CN1874993A - Modafinil compositionsc - Google Patents
Modafinil compositionsc Download PDFInfo
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- CN1874993A CN1874993A CNA2004800319825A CN200480031982A CN1874993A CN 1874993 A CN1874993 A CN 1874993A CN A2004800319825 A CNA2004800319825 A CN A2004800319825A CN 200480031982 A CN200480031982 A CN 200480031982A CN 1874993 A CN1874993 A CN 1874993A
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- YFGHCGITMMYXAQ-UHFFFAOYSA-N 2-[(diphenylmethyl)sulfinyl]acetamide Chemical compound C=1C=CC=CC=1C(S(=O)CC(=O)N)C1=CC=CC=C1 YFGHCGITMMYXAQ-UHFFFAOYSA-N 0.000 title claims abstract description 962
- 229960001165 modafinil Drugs 0.000 title abstract description 11
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 165
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- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 121
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 claims description 121
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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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
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;
(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 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;
(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 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;
(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 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;
(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 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;
(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 aspect of the method, the invention provides the morphology methods that changes Provigil, this method 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 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
(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.
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;
(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.
In yet another aspect, the invention provides the method for producing pharmaceutical composition or medicine, this method 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 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 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 cocrystallization form thing and can form cocrystallization with different with (ii) compatible multiple different 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 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
(ii) separate and comprise that Provigil and cocrystallization form the cocrystallization of thing.
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;
(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 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
(d) separate the cocrystallization that comprises Provigil and cocrystallization formation thing.
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;
(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 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
(d) separate the cocrystallization that comprises Provigil and cocrystallization formation thing.
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;
(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 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
(d) separate the cocrystallization that comprises Provigil and cocrystallization formation thing.
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
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;
(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 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
(d) separate the cocrystallization that comprises Provigil and cocrystallization formation thing.
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
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;
(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 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
(d) separate the cocrystallization that comprises Provigil and cocrystallization formation thing.
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
In one aspect of the method, the invention provides the morphology methods that changes Provigil, this method 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 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
(d) separate the cocrystallization that comprises Provigil and cocrystallization formation thing.
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 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 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 |
Duration of contact (s) | 2.0 |
Frequency of | 10 |
Laser source wavelength (nm) | 785 |
Laser power (%) | 100 |
Iris shape | Pin hole |
Aperture scale (um) | 100 |
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 ℃.
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.
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) |
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 |
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 |
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 |
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 |
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 |
*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 |
**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 |
*=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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 |
| 2 | 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 |
Transformation period (hour) | 2.1±0.7 | 5.1±2.4 |
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.
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.
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 ℃.
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) | ||||||
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 |
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 |
%CV | 14.8 | 21.0 | 39.5 | 44.7 | 45.0 | 21.0 |
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.
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.
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
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
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) | |||||
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 |
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 |
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) |
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.
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.
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.
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.
Also carried out using acetone and the wet grinding that makes water, the both produces the formation of cocrystallization.
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.
Also carried out using acetone and the wet grinding that makes water, the both produces the formation of cocrystallization.
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.
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.
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.
Also carried out using the wet grinding of acetone and use methyl alcohol, the both produces the formation of cocrystallization.
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)
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.
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 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 | ||||||
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 |
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-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 |
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 | 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 |
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 |
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 | Carboxylic acid | Alcohol | Ketone | Mercaptan | Acid amides | Amine | Aniline | Phenol |
Table II
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-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 | |
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 | |
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 | |
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 | |
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 | |
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 | |
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 | ||||||||
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 | |
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-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 | |
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 | |
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 | |
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 | |
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 |
Table II
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-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 | ||
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 | ||
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 | ||
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 | ||
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 | ||
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 | ||
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 | |||||||||
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 | |||
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-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 | |||
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 | ||
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 | |||
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 | |||
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 |
Table II
Cocrystallization forms | |
1, the 5-naphthalene disulfonic acid | |
1-hydroxyl-2-naphthoic acid | |
1-hydroxyl-2-naphthoic acid | |
The 4-benzaminic acid | |
The 4-benzaminic acid | |
4-aminopyridine | |
4-aminopyridine | |
The 4-chlorobenzenesulfonic acid | |
4-ethoxyl phenenyl urea | Superoxide |
4-ethoxyl phenenyl urea | |
7-oxo-DHEA | |
7-oxo-DHEA | |
Acesulfame | |
Acesulfame | Superoxide |
Acetohydroxamic acid | Superoxide |
Acetohydroxamic acid | |
Acetohydroxamic acid | |
VITAMIN B4 | |
VITAMIN B4 | |
Hexanodioic acid | |
L-Ala | |
L-Ala | |
Zyloric | |
Zyloric | |
Arginine | |
Arginine | |
Xitix | |
Xitix | |
Xitix |
Table II
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 | 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 |
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 |
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 |
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 |
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 | |
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 |
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 |
Table II
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 | |
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 | ||||
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 | |
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 | |
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 | |
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 | ||
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 | |
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 |
Table II
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 | |
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 | ||||||||
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 | |
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 | |
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 | |
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 | ||||||||
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 | |
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 |
Table II
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 | ||
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 | ||||||||
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 | ||
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 | ||
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 | ||
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 | ||||||||
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 | ||
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 |
Table II
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 | |||
Aspartic acid | Carbamate | Imidazoles | BF4 | N-SO2 | Thiocarbamide | Iodine | |||
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 | |||
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 | 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 | |||
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 | |||
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 | |||
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 | |||
Tetrahydroxyadipic acid | Imidazoles | BF4 | |||||||
Chrysin | Carbamate | Imidazoles | BF4 | N-SO2 | Thiocarbamide | Iodine |
Table II
Cocrystallization forms thing | |
L-asparagine | |
L-asparagine | Superoxide |
L-asparagine | |
Aspartic acid | |
Aspartic acid | |
Phenylsulfonic acid | |
Phenylformic acid | |
Caffeine | |
Dextrocamphoric acid | |
Capric acid | |
Genistein | |
Genistein | |
Genistein | |
Styracin | |
Citric acid | |
Citric acid | |
The carat imidazoles | |
Cyclohexane sulfamic acid | |
Cyclohexane sulfamic acid | |
Halfcystine | |
Halfcystine | |
Halfcystine | |
N-methylsarcosine | |
N-methylsarcosine | |
D-ribose | |
D-ribose | |
Fumaric acid | |
Tetrahydroxyadipic acid | |
Tetrahydroxyadipic acid | |
Chrysin |
Table II
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
Imidazoles | Amine | Alcohol | Ketone | Mercaptan | Acid amides | Amine | Aniline | Phenol |
Table II
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 | |
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 | |
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 | |
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 | |
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 | |
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 | |
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 | |
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 | ||
Imidazoles | Phosphoric acid ester | Sulfuric ester | Sulfone | Nitric ether | Pyridine | Carboxilic acid | Metal | Aldehyde |
Table II
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 | ||
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 | |
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 | |
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 | |
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 | |
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 | |
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 | |
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 |
Imidazoles | Ester | Ether | Cyano group | Furans | Bromine | Chlorine | The S-heterocycle |
Table II
Cocrystallization forms thing | |||||||
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 | |||||
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 | |
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 | |
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 | |
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 | |
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 | |
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 | |||||||
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 | |||||||||
Chrysin | |||||||||
Chrysin | Phosphoric acid ester | Cyanamide | |||||||
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 | |||
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 | |||
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 | |||
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 | |||
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 | |||
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 | |||
Histidine | Carbamate | Imidazoles | BF4 | N-SO2 | Thiocarbamide | Iodine | |||
Histidine | |||||||||
Quinhydrones | Carbamate | Imidazoles | BF4 | N-SO2 | Thiocarbamide | Iodine | Epoxide | ||
Quinhydrones | |||||||||
Imidazoles | Carbamate | Imidazoles | BF4 | N-SO2 | Thiocarbamide | Iodine |
Table II
Cocrystallization forms | |
Chrysin | |
Chrysin | |
2, the 5- | |
2, the 5-protocatechuic acid | |
Glycosamine, the N-methyl | |
Glycosamine, the N-methyl | |
Glyconic acid | |
Glyconic acid | |
Glucosamine | |
Glucuronic acid | |
Glucuronic acid | |
Glucuronic acid | |
L-glutamic acid | |
L-glutamic acid | |
Glutamine | |
Glutamine | Superoxide |
Glutamine | |
Pentanedioic acid | |
The sheet propylhomoserin | |
Glycine | |
Oxyacetic acid | |
Oxyacetic acid | |
Urobenzoic acid | Superoxide |
Urobenzoic acid | |
Urobenzoic acid | |
Histidine | |
Histidine | |
Histidine | |
Quinhydrones | |
Quinhydrones | |
Imidazoles |
Table II
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 | |
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 | 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 |
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 |
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 |
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 | |
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 |
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 |
Two carbonaphthoic acids | Alcohol | Alcohol | Ketone | Mercaptan | Acid amides | Amine | Aniline | Phenol |
Two carbonaphthoic acids | Phenol | Amine | Ketone | Sulfoxide | N | Pyridine | Cyano group | Aldehyde |
Table II
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 | |
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 | 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 | |
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 | |
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 | |
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 | ||
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 | ||
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 | ||
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 |
Table II
Cocrystallization forms thing | ||||||||
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 | |
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 | |
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 | |
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 | |
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) | 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 | |
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 | |
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 |
Table II
Cocrystallization forms thing | |||||||
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 | |
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 | |
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 | |
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 | |
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) | 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 | |
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 | |
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 |
Table II
Cocrystallization forms thing | |||||||||
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 | |||
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 | |||
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 | |||
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 | |||
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) | 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 | |||
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 | |||
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 |
Table II
Cocrystallization forms thing | |
Ipriflavone | |
Ipriflavone | |
Isoleucine | |
Isoleucine | |
Lactobionic acid | |
Lactobionic acid | |
Lactobionic acid | |
Lauric acid | |
Leucine | |
Leucine | |
Methionin | |
Methionin | |
Toxilic acid | |
Oxysuccinic acid | |
Oxysuccinic acid | |
Propanedioic acid | |
Amygdalic acid | |
Amygdalic acid | |
Methionine(Met) | |
Methionine(Met) | |
Methionine(Met) | |
Niacinamide | |
Niacinamide | Superoxide |
Nicotinic acid | |
Nicotinic acid | |
Vitamin B13 | |
Vitamin B13 | Superoxide |
Oxalic acid | |
Palmitinic acid | |
Two carbonaphthoic acids | |
Two carbonaphthoic acids | |
Two carbonaphthoic acids |
Table II
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 |
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 |
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 | 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 |
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 |
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 | 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, 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 | |||||||||
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 | |
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 | ||||
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 | ||
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 | |
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 | ||
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 | |
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 |
Table II
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 | |
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 | |
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 | 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 | |
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 | ||
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 | ||||||||
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, 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 | |||||||
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 | |
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 | |||||||
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 | |
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 | |
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 | |||||
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 | |
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 |
Table II
Cocrystallization forms thing | |||||||||
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 | |||
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 | |||||||||
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 | |||
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 | |||
Quercetin | |||||||||
Quercetin | Phosphoric acid ester | Cyanamide | |||||||
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 | |||||||||
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, 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 | |
Phenylalanine | |
Phenylalanine | |
Piperazine | |
PROCAINE HCL, PHARMA GRADE | |
PROCAINE HCL, PHARMA GRADE | |
Proline(Pro) | |
Proline(Pro) | |
Tosic acid | |
Pyridoxylamine | |
Pyridoxylamine | |
Pyridoxylamine | |
Pyridoxol (4-Pvridoxic Acid) | |
Pyridoxol (4-Pvridoxic Acid) | |
Pyrrolidonecarboxylic acid | |
Pyrrolidonecarboxylic acid | Superoxide |
Quercetin | |
Quercetin | |
Quercetin | |
Trans-resveratrol | |
Trans-resveratrol | |
Asccharin | Superoxide |
Asccharin | |
Asccharin | |
Asccharin | |
Whitfield's ointment | |
Whitfield's ointment | |
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 | ||||||
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 |
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 |
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 |
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 |
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 | 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 |
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 | |||||||||
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 | |
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 | |
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 | |
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 | |
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 | |
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 | |
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 | ||||||||
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 | |
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 | |
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 | |
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 | |
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 | |
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 | |
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 | |||||||
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 | |
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 | |
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 | |
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 | |
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 | |
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 | |
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 | |||||||||
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 | ||
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 | |||
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 | ||
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 | |||
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 | 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 | |||
Vitamin K5 | Carbamate | Imidazoles | BF4 | N-SO2 | Thiocarbamide | Iodine | Epoxide | ||
Xylitol | Carbamate | Imidazoles | BF4 | N-SO2 | Thiocarbamide | Iodine | Epoxide | ||
Table II
Cocrystallization forms thing | |
Sebacic acid | |
Serine | |
Serine | |
Serine | |
Stearic acid | |
Succsinic acid | |
Tartrate | |
Threonine | |
Threonine | |
Threonine | |
Tris | |
Tris | |
Tryptophane | |
Tryptophane | |
Tryptophane | |
Tyrosine | |
Tyrosine | |
Tyrosine | |
Urea | |
Urea | |
Urea | Superoxide |
Xie Ansuan | |
Xie Ansuan | |
Vitamin K5 | |
Vitamin K5 | |
Xylitol | |
Table III
Table III
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 |
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 | |||
Thioketones | Sulfoxide | Oxo | Chlorine | Bromine | Fragrance | Alkene | Sulfone | Iodine | Azoxy | Potassium |
Table III
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 | |||||
Hydroxamic acid | ||||||||||
Superoxide | Sulphonamide | Aniline | ||||||||
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 | ||||||||||
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 | ||||||||||
Epoxide | ||||||||||
Thioesters | ||||||||||
Thioketones |
Table III
Functional group | ||||
Pyridine | ||||
Imidazoles | ||||
Hydroxamic acid | ||||
Superoxide | ||||
Epoxide | ||||
Thioesters | ||||
Thioketones |
Table III
Table III
Functional group | ||||||||||
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 |
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 | ||||||||||
Nitric ether | ||||||||||
Thiophosphatephosphorothioate-O | ||||||||||
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 | ||||||||||
Alcohol | Ester | Ether | Cyano group | Furans | Bromine | Chlorine | The S-heterocyclic radical | Pyridine | Cyano group |
Table III
Functional group | |||||||||||
Nitric ether | |||||||||||
Thiophosphatephosphorothioate-O | |||||||||||
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 | |||||||||||
Alcohol | The N-heterocyclic radical | Ketone | Phosphoric acid ester | Fluorine | Carbamate | Imidazoles | BF4 | Alkane | Fragrance | N-SO2 |
Table III
Functional group | ||||
Nitric ether | ||||
Thiophosphatephosphorothioate-O | ||||
Phosphoric acid ester | ||||
Ketone | Thiocarbamide | Iodine | ||
Aldehyde | Thiocarbamide | Iodine | Epoxide | |
Mercaptan | ||||
Alcohol | Thiocarbamide | Iodine | Epoxide |
Table III
Table III
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 |
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 |
Secondary amine | Phenol | Phosphoric acid ester | Sulfuric ester | Sulfone | Nitric ether | Pyridine | Fragrance | Carboxylic acid | Metal | Aldehyde |
Table III
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 |
Cyanamide | ||||||||||
Thiocyanic ester | ||||||||||
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 | |||||||||||
Thioether | Sulfuric ester | Sulfone | Alkane | Alcohol | Phosphoric acid ester | ||||||
Ether | Sulfuric ester | Sulfone | Alkane | Alcohol | Phosphoric acid ester | Cyanamide | |||||
Cyanamide | |||||||||||
Thiocyanic ester | |||||||||||
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 | ||||
Thioether | ||||
Ether | ||||
Cyanamide | ||||
Thiocyanic ester | ||||
SP2 amine | ||||
Primary amine | Thiocarbamide | Iodine | ||
Secondary amine | Thiocarbamide | Iodine |
Table III
Table III
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 |
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 |
Table III
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 | |
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 |
Table III
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 | |
Sulfonic acid | |||||||||||
Phospho acid | |||||||||||
Phosphonic acids | |||||||||||
Carboxylic acid | The N-heterocyclic radical | Ketone | Phosphoric acid ester | Fluorine | Carbamate | Imidazoles | BF4 | Alkane | Fragrance | N-SO2 |
Table III
Functional group | ||||
Tertiary amine | Thiocarbamide | Iodine | ||
Acid amides | Thiocarbamide | Iodine | Epoxide | Superoxide |
Sulfonic acid | ||||
Phospho acid | ||||
Phosphonic acids | ||||
Carboxylic acid | Thiocarbamide | Iodine |
Table III
Table III
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 |
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 |
Thiophene | CO |
Table III
Functional group | ||||||||||
Sulfuric ester | ||||||||||
Oxime | Aldehyde | Carboxylic acid | Bromine | Fragrance | Pyridine | BF4 | ||||
Nitrile | Aldehyde | Thioether | Pyridine | N-fragrance | Bromine | Ether | S-fragrance | Thiophene | ||
Diazonium | ||||||||||
Nitro | ||||||||||
The S-heterocycle | Carboxylic acid | Sodium | Cyano group | Chlorine | Furans | |||||
Thiophene |
Table III
Functional group | ||||||||||
Sulfuric ester | ||||||||||
Oxime | ||||||||||
Nitrile | ||||||||||
Diazonium | ||||||||||
Nitro | ||||||||||
The S-heterocycle | ||||||||||
Thiophene |
Table III
Functional group | ||||
Sulfuric ester | ||||
Oxime | ||||
Nitrile | ||||
Diazonium | ||||
Nitro | ||||
The S-heterocycle | ||||
Thiophene |
Table III
Table III
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 pyrroles | CO | Imidazoles | Pyridine | N-fragrance | Aldehyde | Carboxylic acid | Sulfuric ester | Chlorine | Bromine | Oxime |
Furans |
Table III
Functional group | ||||||||||
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 |
Table III
Functional group | ||||||||||
The N-heterocycle | ||||||||||
The O-heterocycle | ||||||||||
The pyrroles | ||||||||||
Furans |
Table III
Functional group | ||||
The N-heterocycle | ||||
The O-heterocycle | ||||
The pyrroles | ||||
Furans |
Claims (85)
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:
(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; 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;
(f) compare with Provigil, the bioavailability of cocrystallization increases; Or
(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:
(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: 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:
(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: 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:
(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 5.04,9.26 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:
(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: 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:
(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: 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:
(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, 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:
(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.
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:
(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 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:
(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 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:
(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 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:
(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 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:
(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 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.
Applications Claiming Priority (24)
Application Number | Priority Date | Filing Date | Title |
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US32777203A | 2003-09-04 | 2003-09-04 | |
US03/27772 | 2003-09-04 | ||
USUS03/27772 | 2003-09-04 | ||
US10/660,202 US7927613B2 (en) | 2002-02-15 | 2003-09-11 | Pharmaceutical co-crystal compositions |
US10/660,202 | 2003-09-11 | ||
US50820803P | 2003-10-02 | 2003-10-02 | |
US60/508,208 | 2003-10-02 | ||
US54275204P | 2004-02-06 | 2004-02-06 | |
US60/542,752 | 2004-02-06 | ||
US40628804A | 2004-02-26 | 2004-02-26 | |
USUS04/06288 | 2004-02-26 | ||
US04/06288 | 2004-02-26 | ||
US56041104P | 2004-04-06 | 2004-04-06 | |
US60/560,411 | 2004-04-06 | ||
US57341204P | 2004-05-21 | 2004-05-21 | |
US60/573,412 | 2004-05-21 | ||
US57917604P | 2004-06-12 | 2004-06-12 | |
US60/579,176 | 2004-06-12 | ||
US58199204P | 2004-06-22 | 2004-06-22 | |
US60/581,992 | 2004-06-22 | ||
US58675204P | 2004-07-09 | 2004-07-09 | |
US60/586,752 | 2004-07-09 | ||
US60/588,236 | 2004-07-15 | ||
PCT/US2004/029013 WO2005023198A2 (en) | 2003-09-04 | 2004-09-04 | Modafinil compositions |
Related Child Applications (1)
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CN2010102933664A Division CN101972240B (en) | 2003-09-04 | 2004-09-04 | Modafinil composition |
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CN1874993B CN1874993B (en) | 2010-12-08 |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102933205A (en) * | 2010-04-28 | 2013-02-13 | 诺弗米克斯有限公司 | Cilostazol cocrystals and compositions |
CN104557733A (en) * | 2015-01-05 | 2015-04-29 | 哈尔滨医科大学 | 5-fluorouracil pharmaceutical co-crystal using pyrazinamide as precursor as well as preparation method and application thereof |
CN104557732A (en) * | 2014-12-16 | 2015-04-29 | 哈尔滨医科大学 | 5-fluorouracil pharmaceutical co-crystal and preparation method and application thereof |
CN105541701A (en) * | 2015-12-11 | 2016-05-04 | 吉林大学珠海学院 | Pharmaceutical cocrystal of deferiprone with maleic acid as precursor, and preparation method thereof |
CN110204438A (en) * | 2019-06-10 | 2019-09-06 | 浙江科技学院 | A kind of separation method of succinic acid, glutaric acid |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7141555B2 (en) * | 2000-12-19 | 2006-11-28 | Cephalon, Inc. | Modafinil compound and cyclodextrin mixtures |
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102933205A (en) * | 2010-04-28 | 2013-02-13 | 诺弗米克斯有限公司 | Cilostazol cocrystals and compositions |
CN104557732A (en) * | 2014-12-16 | 2015-04-29 | 哈尔滨医科大学 | 5-fluorouracil pharmaceutical co-crystal and preparation method and application thereof |
CN104557733A (en) * | 2015-01-05 | 2015-04-29 | 哈尔滨医科大学 | 5-fluorouracil pharmaceutical co-crystal using pyrazinamide as precursor as well as preparation method and application thereof |
CN105541701A (en) * | 2015-12-11 | 2016-05-04 | 吉林大学珠海学院 | Pharmaceutical cocrystal of deferiprone with maleic acid as precursor, and preparation method thereof |
CN110204438A (en) * | 2019-06-10 | 2019-09-06 | 浙江科技学院 | A kind of separation method of succinic acid, glutaric acid |
CN110204438B (en) * | 2019-06-10 | 2021-10-22 | 浙江科技学院 | Method for separating succinic acid and glutaric acid |
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CN1874993B (en) | 2010-12-08 |
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