffractogram are included in the peak of 17.85,24.03 and 26.80 degree;

(c) described cocrystallization is a Provigil: vitamin B13 cocrystallization and described X-ray diffractogram are included in the peak of 9.77,20.52 and 24.03 degree;

(d) described cocrystallization is a Provigil: vitamin B13 cocrystallization and described X-ray diffractogram are included in the peak of 9.77 and 17.85 degree;

(e) described cocrystallization is a Provigil: vitamin B13 cocrystallization and described X-ray diffractogram are included in the peak of 17.85 and 24.03 degree;

(f) described cocrystallization is a Provigil: vitamin B13 cocrystallization and described X-ray diffractogram are included in the peak of 9.77 and 26.80 degree;

(g) described cocrystallization is a Provigil: vitamin B13 cocrystallization and described X-ray diffractogram are included in the peak of 9.77 degree;

(h) described cocrystallization is a Provigil: vitamin B13 cocrystallization and described X-ray diffractogram are included in the peak of 17.85 degree; Or

(i) described cocrystallization is a Provigil: vitamin B13 cocrystallization and described X-ray diffractogram are included in the peak of 24.03 degree.

34. the cocrystallization of claim 33, wherein Provigil R-(-)-Provigil.

35. pharmaceutical composition, wherein composition is solvate form thereof and characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described form is the peak that Provigil acetic acid solvent compound and described X-ray diffractogram are included in 6.17,9.63 and 19.99 degree;

(b) described form is the peak that Provigil acetic acid solvent compound and described X-ray diffractogram are included in 6.17 and 9.63 degree;

(c) described form is the peak that Provigil acetic acid solvent compound and described X-ray diffractogram are included in 19.99 and 21.83 degree;

(d) described form is the peak that Provigil acetic acid solvent compound and described X-ray diffractogram are included in 9.63 and 19.99 degree; Or

(e) described form is the peak that Provigil acetic acid solvent compound and described X-ray diffractogram are included in 6.17 degree.

36. pharmaceutical composition, wherein composition is solvate form thereof and characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described form is the peak that Provigil tetrahydrofuran solvent compound and described X-ray diffractogram are included in 6.97,9.79 and 10.97 degree;

(b) described form is the peak that Provigil tetrahydrofuran solvent compound and described X-ray diffractogram are included in 10.97 and 20.59 degree;

(c) described form is the peak that Provigil tetrahydrofuran solvent compound and described X-ray diffractogram are included in 9.79 and 19.03 degree;

(d) described form is the peak that Provigil tetrahydrofuran solvent compound and described X-ray diffractogram are included in 6.97 and 16.19 degree; Or

(e) described form is the peak that Provigil tetrahydrofuran solvent compound and described X-ray diffractogram are included in 6.97 degree.

37. pharmaceutical composition, wherein composition is solvate form thereof and characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described form is a Provigil 1, and 4-two _ alkane solvents compound and described X-ray diffractogram are included in the peak of 6.93,9.85 and 10.97 degree;

(b) described form is a Provigil 1, and 4-two _ alkane solvents compound and described X-ray diffractogram are included in the peak of 6.93 and 20.65 degree;

(c) described form is a Provigil 1, and 4-two _ alkane solvents compound and described X-ray diffractogram are included in the peak of 10.97 and 18.97 degree;

(d) described form is a Provigil 1, and 4-two _ alkane solvents compound and described X-ray diffractogram are included in the peak of 16.19 and 23.33 degree; Or

(e) described form is a Provigil 1, and 4-two _ alkane solvents compound and described X-ray diffractogram are included in the peak of 6.93 degree.

38. pharmaceutical composition, wherein composition is solvate form thereof and characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described form is the peak that Provigil methanol solvate compound and described X-ray diffractogram are included in 6.15,9.89 and 20.07 degree;

(b) described form is the peak that Provigil methanol solvate compound and described X-ray diffractogram are included in 6.15 and 9.89 degree;

(c) described form is the peak that Provigil methanol solvate compound and described X-ray diffractogram are included in 12.25 and 17.97 degree;

(d) described form is the peak that Provigil methanol solvate compound and described X-ray diffractogram are included in 20.07 and 21.85 degree; Or

(e) described form is the peak that Provigil methanol solvate compound and described X-ray diffractogram are included in 6.15 degree.

39. pharmaceutical composition, wherein composition is solvate form thereof and characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described form is the peak that Provigil Nitromethane 99Min. solvate and described X-ray diffractogram are included in 6.17,9.77 and 20.07 degree;

(b) described form is the peak that Provigil Nitromethane 99Min. solvate and described X-ray diffractogram are included in 12.29 and 15.89 degree;

(c) described form is the peak that Provigil Nitromethane 99Min. solvate and described X-ray diffractogram are included in 6.17 and 20.07 degree;

(d) described form is the peak that Provigil Nitromethane 99Min. solvate and described X-ray diffractogram are included in 9.77 and 22.17 degree; Or

(e) described form is the peak that Provigil Nitromethane 99Min. solvate and described X-ray diffractogram are included in 6.17 degree.

40. pharmaceutical composition, wherein composition is solvate form thereof and characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described form is the peak that Provigil acetone solvent compound and described X-ray diffractogram are included in 6.11,9.53 and 15.81 degree;

(b) described form is the peak that Provigil acetone solvent compound and described X-ray diffractogram are included in 6.11 and 9.53 degree;

(c) described form is the peak that Provigil acetone solvent compound and described X-ray diffractogram are included in 15.81 and 20.03 degree;

(d) described form is the peak that Provigil acetone solvent compound and described X-ray diffractogram are included in 18.11 and 21.63 degree; Or

(e) described form is the peak that Provigil acetone solvent compound and described X-ray diffractogram are included in 6.11 degree.

41. the cocrystallization of claim 1, wherein cocrystallization formation thing is a carboxylic acid.

42. the cocrystallization of claim 41, wherein the carboxylic acid functional of cocrystallization formation thing and the primary amide or the S=O of Provigil interact by hydrogen bonding.

43. the cocrystallization of claim 41, wherein the carboxylic acid functional of cocrystallization formation thing and the dimeric periphery of acid amides of Provigil interact by hydrogen bonding.

44. the cocrystallization of claim 41, wherein the carboxylic acid functional of cocrystallization formation thing and the acid amides dimer and the S=O of Provigil interact by hydrogen bonding.

45. the cocrystallization of claim 41, wherein the carboxylic acid functional of cocrystallization formation thing and two acid amides dimers of Provigil interact by hydrogen bonding.

46. the cocrystallization of claim 1, wherein Provigil R-(-)-Provigil.

47. the cocrystallization of claim 1, wherein Provigil is S-(+)-Provigil.

48. the cocrystallization of claim 8, wherein Provigil R-(-)-Provigil.

49. the cocrystallization of claim 8, wherein Provigil is S-(+)-Provigil.

50. preparation comprises that Provigil and cocrystallization form the medicinal cocrystallization method for compositions of thing, it comprises:

(a) provide Provigil and cocrystallization to form thing, wherein cocrystallization formation thing at room temperature is a solid;

(b) Provigil and cocrystallization are formed thing grinds, heat under crystallization condition, distillation altogether, congruent melting is melted or contact in solution, makes the formation solid phase, Provigil and cocrystallization formation thing hydrogen bonding each other wherein;

(c) separate the cocrystallization that so forms; With

(d) cocrystallization is mixed in the pharmaceutical composition.

51. the method for claim 50, wherein:

(a) cocrystallization forms the cocrystallization formation thing that thing is selected from Table I or Table II; Or

(b) cocrystallization formation thing has at least a ether that is selected from, thioether, alcohol, mercaptan, aldehyde, ketone, thioketones, nitric ether, phosphoric acid ester, thiophosphatephosphorothioate, ester, thioesters, sulfuric ester, carboxylic acid, phosphonic acids, phospho acid, sulfonic acid, acid amides, primary amine, secondary amine, ammonia, tertiary amine, sp2 amine, thiocyanic ester, cyanamide, oxime, nitrile, diazonium, Organohalogen compounds, nitro, the S-heterocycle, thiophene, the N-heterocycle, the pyrroles, the O-heterocycle, furans, epoxide, hydroxamic acid, the functional group of imidazoles and pyridine.

52. preparation comprises that Provigil, cocrystallization form thing and the medicinal cocrystallization method for compositions of termolecular, it comprises:

(b) Provigil and cocrystallization are formed thing grinds, heat, distils altogether, congruent melting is melted under crystallization condition or in solution, contact, make and form solid phase, Provigil and the 3rd molecule bonding each other wherein, and in addition wherein cocrystallization form thing and the 3rd molecule hydrogen bonding each other;

(c) separate the cocrystallization that so forms; With

(d) cocrystallization is mixed in the pharmaceutical composition.

53. the method for claim 52, wherein:

54. preparation comprises the medicinal cocrystallization method for compositions of Provigil and the 2nd API, it comprises:

(a) provide Provigil and the 2nd API, wherein the 2nd API at room temperature is a liquid or solid;

(b) Provigil ground under crystallization condition with the 2nd API, heat, distillation altogether, congruent melting is melted or contact in solution, makes to form solid phase that wherein Provigil and the 2nd API hydrogen bonding are to molecule;

(c) separate the cocrystallization that so forms; With

(d) cocrystallization is mixed in the pharmaceutical composition.

55. the method for claim 54, wherein:

(a) Provigil and the 2nd API hydrogen bonding;

(b) the 2nd API at room temperature is a liquid;

(c) the 2nd API at room temperature is a solid; Or

(d) the 2nd API has at least a functional group that is selected from ether, thioether, alcohol, mercaptan, aldehyde, ketone, thioketones, nitric ether, phosphoric acid ester, thiophosphatephosphorothioate, ester, thioesters, sulfuric ester, carboxylic acid, phosphonic acids, phospho acid, sulfonic acid, acid amides, primary amine, secondary amine, ammonia, tertiary amine, sp2 amine, thiocyanic ester, cyanamide, oxime, nitrile, diazonium, Organohalogen compounds, nitro, S-heterocycle, thiophene, N-heterocycle, pyrroles, O-heterocycle, furans, epoxide, hydroxamic acid, imidazoles and pyridine.

56. the method for claim 50, it further comprises: mix acceptable diluents, vehicle or carrier.

57. preparation comprises that Provigil and cocrystallization form the method for the cocrystallization of thing, it comprises:

(a) provide Provigil and cocrystallization to form thing;

(b) under crystallization condition, Provigil and cocrystallization formation thing ground, heat, be total to distillation, congruent melting is melted or in solution, contact the feasible solid phase that forms; With

(c) separate the cocrystallization that so forms;

Wherein cocrystallization forms thing and is selected from propanedioic acid, benzamide, amygdalic acid, oxyacetic acid, fumaric acid and toxilic acid.

58. regulate the method for the solubleness of the Provigil that is used for pharmaceutical composition, this method comprises:

(a) Provigil and cocrystallization formation compound ground under crystallization condition, heat, be total to distillation, congruent melting is melted or in solution, contact the feasible cocrystallization that forms Provigil and cocrystallization formation compound;

(b) separate cocrystallization, wherein cocrystallization is compared with Provigil and is had adjusted solubleness; With

(c) cocrystallization that will have adjusted solubleness is mixed in the pharmaceutical composition.

59. the method for claim 58 is wherein compared with Provigil, the solubleness of cocrystallization increases.

60. regulate the method for the dose response of the Provigil that is used for pharmaceutical composition, this method comprises:

(b) separate cocrystallization, wherein cocrystallization is compared with Provigil and is had adjusted dose response; With

(c) cocrystallization that will have an adjusted dose response is mixed in the pharmaceutical composition.

61. the method for claim 60 is wherein compared with Provigil, the dose response of cocrystallization increases.

62. regulate the method for the stripping of the Provigil that is used for pharmaceutical composition, this method comprises:

(b) separate cocrystallization, wherein cocrystallization is compared with Provigil and is had adjusted stripping; With

(c) cocrystallization that will have an adjusted stripping is mixed in the pharmaceutical composition.

63. the method for claim 62 is wherein compared with Provigil, the stripping of cocrystallization increases.

64. regulate the method for the bioavailability of the Provigil that is used for pharmaceutical composition, this method comprises:

(b) separate cocrystallization, wherein cocrystallization is compared with Provigil and is had adjusted bioavailability; With

(c) cocrystallization that will have an adjusted bioavailability is mixed in the pharmaceutical composition.

65. the method for claim 64 is wherein compared with Provigil, the bioavailability of cocrystallization increases.

66. increase the method for the stability of the Provigil that is used for pharmaceutical composition, this method comprises:

(b) separate cocrystallization, wherein cocrystallization is compared with Provigil and is had the stability that has increased; With

(c) cocrystallization that will have the stability that has increased is mixed in the pharmaceutical composition.

67. regulate the morphology methods of the Provigil that is used for pharmaceutical composition, this method comprises:

(b) separate cocrystallization, wherein cocrystallization is compared with Provigil and is had different morphology; With

(c) will have adjusted morphologic cocrystallization is mixed in the pharmaceutical composition.

68. pharmaceutical composition, it comprises the cocrystallization of Provigil.

69. the pharmaceutical composition of claim 68, it further comprises acceptable diluents, vehicle or carrier.

70. treatment suffers from the method that fatigue, Infertility, eating disorder, the attention of being correlated with hypnolepsy, multiple sclerosis lack the object of the relevant excessive daytime sleepiness of hyperkinetic syndrome (ADHD), Parkinson's disease, incontinence, sleep apnea or myopathy, it comprises the cocrystallization that comprises Provigil to object drug treatment significant quantity.

71. the method for claim 70, wherein object is a human subjects.

72. pharmaceutical composition, wherein composition is solvate form thereof and characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described form is the peak that R-(-)-Provigil phenylcarbinol solvate and described X-ray diffractogram are included in 7.76,18.57 and 21.53 degree;

(b) described form is the peak that R-(-)-Provigil phenylcarbinol solvate and described X-ray diffractogram are included in 5.77 and 7.76 degree;

(c) described form is the peak that R-(-)-Provigil phenylcarbinol solvate and described X-ray diffractogram are included in 18.57 and 21.53 degree;

(d) described form is the peak that R-(-)-Provigil phenylcarbinol solvate and described X-ray diffractogram are included in 10.48 and 27.73 degree; Or

(e) described form is the peak that R-(-)-Provigil phenylcarbinol solvate and described X-ray diffractogram are included in 7.76 degree.

73. pharmaceutical composition, wherein composition is solvate form thereof and characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described form is the peak that R-(-)-Provigil isopropanol solvent compound and described X-ray diffractogram are included in 5.76,7.77 and 21.53 degree;

(b) described form is the peak that R-(-)-Provigil isopropanol solvent compound and described X-ray diffractogram are included in 10.49 and 18.58 degree;

(c) described form is the peak that R-(-)-Provigil isopropanol solvent compound and described X-ray diffractogram are included in 7.77 and 18.58 degree;

(d) described form is the peak that R-(-)-Provigil isopropanol solvent compound and described X-ray diffractogram are included in 5.76 and 15.79 degree; Or

(e) described form is the peak that R-(-)-Provigil isopropanol solvent compound and described X-ray diffractogram are included in 7.77 degree.

74. pharmaceutical composition, wherein composition is solvate form thereof and characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described form is the peak that R-(-)-Provigil acetonitrile solvent compound and described X-ray diffractogram are included in 6.17,8.16 and 21.86 degree;

(b) described form is the peak that R-(-)-Provigil acetonitrile solvent compound and described X-ray diffractogram are included in 6.17 and 11.19 degree;

(c) described form is the peak that R-(-)-Provigil acetonitrile solvent compound and described X-ray diffractogram are included in 8.16 and 10.19 degree;

(d) described form is the peak that R-(-)-Provigil acetonitrile solvent compound and described X-ray diffractogram are included in 6.17 and 8.16 degree; Or

(e) described form is the peak that R-(-)-Provigil acetonitrile solvent compound and described X-ray diffractogram are included in 6.17 degree.

75. pharmaceutical composition, wherein composition is solvate form thereof and characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described form is the peak that R-(-)-Provigil alcohol solvent compound and described X-ray diffractogram are included in 6.13,9.59 and 20.05 degree;

(b) described form is the peak that R-(-)-Provigil alcohol solvent compound and described X-ray diffractogram are included in 15.69 and 21.55 degree;

(c) described form is the peak that R-(-)-Provigil alcohol solvent compound and described X-ray diffractogram are included in 9.59 and 20.05 degree;

(d) described form is the peak that R-(-)-Provigil alcohol solvent compound and described X-ray diffractogram are included in 6.13 and 15.69 degree; Or

(e) described form is the peak that R-(-)-Provigil alcohol solvent compound and described X-ray diffractogram are included in 6.13 degree.

76. the cocrystallization of claim 8, wherein cocrystallization characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described cocrystallization is a Provigil: 2, and 5-resorcylic acid cocrystallization and described X-ray diffractogram are included in the peak of 7.07,9.07 and 12.31 degree;

(b) described cocrystallization is a Provigil: 2, and 5-resorcylic acid cocrystallization and described X-ray diffractogram are included in the peak of 9.07,18.39 and 21.27 degree;

(c) described cocrystallization is a Provigil: 2, and 5-resorcylic acid cocrystallization and described X-ray diffractogram are included in the peak of 17.63,23.57 and 26.93 degree;

(d) described cocrystallization is a Provigil: 2, and 5-resorcylic acid cocrystallization and described X-ray diffractogram are included in the peak of 9.07 and 16.03 degree;

(e) described cocrystallization is a Provigil: 2, and 5-resorcylic acid cocrystallization and described X-ray diffractogram are included in the peak of 7.51 and 21.27 degree;

(f) described cocrystallization is a Provigil: 2, and 5-resorcylic acid cocrystallization and described X-ray diffractogram are included in the peak of 7.07 and 7.51 degree;

(g) described cocrystallization is a Provigil: 2, and 5-resorcylic acid cocrystallization and described X-ray diffractogram are included in the peak of 9.07 degree;

(h) described cocrystallization is a Provigil: 2, and 5-resorcylic acid cocrystallization and described X-ray diffractogram are included in the peak of 7.07 degree;

(i) described cocrystallization is a Provigil: 2, and 5-resorcylic acid cocrystallization and described X-ray diffractogram are included in the peak of 16.03 degree;

(j) described cocrystallization is a Provigil: 2, and 5-resorcylic acid cocrystallization and described X-ray diffractogram are included in the peak of 7.07,9.07,16.03,18.39,21.27 and 23.57 degree; Or

(k) described cocrystallization is a Provigil: 2, and 5-resorcylic acid cocrystallization and described X-ray diffractogram are included in the peak of 7.51,12.31,14.09,16.03,17.63 and 23.57 degree.

77. the cocrystallization of claim 8, wherein cocrystallization characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described cocrystallization is a Provigil: pentanedioic acid cocrystallization and described X-ray diffractogram are included in the peak of 9.78,18.92 and 21.36 degree;

(b) described cocrystallization is a Provigil: pentanedioic acid cocrystallization and described X-ray diffractogram are included in the peak of 20.50,22.25 and 23.87 degree;

(c) described cocrystallization is a Provigil: pentanedioic acid cocrystallization and described X-ray diffractogram are included in the peak of 8.67,19.74 and 27.16 degree;

(d) described cocrystallization is a Provigil: pentanedioic acid cocrystallization and described X-ray diffractogram are included in the peak of 8.67 and 18.92 degree;

(e) described cocrystallization is a Provigil: pentanedioic acid cocrystallization and described X-ray diffractogram are included in the peak of 9.78 and 20.50 degree;

(f) described cocrystallization is a Provigil: pentanedioic acid cocrystallization and described X-ray diffractogram are included in the peak of 21.36 and 23.87 degree;

(g) described cocrystallization is a Provigil: pentanedioic acid cocrystallization and described X-ray diffractogram are included in the peak of 23.87 degree;

(h) described cocrystallization is a Provigil: pentanedioic acid cocrystallization and described X-ray diffractogram are included in the peak of 8.67 degree;

(i) described cocrystallization is a Provigil: pentanedioic acid cocrystallization and described X-ray diffractogram are included in the peak of 9.78 degree;

(j) described cocrystallization is a Provigil: pentanedioic acid cocrystallization and described X-ray diffractogram are included in the peak of 8.67,9.78,18.92,20.50 and 23.87 degree; Or

(k) described cocrystallization is a Provigil: pentanedioic acid cocrystallization and described X-ray diffractogram are included in the peak of 18.92,20.50,21.36,22.25 and 23.87 degree.

78. the cocrystallization of claim 8, wherein cocrystallization characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described cocrystallization is a Provigil: citric acid cocrystallization and described X-ray diffractogram are included in the peak of 7.06,9.10 and 17.95 degree;

(b) described cocrystallization is a Provigil: citric acid cocrystallization and described X-ray diffractogram are included in the peak of 12.43,13.18 and 20.85 degree;

(c) described cocrystallization is a Provigil: citric acid cocrystallization and described X-ray diffractogram are included in the peak of 5.23,7.06 and 9.10 degree;

(d) described cocrystallization is a Provigil: citric acid cocrystallization and described X-ray diffractogram are included in the peak of 5.23 and 12.43 degree;

(e) described cocrystallization is a Provigil: citric acid cocrystallization and described X-ray diffractogram are included in the peak of 9.10 and 17.95 degree;

(f) described cocrystallization is a Provigil: citric acid cocrystallization and described X-ray diffractogram are included in the peak of 9.10 and 12.43 degree;

(g) described cocrystallization is a Provigil: citric acid cocrystallization and described X-ray diffractogram are included in the peak of 7.06 degree;

(h) described cocrystallization is a Provigil: citric acid cocrystallization and described X-ray diffractogram are included in the peak of 9.10 degree;

(i) described cocrystallization is a Provigil: citric acid cocrystallization and described X-ray diffractogram are included in the peak of 17.95 degree;

(j) described cocrystallization is a Provigil: citric acid cocrystallization and described X-ray diffractogram are included in the peak of 7.06,12.43,13.18,17.95 and 20.85 degree; Or

(k) described cocrystallization is a Provigil: citric acid cocrystallization and described X-ray diffractogram are included in the peak of 7.06,9.10,17.95,21.39 and 22.96 degree.

79. the cocrystallization of claim 8, wherein cocrystallization characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described cocrystallization is a Provigil: L-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 4.56,10.33 and 17.29 degree;

(b) described cocrystallization is a Provigil: L-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 17.29,19.91 and 21.13 degree;

(c) described cocrystallization is a Provigil: L-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 4.56,14.45 and 19.91 degree;

(d) described cocrystallization is a Provigil: L-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 4.56 and 10.33 degree;

(e) described cocrystallization is a Provigil: L-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 17.29 and 19.91 degree;

(f) described cocrystallization is a Provigil: L-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 19.91 and 21.13 degree;

(g) described cocrystallization is a Provigil: L-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 4.56 degree;

(h) described cocrystallization is a Provigil: L-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 10.33 degree;

(i) described cocrystallization is a Provigil: L-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 19.91 degree; Or

(j) described cocrystallization is a Provigil: L-tartrate cocrystallization and described X-ray diffractogram are included in the peak of 4.56,10.33,17.29,19.91 and 21.13 degree.

80. the cocrystallization of claim 8, wherein cocrystallization characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described cocrystallization is a Provigil: oxalic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.99,14.73 and 17.38 degree;

(b) described cocrystallization is a Provigil: oxalic acid cocrystallization and described X-ray diffractogram are included in the peak of 17.38,18.64 and 28.85 degree;

(c) described cocrystallization is a Provigil: oxalic acid cocrystallization and described X-ray diffractogram are included in the peak of 14.73,18.64 and 25.66 degree;

(d) described cocrystallization is a Provigil: oxalic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.99 and 14.73 degree;

(e) described cocrystallization is a Provigil: oxalic acid cocrystallization and described X-ray diffractogram are included in the peak of 17.38 and 18.64 degree;

(f) described cocrystallization is a Provigil: oxalic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.99 and 28.85 degree;

(g) described cocrystallization is a Provigil: oxalic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.99 degree;

(h) described cocrystallization is a Provigil: oxalic acid cocrystallization and described X-ray diffractogram are included in the peak of 14.73 degree;

(i) described cocrystallization is a Provigil: oxalic acid cocrystallization and described X-ray diffractogram are included in the peak of 28.85 degree; Or

(j) described cocrystallization is a Provigil: oxalic acid cocrystallization and described X-ray diffractogram are included in the peak of 5.99,14.73,17.38,18.64 and 28.85 degree.

81. the cocrystallization of claim 8, wherein cocrystallization characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described cocrystallization is a Provigil: palmitinic acid cocrystallization and described X-ray diffractogram are included in the peak of 3.80,6.55 and 7.66 degree;

(b) described cocrystallization is a Provigil: palmitinic acid cocrystallization and described X-ray diffractogram are included in the peak of 10.24,19.48 and 21.09 degree;

(c) described cocrystallization is a Provigil: palmitinic acid cocrystallization and described X-ray diffractogram are included in the peak of 3.80,19.48 and 23.99 degree;

(d) described cocrystallization is a Provigil: palmitinic acid cocrystallization and described X-ray diffractogram are included in the peak of 3.80 and 6.55 degree;

(e) described cocrystallization is a Provigil: palmitinic acid cocrystallization and described X-ray diffractogram are included in the peak of 6.55 and 7.66 degree;

(f) described cocrystallization is a Provigil: palmitinic acid cocrystallization and described X-ray diffractogram are included in the peak of 19.48 and 23.99 degree;

(g) described cocrystallization is a Provigil: palmitinic acid cocrystallization and described X-ray diffractogram are included in the peak of 3.80 degree;

(h) described cocrystallization is a Provigil: palmitinic acid cocrystallization and described X-ray diffractogram are included in the peak of 6.55 degree;

(i) described cocrystallization is a Provigil: palmitinic acid cocrystallization and described X-ray diffractogram are included in the peak of 7.66 degree;

(j) described cocrystallization is a Provigil: palmitinic acid cocrystallization and described X-ray diffractogram are included in the peak of 3.80,7.66,10.24 and 19.48 degree; Or

(k) described cocrystallization is a Provigil: palmitinic acid cocrystallization and described X-ray diffractogram are included in the peak of 3.80,6.55,7.66,10.24,19.48 and 23.99 degree.

82. the cocrystallization of claim 8, wherein cocrystallization characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described cocrystallization is a Provigil: L-proline(Pro) cocrystallization and described X-ray diffractogram are included in the peak of 6.52,8.53 and 10.25 degree;

(b) described cocrystallization is a Provigil: L-proline(Pro) cocrystallization and described X-ray diffractogram are included in the peak of 19.06,22.75 and 25.08 degree;

(c) described cocrystallization is a Provigil: L-proline(Pro) cocrystallization and described X-ray diffractogram are included in the peak of 6.52,10.25 and 19.06 degree;

(d) described cocrystallization is a Provigil: L-proline(Pro) cocrystallization and described X-ray diffractogram are included in the peak of 6.52 and 8.53 degree;

(e) described cocrystallization is a Provigil: L-proline(Pro) cocrystallization and described X-ray diffractogram are included in the peak of 6.52 and 10.25 degree;

(f) described cocrystallization is a Provigil: L-proline(Pro) cocrystallization and described X-ray diffractogram are included in the peak of 19.06 and 22.29 degree;

(g) described cocrystallization is a Provigil: L-proline(Pro) cocrystallization and described X-ray diffractogram are included in the peak of 6.52 degree;

(h) described cocrystallization is a Provigil: L-proline(Pro) cocrystallization and described X-ray diffractogram are included in the peak of 8.53 degree;

(i) described cocrystallization is a Provigil: L-proline(Pro) cocrystallization and described X-ray diffractogram are included in the peak of 19.06 degree;

(j) described cocrystallization is a Provigil: L-proline(Pro) cocrystallization and described X-ray diffractogram are included in the peak of 6.52,10.25,19.06,22.75 and 25.08 degree; Or

(k) described cocrystallization is a Provigil: L-proline(Pro) cocrystallization and described X-ray diffractogram are included in the peak of 8.53,10.25,19.06,22.29 and 25.08 degree.

83. the cocrystallization of claim 8, wherein cocrystallization characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described cocrystallization is a Provigil: Whitfield's ointment cocrystallization and described X-ray diffractogram are included in the peak of 8.92,10.85 and 17.07 degree;

(b) described cocrystallization is a Provigil: Whitfield's ointment cocrystallization and described X-ray diffractogram are included in the peak of 12.18,21.24 and 23.32 degree;

(c) described cocrystallization is a Provigil: Whitfield's ointment cocrystallization and described X-ray diffractogram are included in the peak of 8.92,18.81 and 25.22 degree;

(d) described cocrystallization is a Provigil: Whitfield's ointment cocrystallization and described X-ray diffractogram are included in the peak of 8.92 and 10.85 degree;

(e) described cocrystallization is a Provigil: Whitfield's ointment cocrystallization and described X-ray diffractogram are included in the peak of 17.07 and 21.24 degree;

(f) described cocrystallization is a Provigil: Whitfield's ointment cocrystallization and described X-ray diffractogram are included in the peak of 23.32 and 25.22 degree;

(g) described cocrystallization is a Provigil: Whitfield's ointment cocrystallization and described X-ray diffractogram are included in the peak of 8.92 degree;

(h) described cocrystallization is a Provigil: Whitfield's ointment cocrystallization and described X-ray diffractogram are included in the peak of 10.85 degree;

(i) described cocrystallization is a Provigil: Whitfield's ointment cocrystallization and described X-ray diffractogram are included in the peak of 21.24 degree;

(j) described cocrystallization is a Provigil: Whitfield's ointment cocrystallization and described X-ray diffractogram are included in the peak of 8.92,12.18,17.07,21.24 and 23.32 degree; Or

(k) described cocrystallization is a Provigil: Whitfield's ointment cocrystallization and described X-ray diffractogram are included in the peak of 10.85,14.04,21.24 and 23.32 degree.

84. the cocrystallization of claim 8, wherein cocrystallization characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described cocrystallization is a Provigil: lauric acid cocrystallization and described X-ray diffractogram are included in the peak of 3.12,6.55 and 10.24 degree;

(b) described cocrystallization is a Provigil: lauric acid cocrystallization and described X-ray diffractogram are included in the peak of 6.55,13.97 and 17.62 degree;

(c) described cocrystallization is a Provigil: lauric acid cocrystallization and described X-ray diffractogram are included in the peak of 3.12,21.38 and 23.81 degree;

(d) described cocrystallization is a Provigil: lauric acid cocrystallization and described X-ray diffractogram are included in the peak of 3.12 and 6.55 degree;

(e) described cocrystallization is a Provigil: lauric acid cocrystallization and described X-ray diffractogram are included in the peak of 10.24 and 17.62 degree;

(f) described cocrystallization is a Provigil: lauric acid cocrystallization and described X-ray diffractogram are included in the peak of 21.38 and 23.81 degree;

(g) described cocrystallization is a Provigil: lauric acid cocrystallization and described X-ray diffractogram are included in the peak of 3.12 degree;

(h) described cocrystallization is a Provigil: lauric acid cocrystallization and described X-ray diffractogram are included in the peak of 6.55 degree;

(i) described cocrystallization is a Provigil: lauric acid cocrystallization and described X-ray diffractogram are included in the peak of 21.38 degree;

(j) described cocrystallization is a Provigil: lauric acid cocrystallization and described X-ray diffractogram are included in the peak of 3.12,10.24,16.40,19.02 and 21.38 degree; Or

(k) described cocrystallization is a Provigil: lauric acid cocrystallization and described X-ray diffractogram are included in the peak of 3.12,6.55,10.24,21.38 and 23.81 degree.

85. the cocrystallization of claim 8, wherein cocrystallization characterizes by the x-ray diffractogram of powder that comprises the peak of representing with 2 θ angles, wherein:

(a) described cocrystallization is a Provigil: L MALIC ACID cocrystallization and described X-ray diffractogram are included in the peak of 4.62,9.32 and 19.30 degree;

(b) described cocrystallization is a Provigil: L MALIC ACID cocrystallization and described X-ray diffractogram are included in the peak of 9.32,10.32 and 21.48 degree;

(c) described cocrystallization is a Provigil: L MALIC ACID cocrystallization and described X-ray diffractogram are included in the peak of 19.30,21.48 and 24.26 degree;

(d) described cocrystallization is a Provigil: L MALIC ACID cocrystallization and described X-ray diffractogram are included in the peak of 4.62 and 9.32 degree;

(e) described cocrystallization is a Provigil: L MALIC ACID cocrystallization and described X-ray diffractogram are included in the peak of 9.32 and 10.32 degree;

(f) described cocrystallization is a Provigil: L MALIC ACID cocrystallization and described X-ray diffractogram are included in the peak of 19.30 and 21.48 degree;

(g) described cocrystallization is a Provigil: L MALIC ACID cocrystallization and described X-ray diffractogram are included in the peak of 4.62 degree;

(h) described cocrystallization is a Provigil: L MALIC ACID cocrystallization and described X-ray diffractogram are included in the peak of 9.32 degree;

(i) described cocrystallization is a Provigil: L MALIC ACID cocrystallization and described X-ray diffractogram are included in the peak of 19.30 degree;

(j) described cocrystallization is a Provigil: L MALIC ACID cocrystallization and described X-ray diffractogram are included in the peak of 4.62,15.83,17.38,19.30 and 21.48 degree; Or

(k) described cocrystallization is a Provigil: L MALIC ACID cocrystallization and described X-ray diffractogram are included in the peak of 9.32,10.32,17.38,19.30,21.48 and 24.26 degree.