KR101184797B1 - Modafinil compositions - Google Patents

Abstract

Co-crystals and solvates of racemic, enantiomerically pure, and enantiomerically mixed modafinil were formed and some important physical properties were adjusted. The solubility, solubility, bioavailability, dose response and stability of modafinil can be adjusted to enhance efficacy in pharmaceutical compositions.

Modafinil, co-crystal, solvate, solubility, solubility, bioavailability, dose response, stability, pharmaceutical composition

Description

Modafinil compositions

Reference to Related Applications

This application is filed with US Patent Application No. 10 / 378,956, filed March 3, 2003; US Provisional Patent Application No. 60 / 463,962, filed April 18, 2003; / 451,213 filed Feb. 28, 2003, and US Patent Application No. 60 / 487,064, filed Jul. 11, 2003, filed International Patent Application PCT / US03 / 27772. (Filed September 4, 2003). U.S. Patent Application No. 10 / 378,956, filed Mar. 3, 2003, claims a right of provision of U.S. Provisional Patent Application No. 60 / 360,768, filed March 1,2002.

This application is also part of US patent application Ser. No. 10 / 660,202 (filed Sep. 11, 2003), which claims a right of international patent application PCT / US03 / 27772 (filed Sep. 4, 2003). It is a continuous application. U.S. Patent Application No. 10 / 660,202, filed Sep. 11, 2003, also discloses U.S. Provisional Patent Application No. 60 / 406,974, filed August 30,2002, U.S. Provisional Patent Application No. 60 / US Patent Application No. 10 / 232,589 (2002, filed May 15, 2002) and US Provisional Patent Application No. 60 / 356,764 (filed February 15, 2002). US Patent Application No. 10 / 637,829, filed Aug. 3, 2003, filed September 9, 2002, filed September 10,95,995, filed November 18,2002. Filed). U.S. Patent Application No. 10 / 660,202 (filed Sep. 11, 2003) also discloses U.S. Provisional Patent Application No. 60 / 463,962 (filed April 18, 2003), U.S. Provisional Patent Application No. 60 / 444,315 (filed Jan. 31, 2003), U.S. Provisional Patent Application No. 60 / 439,282 (filed Jan. 10, 2003) and U.S. Provisional Patent Application No. 60 / 384,152 (31 May 2002) US patent application Ser. No. 10 / 449,307, filed May 30, 2003, filed with an interest of date. U.S. Patent Application No. 10 / 660,202 (filed Sep. 11, 2003) is also a partial serial application of U.S. Patent Application No. 10 / 601,092 (filed June 20, 2003). U.S. Patent Application No. 10 / 660,202 (filed Sep. 11, 2003), U.S. Provisional Patent Application No. 60 / 451,213 (filed Feb. 28, 2003), U.S. Provisional Patent Application No. 60 / 463,962 US Patent Application No. 60 / 487,064, filed Jul. 11, 2003, filed April 18,2003.

This application also claims U.S. Provisional Patent Application No. 60 / 451,213 (filed Feb. 28, 2003), U.S. Provisional Patent Application No. 60 / 487,064 (filed July 11, 2003), International Patent Application PCT / US03 / 27772 (filed September 4, 2003), US Patent Application No. 10 / 660,202 (filed September 11, 2003), International Patent Application PCT / US03 / 06662 (March 2003) United States Provisional Patent Application 60 / 508,208 (filed October 2, 2003), United States Provisional Patent Application 60 / 542,752 (filed February 6, 2004), United States Provisional Patent Application No. 60 / 463,962 (filed April 18, 2003), U.S. Patent Application No. 10 / 449,307 (filed May 30, 2003), U.S. Provisional Patent Application No. 60 / 456,027 ( Filed March 18, 2003, US Patent Application No. 10 / 601,092 (filed June 20, 2003), International Patent Application PCT / US03 / 19574, filed June 20, 2003 And claims of international patent application PCT / US03 / 41273 (filed December 24, 2003). In International Patent Application No. PCT / US04 / 06288 (filed by February 26, dated 2004) it is part of the continuous application.

This application also discloses U.S. Provisional Patent Application No. 60 / 508,208 (filed Oct. 2, 2003), U.S. Provisional Patent Application No. 60 / 542,752 (filed February 6, 2004), U.S. Provisional Patent US 60 / 560,411 filed April 6, 2004 US Provisional Patent Application 60 / 573,412 filed May 21, 2004 US Provisional Patent Application 60 / 579,176 2004 U.S. Provisional Patent Application No. 60 / 581,992, filed Jun. 22, 2004, U.S. Provisional Patent Application No. 60 / 586,752, filed Jul. 9, 2004 ) And US Provisional Patent Application 60 / 588,236, filed Jul. 15, 2004.

All of the above-claimed applications are hereby incorporated by reference in their entirety.

The present invention relates to API-containing compositions, pharmaceutical compositions comprising such APIs, and methods for their preparation.

The active pharmaceutical ingredient (API or APIs) in the pharmaceutical composition can be prepared in a variety of different forms. Such APIs can be prepared to have a variety of different chemical forms, including chemical derivatives, solvates, hydrates, co-crystals or salts. The APIs can also be prepared to have different physical forms. For example, APIs may be amorphous, have different crystalline polymorphs, or may exist in different solvation or hydration states. By varying the form of an API, it is possible to change its physical properties. For example, crystalline polymorphs typically have different solubility so that thermodynamically more stable polymorphs are less soluble than thermodynamically less stable polymorphs. Pharmaceutical polymorphs may differ in characteristics such as shelf life, bioavailability, morphology, vapor pressure, density, color and compressibility. Thus, varying the crystalline state of an API is one of many ways to adjust its physical properties.

A new form of the APIs would be advantageous, especially with improved properties as oral formulations. Specifically, it is desirable to identify improved forms of APIs that exhibit significantly improved properties, including increased water solubility and increased stability. In addition, it is desirable to improve the manufacture or processability of pharmaceutical formulations. For example, acicular crystal form or appearance of APIs causes aggregation even in compositions in which the API is mixed with other materials, resulting in a non-uniform mixture. Needle-shaped forms may cause filtration problems. See Mirmehrabi et al. J. Pharm. Sci. Vol. 93, No. 7, pp. 1692-1700, 2004. It is also desirable to increase the rate of dissolution in API-containing pharmaceutical compositions in water, to increase the bioavailability of orally administered compositions and to initiate a therapeutic effect more quickly. In addition, when administered to a subject, it is possible to reach peak plasma levels more quickly, to maintain therapeutic plasma concentrations for longer periods of time, and to increase overall exposure compared to equivalent amounts of API in the form currently known. Some form of API is desired.

Modafinil, an API used to treat subjects with paroxysmal sleep symptoms, is practically insoluble in water. Modafinil (CAS Registry No. 68693-11-8) is represented by Formula I:

Modafinil is a chiral molecule due to chiral S═O groups. Thus, modafinil exists as two isomers, R-(-)-modafinil and S-(+)-modafinil. Particularly advantageous is a new form of modafinil with improved properties as an oral formulation. Specifically, it is desirable to identify improved forms of modafinil with significantly increased water solubility and significantly increased both chemical and morphological stability. It is also desirable to increase the dissolution rate of API-containing pharmaceutical compositions in water, to increase the bioavailability of orally administered compositions, and to initiate a therapeutic effect more quickly. In addition, when administered to a subject, compared to an equivalent amount of API in the form of the presently known form, it is possible to reach peak plasma levels more quickly and / or to maintain plasma concentrations for longer periods at higher doses and with greater overall exposure. Certain types of APIs are needed to build them.

Summary of the Invention

It has been found by the present invention that co-crystals and solvates of modafinil can be obtained which have a significant number of different properties compared to the free form API.

Thus, in a first aspect the present invention provides co-crystals of modafinil, wherein the co-crystal formers are ethers, thioethers, alcohols, thiols, aldehydes, ketones, thioketones, nitrate esters, phosphate esters, thiophosphates Esters, esters, thioesters, sulfate esters, carboxylic acids, phosphonic acids, phosphinic acids, sulfonic acids, amides, primary amines, secondary amines, ammonia, tertiary amines, sp2 amines, thiocyanates, cyanamides, oximes , Nitrile, diazo, organohalide, nitro, S-heterocyclic ring, thiophene, N-heterocyclic ring, pyrrole, O-heterocyclic ring, furan, epoxide, hydroxamic acid, imidazole or Pyridine.

The invention further provides pharmaceutical compositions comprising co-crystals of modafinil. Typically, such pharmaceutical compositions further comprise one or more pharmaceutically acceptable carriers, diluents or excipients. Pharmaceutical compositions according to the invention are described in further detail below.

In a further aspect, the invention

(a) providing modafinil;

(b) providing a co-crystal former that is compatible with the functional group of modafinil, such that the co-crystal former and modafinil can form a co-crystal;

(c) polishing, heating, co-subliming, co-melting or contacting modafinil in solution with a co-crystal former under crystallization conditions to form a solid phase; And

(d) separating the co-crystals comprising modafinil and a co-crystal former

It provides a method of producing a co-crystal of modafinil, comprising.

In one embodiment, the co-crystal former is ether, thioether, alcohol, thiol, aldehyde, ketone, thioketone, nitrate ester, phosphate ester, thiophosphate ester, ester, thioester, sulfate ester, carboxylic acid, phosphonic acid , Phosphinic acid, sulfonic acid, amide, primary amine, secondary amine, ammonia, tertiary amine, sp2 amine, thiocyanate, cyanamide, oxime, nitrile, diazo, organohalide, nitro, S-heterocyclo It has at least one functional group selected from the group consisting of a click ring, thiophene, N-heterocyclic ring, pyrrole, O-heterocyclic ring, furan, epoxide, hydroxamic acid, imidazole or pyridine.

Embodiments of the invention, including but not limited to co-crystals, polymorphs, and solvates, include racemic modafinil, enantiomerically pure modafinil (ie, R-(-)-modafinil or S-(+ ) -Modafinil), or enhanced modafinil (eg, about 55 to about 90% ee). Similarly, co-crystal formers and solvent molecules (eg, in solvates) may be present in racemic, enantiomerically pure, or enhanced forms in embodiments of the present invention.

In a further aspect, the invention

(a) providing modafinil;

(b) providing a co-crystal former that is compatible with the functional group of modafinil, such that the co-crystal former and modafinil can form a co-crystal;

(c) polishing, heating, co-subliming, co-melting or contacting modafinil in solution with a co-crystal former under crystallization conditions to form a solid phase; And

(d) separating the co-crystals comprising modafinil and a co-crystal former

It provides a method of increasing the solubility of modafinil in water, simulated gastric juice (SGF) or simulated serous (SIF) for use in pharmaceutical compositions or drugs.

In a further aspect, the invention

(a) providing modafinil;

(b) providing a co-crystal former that is compatible with the functional group of modafinil, such that the co-crystal former and modafinil can form a co-crystal;

(c) polishing, heating, co-subliming, co-melting or contacting modafinil in solution with a co-crystal former under crystallization conditions to form a solid phase; And

(d) separating the co-crystals comprising modafinil and a co-crystal former

It provides a method of adjusting the solubility of modafinil, comprising: increasing the rate of dissolution or increasing the rate of dissolution in simulated gastric juice or simulated intestinal fluid, or in a solvent or a plurality of solvents.

In a further aspect, the invention

(a) providing modafinil;

(b) providing a co-crystal former that is compatible with the functional group of modafinil, such that the co-crystal former and modafinil can form a co-crystal;

(c) polishing, heating, co-subliming, co-melting or contacting modafinil in solution with a co-crystal former under crystallization conditions to form a solid phase; And

(d) separating the co-crystals comprising modafinil and a co-crystal former

By adjusting the bioavailability of modafinil, increasing the AUC, shortening the T _max time, increasing the time at which the concentration of modafinil is greater than or equal to 1/2 T _max , or C Provides a way to increase _max .

In a further aspect, the invention

(a) providing modafinil;

(b) providing a co-crystal former that is compatible with the functional group of modafinil, such that the co-crystal former and modafinil can form a co-crystal;

(c) polishing, heating, co-subliming, co-melting or contacting modafinil in solution with a co-crystal former under crystallization conditions to form a solid phase; And

(d) separating the co-crystals comprising modafinil and a co-crystal former

It provides a method of modulating the dose response of modafinil for use in a pharmaceutical composition or drug, comprising.

In a further aspect, the present invention also provides

(a) providing modafinil;

(b) providing a co-crystal former that is compatible with the functional group of modafinil, such that the co-crystal former and modafinil can form a co-crystal;

(c) polishing, heating, co-subliming, co-melting or contacting modafinil in solution with a co-crystal former under crystallization conditions to form a solid phase; And

(d) separating the co-crystals comprising modafinil and a co-crystal former

A method of improving the stability of modafinil (compared to a reference form, such as the free form of modafinil), is provided.

In a further aspect, the present invention

(a) providing modafinil;

(b) providing a co-crystal former that is compatible with the functional group of modafinil, such that the co-crystal former and modafinil can form a co-crystal;

(c) polishing, heating, co-subliming, co-melting or contacting modafinil in solution with a co-crystal former under crystallization conditions to form a solid phase; And

(d) separating the co-crystals comprising modafinil and a co-crystal former

It provides a method of modifying the form of modafinil, including.

In a further aspect, the present invention

(a) providing a co-crystal former ( ii ) that is compatible with the functional groups of modafinil ( i ) and modafinil, such that the co-crystal former and modafinil can form co-crystals; And

(b) for each combination of modafinil and co-crystal former,

  (i) grinding, heating, co-subliming, co-melting or contacting modafinil in solution with a co-crystal former under crystallization conditions to form a solid phase; And

  (ii) separating co-crystals comprising modafinil and a co-crystal former

Screening for co-crystals of modafinil with a co-crystal former

It provides a method for screening for a co-crystal compound, including.

Another aspect is

(a) providing a plurality of different co-crystal formers ( ii ) that are compatible with the functional groups of modafinil ( i ) and modafinil, so that each co-crystal former and modafinil can form co-crystals step; And

(b) for each combination of modafinil and co-crystal former,

  (i) the process of polishing, heating, co-subliming, co-melting or contacting modafinil in solution with a co-crystal former to form a solid phase; And

  (ii) separating co-crystals comprising modafinil and a co-crystal former

Screening for co-crystals of modafinil with a co-crystal former

It relates to a method for screening for a co-crystal compound, comprising.

In a further aspect, the present invention provides a co-crystal composition comprising co-crystals, which co-crystals include modafinil and a co-crystal former. In a further embodiment, the co-crystals have improved properties compared to free forms, including hydrates and solvates. In further embodiments, the improved properties are selected from the group consisting of increased solubility, increased solubility, increased bioavailability, increased dose response, or other properties described herein.

In another embodiment, the present invention provides malonic acid, glycolic acid, fumaric acid, tartaric acid, citric acid, succinic acid, gentic acid, oxalic acid, 1-hydroxy-2-naphthoic acid, orotic acid, glutaric acid, L-tartaric acid, palmaric acid. Co-crystals comprising modafinil and a co-crystal former selected from the group consisting of mitic acid, L-proline, salicylic acid, lauric acid, L-malic acid and maleic acid are provided.

In a further aspect, the present invention provides the following co-crystals: modafinil: malonic acid, modafinil: glycolic acid, modafinil: maleic acid, modafinil: L-tartaric acid, modafinil: citric acid, modafinil: succinic acid , Modafinil: DL-tartaric acid, modafinil: fumaric acid (form I), modafinil: fumaric acid (form II), modafinil: gentisic acid, modafinil: oxalic acid, modafinil: 1-hydroxy-2-naphthoic acid , R-(-)-modafinil: malonic acid, R-(-)-modafinil: succinic acid, R-(-)-modafinil: citric acid, R-(-)-modafinil: DL-tartaric acid, R- (-)-Modafinil: 1-hydroxy-2-naphthoic acid, R-(-)-modafinil: orotic acid, R-(-)-modafinil: glutaric acid, R-(-)-moda Finyl: L-tartaric acid, R-(-)-modafinil: palmitic acid, R-(-)-modafinil: L-proline, R-(-)-modafinil: salicylic acid, R-(-)-moda Finyl: lauric acid, R-(-)-modafinil: L-malic acid, and R-(-)-modafinil: gentisic acid.

In another embodiment, the present invention provides novel polymorphs or co-crystals of racemic modafinil (form VII).

In another embodiment, the present invention provides the following modafinil solvates: acetic acid, tetrahydrofuran, 1,4-dioxane, methanol, nitromethane, acetone, o-xylene, benzene, ethanol, benzyl alcohol, isopropanol, Acetonitrile and toluene.

The method according to the invention may each comprise additional step (s) of incorporating the modafinil co-crystals thus prepared into the pharmaceutical composition.

In another embodiment, the pharmaceutical composition comprises a modified release profile of one or more of racemic modafinil, R-(-)-modafinil and S-(+)-modafinil. Such a modified release profile may include, for example, two or more plasma concentration maximums, such as a dual-release profile.

The present invention further provides a drug comprising a co-crystal of modafinil; And methods for producing the same. Typically, the drug further comprises one or more pharmaceutically acceptable carriers, diluents or excipients. The drugs according to the invention are described in further detail below.

The method according to the invention may each comprise additional step (s) of incorporating the modafinil co-crystals thus prepared into the drug.

In a further aspect of the invention, modafinil is an active pharmaceutical agent for the following diseases: excessive daytime sleepiness associated with paroxysmal sleep, multiple sclerosis related fatigue, infertility, eating disorders, attention deficit hyperactivity disorder (ADHD), Parkinson's disease ( Parkinson's disease), incontinence, sleep apnea or myopathy, a method for treating a subject, preferably a human subject. Such methods include administering to the subject a therapeutically effective amount of a co-crystal or solvate comprising modafinil or a polymorph of modafinil.

1 is a PXRD diffractogram of a co-crystal comprising modafinil and malonic acid.

2 is a DSC thermogram of a co-crystal comprising modafinil and malonic acid.

3 is a TGA thermogram of co-crystals comprising modafinil and malonic acid.

4A and 4B show Raman spectra of co-crystals including modafinil and malonic acid (FIG. 4A), and modafinil (bottom spectrum), malonic acid (middle spectrum) and modafinil and malonic acid Three Raman spectra of the co-crystal (upper spectrum) (FIG. 4B).

5A and 5B show infrared spectra of co-crystals including modafinil and malonic acid (FIG. 5A), and co-crystals including modafinil (top spectrum), malonic acid (middle spectrum) and modafinil and malonic acid. Three infrared spectra of the (bottom spectrum) (FIG. 5B).

6A is a PXRD diffractogram of co-crystals comprising modafinil and malonic acid.

6B is a DSC thermogram of co-crystals (obtained by polishing) comprising modafinil and malonic acid.

7 is a packing diagram for modafinil: malonic acid co-crystal.

8A and 8B are PXRD diffractograms of co-crystals including modafinil and glycolic acid, respectively, as background removed and collected.

9A and 9B are PXRD diffractograms of co-crystals including modafinil and maleic acid, respectively, as background removed and collected.

10 is a PXRD diffractogram of co-crystals comprising modafinil and L-tartaric acid.

FIG. 11A is a PXRD diffractogram of a co-crystal comprising modafinil and citric acid. FIG.

FIG. 11B is a DSC thermogram of co-crystals comprising modafinil and citric acid. FIG.

12A and 12B are PXRD diffractograms of co-crystals including modafinil and succinic acid, respectively, as background removed and collected.

FIG. 13 is a DSC thermogram of co-crystals comprising modafinil and succinic acid. FIG.

14 is a packing diagram of co-crystals comprising modafinil and succinic acid.

FIG. 15 is a PXRD diffractogram of co-crystals comprising modafinil and DL-tartaric acid. FIG.

FIG. 16 is a PXRD diffractogram of co-crystals comprising modafinil and fumaric acid (form I). FIG.

FIG. 17 is a co-crystal packing diagram comprising modafinil and fumaric acid (form I). FIG.

FIG. 18 is a PXRD diffractogram of co-crystals comprising modafinil and fumaric acid (form II). FIG.

FIG. 19 is a PXRD diffractogram of co-crystals comprising modafinil and gentisinic acid. FIG.

20 is a PXRD diffractogram of co-crystals including modafinil and oxalic acid.

FIG. 21 is a PXRD diffractogram of a co-crystal comprising modafinil and 1-hydroxy-2-naphthoic acid. FIG.

22 is a PXRD diffractogram of a co-crystal comprising R-(-)-modafinil and malonic acid.

FIG. 23 is a DSC thermogram of a co-crystal comprising R-(-)-modafinil and malonic acid. FIG.

24 is a PXRD diffractogram of a co-crystal comprising R-(-)-modafinil and succinic acid.

FIG. 25 is a DSC thermogram of a co-crystal comprising R-(-)-modafinil and succinic acid. FIG.

FIG. 26 is a PXRD diffractogram of a co-crystal comprising R-(-)-modafinil and citric acid. FIG.

FIG. 27 is a DSC thermogram of a co-crystal comprising R-(-)-modafinil and citric acid. FIG.

FIG. 28 is a PXRD diffractogram of a co-crystal comprising R-(-)-modafinil and DL-tartaric acid. FIG.

29 is a DSC thermogram of co-crystals comprising R-(-)-modafinil and DL-tartaric acid.

30 is a PXRD diffractogram of a co-crystal comprising R-(-)-modafinil and 1-hydroxy-2-naphthoic acid.

FIG. 31 is a DSC thermogram of co-crystals comprising R-(-)-modafinil and 1-hydroxy-2-naphthoic acid. FIG.

32 is a PXRD diffractogram of co-crystals comprising R-(-)-modafinil and 1-hydroxy-2-naphthoic acid obtained from high throughput experiments.

FIG. 33 is a PXRD diffractogram of a co-crystal comprising R-(-)-modafinil and orotic acid. FIG.

FIG. 34 is a DSC thermogram of co-crystal comprising R-(-)-modafinil and orotic acid. FIG.

FIG. 35 is a PXRD diffractogram of a solvate comprising modafinil and acetic acid. FIG.

36 is a TGA thermogram of solvate containing modafinil and acetic acid.

FIG. 37 is a DSC thermogram of solvate containing modafinil and acetic acid. FIG.

38 is a Raman spectrum of a solvate containing modafinil and acetic acid.

FIG. 39 is a PXRD diffractogram of a solvate comprising modafinil and tetrahydrofuran. FIG.

40 is a PXRD diffractogram of a solvate comprising modafinil and 1,4-dioxane.

Fig. 41 is a PXRD diffractogram of a solvate containing modafinil and methanol.

FIG. 42 is a TGA thermogram of solvate comprising modafinil and methanol. FIG.

43 is a DSC thermogram of solvate containing modafinil and methanol.

FIG. 44 is a PXRD diffractogram of a solvate comprising modafinil and nitromethane. FIG.

45 is a PXRD diffractogram of the solvate comprising modafinil and acetone.

46 is a PXRD diffractogram of a possible solvate comprising modafinil and acetone.

FIG. 47 is a PXRD diffractogram of possible solvates including modafinil and 1,2-dichloroethane.

FIG. 48 is a PXRD diffractogram of the polymorph (mod VII) of modafinil.

FIG. 49 is a stability plot of modafinil: malonic acid co-crystals over 26 weeks.

50 is a closer look at the stability plot of modafinil: malonic acid co-crystals over 26 weeks.

FIG. 51 compares the PXRD diffractograms of modafinil: malonic acid co-crystals after withstanding some environmental conditions.

FIG. 52 is a solubility profile of several formulations of modafinil free form and modafinil: malonic acid.

FIG. 53 is an in vitro solubility profile of modafinil: malonic acid co-crystals in SGF and SIF.

FIG. 54 is an in vitro solubility profile of modafinil: malonic acid co-crystal in HCl.

Figure 55 is a DVS plot of modafinil: malonic acid co-crystal.

56 is pharmacokinetics of modafinil: malonic acid co-crystals from dogs.

FIG. 57 is a PXRD diffractogram of a co-crystal comprising R-(-)-modafinil and gentisic acid. FIG.

FIG. 58 is a packing diagram of acetone channel solvate of modafinil.

59 is an additional packing diagram of acetone channel solvate of modafinil.

60 is a PXRD diffractogram of o-xylene solvate.

FIG. 61 is Raman spectrum (middle spectrum) of o-xylene solvate.

62 is a TGA thermogram of o-xylene solvate.

63 is a DSC thermogram of o-xylene solvate.

64 is a PXRD diffractogram of a benzene solvate.

65 is Raman spectrum (medium spectrum) of benzene solvate.

66 is a TGA thermogram of benzene solvate.

67 is a DSC thermogram of benzene solvate.

Fig. 68 is a PXRD diffractogram of toluene solvate.

69 is a Raman spectrum (medium spectrum) of toluene solvate.

70 is a TGA thermogram of toluene solvate.

71 is a DSC thermogram of toluene solvate.

72 is a PXRD diffractogram of R-(-)-modafinil ethanol solvate.

73 is a TGA thermogram of R-(-)-modafinil ethanol solvate.

74 is a PXRD diffractogram of the R-(-)-modafinil benzyl alcohol solvate.

FIG. 75 is a DSC thermogram of R-(-)-modafinil benzyl alcohol solvate.

FIG. 76 is a TGA thermogram of R-(-)-modafinil benzyl alcohol solvate.

FIG. 77 is a PXRD diffractogram of the R-(-)-modafinil isopropanol solvate.

78 is a PXRD diffractogram of the R-(-)-modafinil acetonitrile solvate.

79 is a PXRD diffractogram of the R-(-)-modafinil: glutaric acid co-crystal.

80 is a PXRD diffractogram of the R-(-)-modafinil: citric acid co-crystal.

FIG. 81 is a PXRD diffractogram of an R-(-)-modafinil: L-tartaric acid co-crystal.

82A and 82B are PXRD diffractograms of R-(-)-modafinil: oxalic acid co-crystal.

83 is a PXRD diffractogram of the R-(-)-modafinil: palmitic acid co-crystal.

84 is a PXRD diffractogram of the R-(-)-modafinil: L-proline co-crystal.

FIG. 85 is a PXRD diffractogram of an R-(-)-modafinil: salicylic acid co-crystal.

86 is a PXRD diffractogram of an R-(-)-modafinil: lauric acid co-crystal.

87 is a PXRD diffractogram of an R-(-)-modafinil: L-malic acid co-crystal.

Since the structure of modafinil includes a stereocenter, it may be present in any ratio of racemate, one of two pure isomers, or two isomeric pairs. The chemical name of racemic modafinil is (±) -2-[(diphenylmethyl) sulfinyl] acetamide. The isomeric pairs of racemic modafinil are R-(-)-2-[(diphenylmethyl) sulfinyl] acetamide or R-(-)-modafinil and S-(+)-2-[(diphenyl Methyl) sulfinyl] acetamide or S-(+)-modafinil.

As used herein and unless otherwise defined, the term “enantiomerically pure” includes compositions that are substantially enantiomerically pure, including, for example, about 90, 91, 92, 93, 94 Compositions with at least 95, 96, 97, 98 or 99% enantiomeric excess. Enantiomeric excess is defined as% enantiomer A-% enantiomer B, or as the following spin equation: ee% = 100 * ([R]-[S] / ([R] + [S]) [Where R is a mole of R-(-)-modafinil and S is a mole of S-(+)-modafinil].

As used herein, the term “modafinil” includes racemates, other mixtures of R- and S-isomers, and single enantiomers, but specifically racemates, R-isomers, S-isomers, or It can be described as all mixtures of both R- and S-isomers.

As used herein and unless otherwise defined, the term "racemic co-crystal" refers to a co-crystal consisting of an equimolar mixture of modafinil enantiomers, co-crystal formers, or both. For example, a co-crystal comprising modafinil and a non-stereomeric co-crystal former is a "racemic co-crystal" only when an equimolar mixture of modafinil enantiomers is present. Similarly, a co-crystal comprising modafinil and a stereoisomeric co-crystal former is a "racemic co-crystal" only if an equimolar mixture of modafinil enantiomer and an equimolar mixture of co-crystal former enantiomer are present. Decision ".

 As used herein and unless otherwise defined, the term "enantiomerically pure co-crystal" refers to a co-crystal composed of modafinil and a stereoisomer or non-stereoisomer co-crystal former, wherein the stereo Enantiomeric excess of the adult species is at least about 90% ee (enantiomeric excess).

As used herein, the term “co-crystal” refers to a crystalline material composed of two or more unique solids under room temperature (22 ° C.), each containing unique physical characteristics such as structure, melting point and heat of fusion. Except where specifically stated that the API may be a liquid at room temperature. Co-crystals of the present invention include co-crystal formers or derivatives thereof H-linked to modafinil. Co-crystal formers may be H-linked directly to modafinil or may be H-linked to additional molecules that are bound to modafinil. Such additional molecules may be H-linked to modafinil or may be ionically bound to modafinil. The additional molecule may be a different API. Solvates of modafinil compounds that do not further comprise a co-crystal former are not co-crystals according to the present invention. However, co-crystals may include one or more solvate molecules of the crystalline lattice. That is, a co-crystal, or co-crystal solvate, which further comprises a compound or solvent that is liquid at room temperature, is a co-crystal according to the invention, but a crystal consisting only of modafinil and one or more liquids (at room temperature) Sex materials are not co-crystals for the purposes of the present invention. Other molecular recognition methods may also exist, including pi-lamination, guest-host complexation, and van der Waals interactions. Among the above-listed interactions, since hydrogen bonds are the predominant interactions in the formation of co-crystals and are the interactions required in accordance with the present invention, there is a non- Covalent bonds are formed. Due to the hydrogen bonding, several different intermolecular conformations can occur. For example, hydrogen bonds can form dimers, linear chains, or cyclic structures. These conformations may further include triads separated from the extended (two-dimensional) hydrogen bonding network (network). Another embodiment provides co-crystals wherein the co-crystal former is a second API. In another embodiment, the co-crystal former is not an API.

For the purposes of the present invention, the chemical and physical properties of modafinil in the co-crystal form can be compared with reference compounds that are modafinil in different forms. Such a reference compound may be specified (specified) as a free form, or more specifically, may be an anhydride or a hydrate in free form, or more specifically, for example, a free form hemihydrate, monohydrate, dihydrate, trihydrate It may be a cargo, tetrahydrate, pentahydrate or solvate. For example, the reference compound for the free form of modafinil with the co-crystal former may be free form modafinil. Reference compounds may be specified as crystalline or amorphous. The reference compound may also be embodied as a polymorph known to be the most stable of the reference compounds of the type specified above.

The ratio of modafinil to co-crystal former may be stoichiometric or non-stoichiometric in accordance with the present invention. Non-limiting examples such as 1: 1, 1: 1.5, 1.5: 1, 1: 2 and 2: 1 ratios of modafinil: co-crystal formers are acceptable. Also included in the present invention are co-crystals with spaces in the crystalline lattice. For example, about 0.01, 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 in the crystalline lattice. Or co-crystals with up to 20% space are included in the present invention. These spaces may be due to lack of modafinil molecules from the crystalline lattice, lack of co-crystal formers, or both.

Surprisingly, where modafinil and selected co-crystal formers can form co-crystals, the co-crystals produced thereby are often compared to the free form of modafinil, especially in the following aspects, with improved properties of modafinil Has been found to cause: solubility, solubility, bioavailability, stability, C _max , T _max , processability (including compressibility), longer lasting therapeutic plasma concentrations, and the like. For example, because of the low solubility of modafinil in water, the co-crystal form of modafinil is particularly advantageous. In addition, the co-crystal properties conferred on modafinil are also useful because they can improve the bioavailability of modafinil and improve plasma and / or serum concentration of modafinil. This is particularly advantageous for oral-administrable formulations. Moreover, the dose response of modafinil can be improved by, for example, increasing the potency of modafinil and / or increasing the maximum obtainable response by increasing biological activity per dosage equivalent.

Thus, in a first aspect the invention provides that such modafinil and co-crystal former can be co-crystallized from solution phase under crystallization conditions or can be co-crystallized from a solid state, for example, by polishing or heating. Provided are pharmaceutical compositions (or drugs) comprising co-crystals of modafinil and a co-crystal former. In another aspect, the co-crystal former is ether, thioether, alcohol, thiol, aldehyde, ketone, thioketone, nitrate ester such that modafinil and the co-crystal former can be co-crystallized from solution phase under crystallization conditions. , Phosphate ester, thiophosphate ester, ester, thioester, sulfate ester, carboxylic acid, phosphonic acid, phosphinic acid, sulfonic acid, amide, primary amine, secondary amine, ammonia, tertiary amine, sp2 amine, thiosia Nate, Cyanamide, Oxime, Nitrile, Diazo, Organohalide, Nitro, S-Heterocyclic Ring, Thiophene, N-Heterocyclic Ring, Pyrrole, O-Heterocyclic Ring, Furan, Epoxide, Hydrate At least one functional group selected from the group consisting of loxamic acid, imidazole and pyridine, or a functional group in the table herein.

In another embodiment, an excess (greater than 1 molar equivalent of 1: 1 co-crystal) of co-crystal former can be used to drive the formation of stoichiometric co-crystals. For example, the amount of co-crystals is 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100 times greater than the stoichiometric amount for a given co-crystal. By adding a crystal former, co-crystals with stoichiometric ratios of 1: 1, 2: 1 or 1: 2 can be produced. The use of excess co-crystal formers as described above to form co-crystals can be used in solution or when grinding modafinil and co-crystal formers to cause co-crystal formation.

In another aspect of the invention, the modafinil co-crystal further comprises a co-crystal former which is hydrogen bonded via a desirable interaction between two or more functional groups. For example, modafinil and malonic acid are co-crystallized through the interaction between the carboxylic acid function of the co-crystal former and the sulfoxide and amide functional groups of modafinil.

In another aspect of the invention, the co-crystals comprise modafinil, which forms a dimeric primary amide structure via a hydrogen bond having a R ² ₂ (8) motif. See, eg, J. Bernstein, Polymorphism in Molecular Crystals , Oxford University Press, 2002, pp. 55-59, or MC Etter, Acct. Chem. Res., 1990, 23, 120, or MC Etter, J. Phys. Chem., 1991, 95, 4601. In this structure, the NH ₂ moiety may participate in hydrogen bonding with, for example, a donor or acceptor moiety from a co-crystal former or an additional (third) molecule, and the C═O moiety forms a co-crystal formation. It may participate in hydrogen bonding with donor moieties from the agent or additional molecule. In a further embodiment, the dimeric primary amide structure (formed by two modafinil molecules) is derived from one, two, three or four hydrogen bond donors (one, two, three, or four co-crystal formers). It further includes). In a further embodiment, the dimeric primary amide structure further comprises one or two hydrogen bond acceptors (derived from one or two co-crystal formers). In a further embodiment, the dimeric primary amide structure further comprises a combination of hydrogen bond donor and acceptor. For example, the dimeric primary amide structure may have one hydrogen bond donor and one hydrogen bond acceptor, one hydrogen bond donor and two hydrogen bond acceptors, two hydrogen bond donors and one hydrogen bond acceptor, and two hydrogen bonds. It may further comprise a binding donor and two hydrogen bond acceptors, or three hydrogen bond donors and a hydrogen bond acceptor.

Co-crystals of the present invention are formed in which modafinil and a co-crystal former are bonded together through hydrogen bonding. There may also be other non-covalent interactions, including pi-lamination and van der Waals interactions.

In one embodiment, the co-crystal former is selected from the co-crystal formers of Tables I and II. In other embodiments, the co-crystal formers of Table I are embodied as Class 1, Class 2, or Class 3 co-crystal formers (see column labeled "Class" in Table I). Table I describes the multiple pK _a values for co-crystal formers with multiple functional groups. Certain functional groups corresponding to specific pK _a values are readily apparent to those skilled in the art.

In another embodiment, specific functional groups of co-crystal formers that interact with modafinil are specified [eg, columns of Table I, labeled “functional” and “molecular structure”), and “co-crystals. Column of Table II labeled "former functional groups".

In another embodiment, the co-crystals comprise one or more co-crystal formers. For example, two, three, four, five or more co-crystal formers may be incorporated into the co-crystal with modafinil. Co-crystals comprising two or more co-crystal formers and an API are bonded together through hydrogen bonding. In one embodiment, the incorporated co-crystal former is hydrogen bonded to the modafinil molecule. In another embodiment, the co-crystal former is hydrogen bonded to the modafinil molecule or incorporated co-crystal former.

In each process according to the invention, modafinil needs to be contacted with a co-crystal former. This may include grinding two solids together or melting one or both components and recrystallizing them. This may also include solubilizing modafinil followed by the addition of a co-crystal former, or by solubilizing the co-crystal former followed by the addition of modafinil. Crystallization conditions apply to modafinil and co-crystal formers. This can alter the solution properties such as pH or temperature and typically requires drying the solution to remove the solvent, usually concentrating the solute. Removing the solvent, over time, modifies both modafinil and the co-crystal former to promote crystallization. For example, co-crystals can be crystallized using evaporation, cooling, or the addition of antisolvents. In another embodiment, a slurry comprising modafinil and a co-crystal former is used to form co-crystals. Once the solid phase comprising any crystals is formed, it can be tested as described herein.

The co-crystals obtained as a result of the process steps can be easily incorporated into pharmaceutical compositions (or drugs) by conventional means. Pharmaceutical compositions and drugs are generally discussed in further detail below, which may further include pharmaceutically acceptable diluents, excipients or carriers.

In a further aspect, the invention

(a) providing modafinil;

(b) providing a co-crystal former that is compatible with the functional group of modafinil, such that the co-crystal former and modafinil can form a co-crystal;

(c) polishing, heating, co-subliming, co-melting or contacting modafinil in solution with a co-crystal former under crystallization conditions to form a solid phase; And

(d) separating the co-crystals comprising modafinil and a co-crystal former

It provides a method of producing a co-crystal of modafinil, comprising.

In certain embodiments, the co-crystal former is ether, thioether, alcohol, thiol, aldehyde, ketone, thioketone, nitrate ester, phosphate ester, thiophosphate ester, ester, thioester, sulfate ester, carboxylic acid, phosphonic acid , Phosphinic acid, sulfonic acid, amide, primary amine, secondary amine, ammonia, tertiary amine, sp2 amine, thiocyanate, cyanamide, oxime, nitrile, diazo, organohalide, nitro, S-heterocyclo It has at least one functional group selected from the group consisting of a click ring, thiophene, N-heterocyclic ring, pyrrole, O-heterocyclic ring, furan, epoxide, hydroxamic acid, imidazole or pyridine.

In a further aspect, the invention

(a) providing modafinil;

(b) providing a co-crystal former that is compatible with the functional group of modafinil, such that the co-crystal former and modafinil can form a co-crystal;

(c) polishing, heating, co-subliming, co-melting or contacting modafinil in solution with a co-crystal former under crystallization conditions;

(d) separating the co-crystals thus formed; And

(e) incorporating the co-crystal into a pharmaceutical composition or drug

It provides a pharmaceutical composition or a method for producing a drug comprising a.

In another embodiment, the method of forming co-crystals includes a metastable form of modafinil, a co-crystal former, or both. Metastable forms can be, for example, but not limited to, polymorphs, solvates, or hydrates of modafinil or co-crystal formers. While not being bound by a particular theory, incorporating metastable forms can promote co-crystal formation through increased thermodynamic driving forces.

Assaying the solid phase to see if co-crystals of modafinil and the co-crystal former are present can be carried out by conventional methods known in the art. For example, it is convenient and common to use powder X-ray diffraction techniques that assess the presence of co-crystals. This can work by comparing the diffractograms of modafinil, co-crystal former and putative co-crystals to establish that true co-crystals have formed. Other techniques used in a similar manner include differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), infrared spectroscopy (IR) and Raman spectroscopy. In identifying co-crystal structures, single crystal X-ray diffraction is particularly useful.

In a further aspect, the invention

(a) providing a co-crystal former ( ii ) that is compatible with the functional groups of modafinil ( i ) and modafinil, such that the co-crystal former and modafinil can form co-crystals; And

(b) for each combination of modafinil and co-crystal former,

  (i) grinding, heating, co-subliming, co-melting or contacting modafinil in solution with a co-crystal former under crystallization conditions to form a solid phase; And

  (ii) separating co-crystals comprising modafinil and a co-crystal former

Screening for co-crystals of modafinil with a co-crystal former

It provides a method for screening for a co-crystal compound, including.

Another aspect is

(a) providing a plurality of different co-crystal formers ( ii ) that are compatible with the functional groups of modafinil ( i ) and modafinil, such that the co-crystal former and modafinil are capable of forming co-crystals step; And

(b) for each combination of modafinil and co-crystal former,

  (i) grinding, heating, co-subliming, co-melting or contacting modafinil in solution with each co-crystal former under crystallization conditions to form a solid phase; And

  (ii) separating co-crystals comprising modafinil and a co-crystal former

Screening for co-crystals of modafinil with a co-crystal former

It relates to a method for screening for a co-crystal compound, comprising.

The present invention includes several co-crystals, including modafinil and a carboxylic acid co-crystal former. Some examples thereof include modafinil co-crystals including malonic acid, tartaric acid (L- and DL-), succinic acid, citric acid, fumaric acid, gentisic acid, oxalic acid, and 1-hydroxy-2-naphthoic acid. These examples represent mono-, di- and tri-carboxylic acid co-crystal formers. Other acids, including carboxylic acids, may be used with modafinil as co-crystal formers, including but not limited to palmitic acid, orotic acid, adipic acid, and the like. These co-crystal formers may comprise one, two, three or more carboxylic acid functional groups. Co-crystal formers may also include non-carboxylic acid molecules, including but not limited to urea, saccharin, and caffeine.

In another embodiment, the co-crystals comprise modafinil and carboxylic acids as co-crystal formers. In another embodiment, such carboxylic acid co-crystal formers have one, two, three or more carboxylic acid functional groups.

Several co-crystals may exhibit one or more specific interactions between modafinil and a carboxylic acid co-crystal former. For example, the carboxylic acid functional group may interact via hydrogen bonding with the primary amide and / or S═O functional group of modafinil. In another embodiment, the carboxylic acid functional groups from the co-crystal former interact with hydrogen bonds with the primary amide functional groups or S═O functional groups of modafinil. In another embodiment, the carboxylic acid functional groups from the co-crystal former interact with the ends of the amide dimers of modafinil through hydrogen bonding. In another embodiment, the carboxylic acid functional groups from the co-crystal former interact with hydrogen bonds with the amide dimers and S═O functional groups of modafinil. In another embodiment, the carboxylic acid functional group from the co-crystal former interacts with two amide dimers of modafinil via hydrogen bonding.

Modafinil and some co-crystal formers of the present invention have one or more chiral centers and can therefore exist in a variety of stereoisomeric steric configurations. Due to these chiral centers, modafinil and some co-crystal formers of the present invention are present not only as racemates, mixtures of enantiomers and individual enantiomers, but also as mixtures of diastereomers and diastereomers. . All of the above racemates, enantiomers and diastereomers, including, for example, cis- and trans-isomers, R- and S-enantiomers, and (D)-and (L) -isomers It is in range. Co-crystals of the present invention may include isomeric forms of modafinil or co-crystal formers, or both. Isomeric forms of modafinil and co-crystal formers include, but are not limited to, stereoisomers such as enantiomers and diastereomers. In one embodiment, the co-crystals may comprise racemic modafinil and / or co-crystal formers. In another embodiment, the co-crystals may comprise enantiomerically pure R- or S-modafinil and / or co-crystal formers. In another embodiment, the co-crystals of the present invention have enantiomeric excess of 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%, 99 Co-crystal former or modafinil, which is greater than%, or any intermediate value there between. Some non-limiting examples of stereoisomeric co-crystal formers include tartaric acid and malic acid. In another embodiment, the polymorph or solvate of the present invention has an enantiomeric excess of 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 Modafinil, which is%, greater than 99%, or any intermediate value between them.

"Enhanced" modafinil according to the present invention comprises at least about 5, 6, 7, 8, 9 or 10% by weight of both the R-(-)-and S-(+)-isomers of modafinil , 91, 92, 93, 94 or 95% by weight or less. For example, a composition comprising 67% by weight of R-(-)-modafinil and 33% by weight of S-(+)-modafinil is a reinforced modafinil composition. In this example, the composition is neither racemic nor enantiomerically pure. The term "reinforced R-(-)-modafinil" refers to a composition of modafinil containing more than 50% R-(-)-modafinil and less than 50% S-(+)-modafinil. Can be used. Likewise, the term "reinforced S-(+)-modafinil" describes a composition of modafinil containing more than 50% S-(+)-modafinil and less than 50% R-(-)-modafinil. It can be used to.

The terms "R-(-)-modafinil" and "S-(+)-modafinil" refer to enhanced modafinil, enantiomerically pure modafinil, or substantially enantiomerically pure modafinil. It may be used, but specifically excludes enhanced modafinil, enantiomerically pure modafinil, and / or substantially enantiomerically pure modafinil.

Co-crystals, solvates and polymorphs comprising enantiomerically pure and / or enantiomerically fortified components (eg modafinil or co-crystal formers) are corresponding components comprising racemic components. Its chemical and / or physical properties can be adjusted in comparison to co-crystals. For example, modafinil: malonic acid co-crystal from Example 1 includes racemic modafinil. Enantiomerically pure R-(-)-modafinil: malonic acid is included within the scope of the present invention. Likewise enantiomerically pure S-(+)-modafinil: malonic acid is included within the scope of the present invention. Co-crystals comprising enantiomerically pure components can be adjusted, for example, in terms of activity, bioavailability or solubility compared to corresponding co-crystals comprising racemic components. As an example, the co-crystal R-(-)-modafinil: malonic acid may have adjusted properties compared to the racemic modafinil: malonic acid co-crystal.

Polymorphs and solvates of modafinil can be prepared with racemic modafinil, enantiomerically pure modafinil, or all mixtures of R-(-)-modafinil and S-(+)-modafinil according to the invention. It may be.

In another embodiment, the present invention comprises a pharmaceutical composition comprising co-crystals with enantiomerically pure modafinil and / or co-crystal formers, adjusted in comparison to racemic co-crystals in terms of bioavailability. Or drugs. In another aspect, the invention provides a pharmaceutical composition or drug comprising a co-crystal with enantiomerically pure modafinil and / or a co-crystal former, adjusted in terms of activity compared to racemic co-crystals. Include. In another aspect, the present invention provides a pharmaceutical composition or drug comprising a co-crystal with enantiomerically pure modafinil and / or a co-crystal former, adjusted in terms of solubility in comparison to racemic co-crystals. Include.

In another embodiment, the pharmaceutical composition or drug may be formulated to contain co-crystal form of modafinil as micronized or nano-sized particles. More specifically, another aspect is to link the processing of pure modafinil into co-crystal form with a process that produces a controlled particle size for manipulation into a pharmaceutical dosage form. This embodiment combines the two processing steps into a single step through techniques including, but not limited to, polishing, alloying or sintering (ie, heating the powder mixture) and the like. Linking these processes is a serious problem in the separation and storage of bulk drugs required for certain formulations, which may in some cases be difficult to isolate (eg, amorphous, chemical or physically unstable). Overcome

Solubility adjustment

In a further aspect, the invention

(a) providing modafinil;

(b) providing a co-crystal former that is compatible with the functional group of modafinil, such that the co-crystal former and modafinil can form a co-crystal;

(c) polishing, heating, co-subliming, co-melting or contacting modafinil in solution with a co-crystal former under crystallization conditions to form a solid phase; And

(d) separating the co-crystals comprising modafinil and a co-crystal former

It provides a method of increasing the solubility of modafinil in water, simulated gastric juice (SGF) or simulated serous (SIF) for use in pharmaceutical compositions or drugs.

In one embodiment, the solubility of modafinil is adjusted so that the water solubility (mg / mL) is increased by 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 more than the free form. Let's do it. The solubility of modafinil can be determined by chromatography (e.g. HPLC), or by spectroscopic measurement of the amount of modafinil in a saturated solution, e. It can measure by all the conventional methods, such as photography.

In another embodiment, a composition or drug comprising the co-crystals, solvates and polymorphs of the present invention can be compared to the free form modafinil as found in PROVIGIL® (Cephalon, Inc.). RE 37,516]. For example, the bioavailability of a composition or drug of the invention can be compared with the bioavailability of PROVIGIL. As an embodiment of the present invention, the solubility is reduced to 2, 3, 4, 5, 7, 10, 15, 20, 25, by making co-crystals of a reference form (e.g., crystalline or amorphous free form, hydrate or solvate). It can be increased by 50, 75, or 100 times. Additional water solubility can be measured in simulated gastric juice (SGF) or simulated intestinal fluid (SIF) rather than water. The SGF (not diluted) of the present invention combines 1 g / L Triton X-100 and 2 g / L NaCl in water and adjusts the pH using 20 mM HCl to obtain a solution having a final pH of 1.7. It manufactures by obtaining. If the pH of the final solution is 7.5, the SIF is 0.68% monovalent potassium phosphate, 1% pancreatin and sodium hydroxide. The pH of the solvent used is also 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 or 12, or any pH between consecutive values may be specified.

Examples of such embodiments include co-crystal compositions wherein the water solubility at 37 ° C. and pH 7.0 is increased at least five times compared to the reference form; Co-crystal compositions having increased solubility in SGF by at least 5 times compared to the reference form; Co-crystal compositions that have a five-fold increase in solubility in SIF compared to the reference form are included.

Solubility Adjustment

In another aspect of the present invention, by adjusting the solubility profile of modafinil, the rate of water solubility is increased, or the rate of dissolution in simulated gastric juice or simulated serous fluid, or in a solvent or a plurality of solvents. Dissolution rate is the rate at which API solids dissolve in the dissolution medium. For APIs (eg steroids) where the rate of absorption is faster than the rate of dissolution, the rate limiting step in the absorption process is often the rate of dissolution. Because of the limited residence time at the absorption site, those APIs that do not dissolve before removal of these APIs from the intestinal absorption site are considered obsolete. Thus, the rate of dissolution has a significant impact on the performance of APIs that dissolve to insufficient levels. Because of these factors, the dissolution rate of APIs in solid dosage forms is an important and common good quality control parameter used in the APIs manufacturing process. The following equation is an approximate dissolution rate:

Dissolution Rate = KS (C _s -C)

In the above, K is the dissolution rate constant, S is the surface area, C _s is the apparent solubility, and C is the concentration of API in the dissolution medium.

For fast API absorption, C _s -C is approximately equal to C _s .

The dissolution rate of modafinil can be measured by conventional methods known in the art.

As compared to the reference form (eg free form), the increase in dissolution rate of the co-crystal is greater than the reference form (eg free form) in the same solution, for example 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100%, or 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 75, 100, It may be specified as 125, 150, 175, 200, 250, 300, 350, 400, 500, 1000, 10,000, or 100,000 times or more. The conditions for measuring the dissolution rate are the same as discussed above. Solubility increase can be further manifested as the time the composition remains supersaturated before reaching equilibrium solubility.

In a further aspect, the invention

(a) providing modafinil;

(b) providing a co-crystal former that is compatible with the functional group of modafinil, such that the co-crystal former and modafinil can form a co-crystal;

(c) polishing, heating, co-subliming, co-melting or contacting modafinil in solution with a co-crystal former under crystallization conditions to form a solid phase; And

(d) separating the co-crystals comprising modafinil and a co-crystal former

It provides a method of adjusting the solubility of modafinil, including increasing the rate of water solubility, or increasing the rate of dissolution in simulated gastric juice or simulated intestinal fluid, or in a solvent or a plurality of solvents.

Examples of such embodiments include, at 37 ° C. and pH 7.0, co-crystal compositions wherein the dissolution rate in aqueous solution is increased by at least 5 times compared to the reference form; Co-crystal compositions in which the rate of dissolution in SGF is increased at least 5 times compared to the reference form; Co-crystal compositions in which the dissolution rate in SIF is increased at least five times compared to the reference form are included.

Bioavailability Adjustment

The methods of the invention are used to prepare pharmaceutical modafinil formulations with higher solubility, dissolution rate and bioavailability. Bioavailability can be improved by increasing AUC, shortening T _max (time to reach peak blood serum level), or increasing C _max . The present invention can produce higher modafinil plasma concentrations compared to the free form (reference form).

AUC is the area under the plasma concentration plot (not log of these concentrations) of the API versus time after API administration. It is convenient to measure this area by the following "trapezoidal formula": connect the data points by straight intercept, draw a vertical line from the abscissa to each data point, and calculate the sum of the areas of the triangle and the trapezoid thus constructed by computer. do. Not the last measured concentration (time t _n C under _n) is zero (0), AUC up to infinite time from t _n are evaluated as C _n / k _el.

AUC is particularly useful for evaluating the bioavailability of APIs and for evaluating the total clearance of APIs (Cl _T ). After a single intravenous administration, for a single compartment system according to the primary elimination kinetics, the AUC is D / Cl _T where D is the dosage; On the other hand, AUC is C _o / k _el , where k _el is the API erase rate constant. When using routes other than intravenous, the AUC is F · D / Cl _T where F is the absolute bioavailability of the API.

In a further aspect, the invention

(a) providing modafinil;

(b) providing a co-crystal former that is compatible with the functional group of modafinil, such that the co-crystal former and modafinil can form a co-crystal;

(c) polishing, heating, co-subliming, co-melting or contacting modafinil in solution with a co-crystal former under crystallization conditions to form a solid phase; And

(d) separating the co-crystals comprising modafinil and a co-crystal former

By adjusting the bioavailability of modafinil, increasing the AUC, shortening the T _max time, increasing the time at which the concentration of modafinil is greater than or equal to 1/2 T _max , or C Provides a way to increase _max .

Examples of such embodiments include co-crystal compositions in which the T _max time is increased by at least 5% relative to the reference form; Co-crystal compositions having a T _max time increased by at least 10% compared to the reference form; Co-crystal compositions having an increased T _max time of at least 15% compared to the reference form; Co-crystal compositions having an increased T _max time of at least 20% compared to the reference form; Co-crystal compositions having a T _max time increased by at least 25% compared to the reference form; Co-crystal compositions having a T _max time increased by at least 30% compared to the reference form; Co-crystal compositions having an increased T _max time of at least 35% compared to the reference form; Co-crystal compositions having a T _max time increased by at least 40% compared to the reference form; Co-crystal compositions having an AUC increased by at least 5% relative to the reference form; Co-crystal compositions having an AUC increased by at least 10% compared to the reference form; Co-crystal compositions having an AUC increased by at least 15% compared to the reference form; Co-crystal compositions having an AUC increased by at least 20% compared to the reference form; Co-crystal compositions having an AUC increased by at least 25% compared to the reference form; Co-crystal compositions having an AUC increased by at least 30% compared to the reference form; Co-crystal compositions having an AUC increased by at least 35% compared to the reference form; Co-crystal compositions with an AUC increased by at least 40% compared to the reference form are included. Other examples include those in which the reference form is crystalline, the reference form is amorphous, or the reference form is an anhydrous crystalline form of modafinil.

Capacity response adjustment

In a further aspect, the invention

(a) providing modafinil;

(b) providing a co-crystal former that is compatible with the functional group of modafinil, such that the co-crystal former and modafinil can form a co-crystal;

(c) polishing, heating, co-subliming, co-melting or contacting modafinil in solution with a co-crystal former under crystallization conditions to form a solid phase; And

(d) separating the co-crystals comprising modafinil and a co-crystal former

It provides a method of modulating the dose response of modafinil for use in a pharmaceutical composition or drug, comprising.

Dose response is a quantitative correlation between response size and the dose that elicits this response and can be measured by conventional means known in the art. For API-cell systems the curve regarding the effect (as dependent variable) on the dose (as independent variable) is the “dose-response curve”. Typically, the dose-response curve is a response measured against the API plotted for a given API dose (mg / kg). This dose response curve can also be the curve of the AUC against a given API dose.

In embodiments of the present invention, the co-crystals of the present invention exhibit increased dose response curves or corresponding linear dose response curves than the corresponding reference compounds.

Increased stability

In a further aspect, the present invention also provides

(a) providing modafinil;

(b) providing a co-crystal former that is compatible with the functional group of modafinil, such that the co-crystal former and modafinil can form a co-crystal;

(c) polishing, heating, co-subliming, co-melting or contacting modafinil in solution with a co-crystal former under crystallization conditions to form a solid phase; And

(d) separating the co-crystals comprising modafinil and a co-crystal former

A method of improving the stability of modafinil (compared to a reference form, such as the free form of modafinil), is provided.

In a preferred embodiment, the compositions of the present invention including formulations comprising modafinil co-crystals, solvates, and modafinil are suitable for pharmaceutical use. Preferably, modafinil or a formulation thereof of the present invention is stable to the extent that less than 0.2% of any degradation products are formed when they are stored at 30 ° C. for 2 years. The term digest is referred to herein as a single type of chemical reaction product (s). For example, for the purposes of the present invention, if a hydrolysis event occurs that splits a particular molecule into two products, it will be considered as a single digest. More preferably, when stored at 40 ° C. for 2 years, either decomposition product forms less than 0.2%. On the other hand, if any of the degradation products form 0.2% or less than 0.15%, or 0.1% when stored for 3 months at 30 ° C, or if either degradation products are 0.2% or 0.15 when stored for 3 months at 40 ° C, Less than%, or 0.1%. Additionally, when stored for 4 weeks at 60 ° C., either decomposition product forms less than 0.2% or 0.15%, or 0.1%. Relative humidity (RH) can be specified as ambient RH, 75% RH, or as every single integer between 1 and 99% RH. In another embodiment, a single dose of the present invention comprises less than 0.5%, 0.2% or 0.1% of analyte when administered to a particular subject.

Mode adjustment

In a further aspect, the present invention

(a) providing modafinil;

(b) providing a co-crystal former that is compatible with the functional group of modafinil, such that the co-crystal former and modafinil can form a co-crystal;

(c) polishing, heating, co-subliming, co-melting or contacting modafinil in solution with a co-crystal former under crystallization conditions to form a solid phase; And

(d) separating the co-crystals comprising modafinil and a co-crystal former

It provides a method of modifying the form of modafinil, including.

In certain embodiments, the co-crystals may interact with the interaction between modafinil and the co-crystal former, for example, between the co-crystal formers where the H-bond carries the amino group of modafinil and the corresponding interactive group in Table III. Which occurs or comprises or consists of modafinil and a co-crystal former. In a further embodiment, the co-crystals comprise modafinil and the co-crystal formers of Table I or II. In one aspect of the invention, the H-bond acceptor on the first molecule and the H-binding donor on the second molecule, wherein the first and second molecules are each co-crystal former and modafinil Or co-crystal formers with modafinil) are included in the present invention only.

Co-crystals may include two or more chemicals within their co-crystalline structure. For example, the co-crystals may further include solvent molecules, water molecules, salts, and the like. Co-crystals may also include APIs and two or more co-crystal formers, co-crystal formers and two or more APIs, two or more APIs, or two or more co-crystal formers.

As defined herein, tertiary co-crystals are co-crystals that contain three distinct chemicals in stoichiometric proportions, each of which is a solid at room temperature, provided that the API can be liquid at room temperature . Specifically stated, tertiary co-crystals comprise three distinct chemicals, for example API: co-crystal former (1): co-crystal former (2), with the ratio of these components being For example, it may be 1: 1: 1, 2: 1: 1, 2: 1: 2, 2: 1: 0.5, 2: 2: 1, etc., but is not limited thereto. Tertiary co-crystals may be combined with other component combinations, such as API (l): API (2): co-crystal formers, API (1): API (2): API (3), and co-crystals Forming agent (1): Co-crystal former (2): Co-crystal former (3) etc. may be included.

In another aspect, the invention provides co-crystals comprising modafinil and a co-crystal former selected from the group consisting of: malonic acid, glycolic acid, fumaric acid, tartaric acid, citric acid, succinic acid, gentic acid, oxalic acid , 1-hydroxy-2-naphthoic acid, orotic acid, glutaric acid, L-tartaric acid, palmitic acid, L-proline, salicylic acid, lauric acid, L-malic acid and maleic acid.

In a further aspect, the present invention provides the following co-crystals: modafinil: malonic acid, modafinil: glycolic acid, modafinil: maleic acid, modafinil: L-tartaric acid, modafinil: citric acid, modafinil: succinic acid , Modafinil: DL-tartaric acid, modafinil: fumaric acid (form I), modafinil: fumaric acid (form II), modafinil: gentisic acid, modafinil: oxalic acid, modafinil: 1-hydroxy-2-naphthoic acid, R-(-)-modafinil: malonic acid, R-(-)-modafinil: succinic acid, R-(-)-modafinil: citric acid, R-(-)-modafinil: DL-tartaric acid, R- ( -)-Modafinil: 1-hydroxy-2-naphthoic acid, R-(-)-modafinil: orotic acid, R-(-)-modafinil: glutaric acid, R-(-)-modafinil : L-tartaric acid, R-(-)-modafinil: palmitic acid, R-(-)-modafinil: L-proline, R-(-)-modafinil: salicylic acid, R-(-)-modafinil : Lauric acid, R-(-)-modafinil: L-malic acid, and R-(-)-modafinil: gentisic acid.

In another embodiment, the present invention provides novel polymorphs or co-crystals of racemic modafinil (form VII).

In another embodiment, the present invention provides the following modafinil solvates: acetic acid, tetrahydrofuran, 1,4-dioxane, methanol, nitromethane, acetone, o-xylene, benzene and toluene.

Pharmaceutically acceptable co-crystals can be administered by controlled or delayed release means. Controlled release pharmaceutical products have a common goal of improving drug therapy over that achieved by non-controlled release counterparts. Ideally, the use of controlled release formulations that are optimally designed for medical use is characterized by the use of minimal drugs to treat or inhibit the disease in a minimum amount of time. Advantages of controlled release formulations include: 1) prolonged drug activity; 2) the frequency of administration is reduced; 3) the patient's treatment compliance is increased; 4) the total drug dose is utilized in lesser amounts; 5) local or systemic side effects are reduced; 6) drug accumulation is minimized; 7) blood level fluctuations are reduced; 8) treatment efficacy is improved; 9) reduce the enhancement or loss of drug activity; 10) Improve the rate of control of a disease or condition (Kim, Cherng-ju, Controlled Release Dosage Form Design, 2 Technomic Publishing, Lancaster, Pa .: 2000).

Conventional dosage forms generally provide rapid or immediate drug release from the formulation. Depending on the pharmacology and pharmacokinetics of the drug, the use of conventional dosage forms can cause wide variation in drug concentrations in the patient's blood and other tissues. Such variations can affect a number of parameters, such as the number of doses, onset of action, duration of efficacy, maintenance of therapeutic blood levels, toxicity, side effects, and the like. Advantageously, controlled release formulations can be used to control the onset of action, duration of action, plasma levels within peak drug concentrations, and peak blood levels. In particular, using controlled or prolonged release dosage forms or formulations, which can occur from both during the administration of a particular drug (ie, progressing below the minimum therapeutic level), as well as when the toxicity levels for such drugs are exceeded. In addition, the maximum efficacy of the drug can be achieved while minimizing potentially adverse effects and safety concerns.

Most controlled release formulations release an initial amount of a drug (active ingredient) that immediately produces the desired therapeutic effect, while other and other drugs are gradually and continuously administered to maintain this therapeutic or prophylactic level over time. Designed to release. In order to maintain a constant level of drug in the body, the drug must be released from the dosage form at a rate that can replace the amount of drug that is metabolized and released from the body. Controlled release of the active ingredient can be stimulated by a variety of conditions including, but not limited to, pH, ionic strength, osmotic pressure, temperature, enzymes, water, and other physiological conditions or compounds.

Various known controlled or extended release dosage forms, formulations and devices can be adapted to be suitable for use in the co-crystals and compositions of the present invention. Examples thereof include US Pat. No. 3,845,770; 3,916,899; 3,536,809; 3,536,809; 3,598,123; 3,598,123; 4,008,719; 4,008,719; No. 5,674,533; 5,059,595; 5,059,595; 5,591,767; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,639,476; 5,354,556; 5,354,556; 5,733,566; And 6,365,185 B1, each of which is incorporated herein by reference. Using these dosage forms, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems [e.g. OROS® (Alza Corporation, Mountain View, Calif. USA)], multilayer coatings By slow or controlled release of one or more active ingredients using particulates, liposomes or microspheres, or combinations thereof, the desired release profile can be provided in various ratios. In addition, by using the ion exchange material to prepare immobilized and adsorbed co-crystals, the drug can be delivered in a controlled manner. Examples of specific anion exchangers include, but are not limited to, Duolite® A568 and Doolide AP143 (Rohm & Haas, Spring House, PA. USA).

One aspect of the invention encompasses unit dosage forms comprising a pharmaceutically acceptable co-crystal, or solvate, hydrate, dehydrate, anhydrous or amorphous form thereof, and one or more pharmaceutically acceptable excipients or diluents, Wherein the pharmaceutical composition, drug or dosage form is formulated for controlled release. Specific dosage forms utilize an osmotic drug delivery system.

Certain well known osmotic drug delivery systems are referred to as OROS® (Alza Corporation, Mountain View, Calif. USA). Such techniques can be readily adapted to deliver the compounds and compositions of the present invention. Various aspects of the technology are described in US Pat. No. 6,375,978 Bl; 6,368,626 B1; 6,342,249 B1; 6,333,050 B2; 6,287,295 B1; 6,283,953 B1; 6,270,787 B1; 6,245,357 B1; And 6,132,420, each of which is incorporated herein by reference. Specific adaptations of OROS® that can be used to administer the compounds and compositions of the present invention include OROS® Push-Pull ™, Delayed Push-Pull ™, Multi-layer Push-Pull ™, and Push-Stick ™ systems, all of which are widely used. Known), but is not limited thereto. See http://www.alza.com. Additional OROS® systems that can be used for controlled oral delivery of the compounds and compositions of the present invention include OROS®-CT and L-OROS®. And Delivery Times, vol. II, issue II (Alza Corporation).

Conventional OROS® oral dosage forms compress drug powders (e.g., co-crystals) to become hard tablets, coat these tablets with cellulose derivatives to form semi-permeable membranes, and then drill holes in such coatings (e.g., For example, using a laser), Kim, Cherng-ju, Controlled Release Dosage Form Design, 231-238 (Technomic Publishing, Lancaster, Pa .: 2000). An advantage of this dosage form is that the rate of delivery of the drug is not affected by physiological or experimental conditions. Even drugs that exhibit pH-dependent solubility can be delivered at a constant rate regardless of the pH of the delivery medium. However, because these benefits are also provided by increased osmotic pressure in the dosage form after administration, conventional OROS® drug delivery systems do not effectively deliver drugs with low water solubility (see document at 234, supra). Since the co-crystals of the present invention may have significantly higher solubility in water than modafinil itself, they are well suited for delivery to patients based on osmotic pressure. However, the present invention encompasses the incorporation of conventional crystalline modafinil (eg, pure modafinil without co-crystal former), and isomers and isomeric mixtures thereof into OROS® dosage forms.

Specific dosage forms of the invention include a wall defining a cavity (the wall has a discharge orifice formed or formable therein and at least a portion of the wall is semi-permeable); An expandable layer located in the cavity away from the exit orifice and in fluid communication with the semi-permeable portion of the wall; An anhydrous or substantially anhydrous drug layer located in a cavity adjacent to the exit orifice and in direct or indirect contact correlation with the expandable layer; And a fluidity-enhancing layer interposed between the inner surface of the wall and at least the outer surface of the drug layer located in the cavity, wherein the drug layer is co-crystal, or solvate, hydrate, dehydrate, anhydrous or amorphous form thereof. [Reference: US Pat. No. 6,368,626, which is incorporated herein by reference in its entirety].

Another specific dosage form of the invention is a wall defining a cavity, which wall has a discharge orifice formed or formable therein and at least a portion of the wall is semi-permeable; An expandable layer located in the cavity away from the exit orifice and in fluid communication with the semi-permeable portion of the wall; A drug layer located in a cavity adjacent to the exit orifice and in direct or indirect contact correlation with the expandable layer, the drug layer comprising a liquid active agent formulation absorbed within the porous particles, the porous particles comprising the liquid active agent It is adapted to withstand the densification force sufficient to form a densified drug layer without significantly exuding the formulation, the dosage form optionally having a placebo layer between the discharge orifice and the drug layer, wherein the active agent formulation is co- Crystals, or solvates, hydrates, dehydrates, anhydrous or amorphous forms thereof (see US Pat. No. 6,342,249, which is incorporated herein by reference in its entirety).

In another embodiment, the pharmaceutical composition or drug comprises a mixture of a novel form of modafinil (eg, co-crystal) and a free form of modafinil. Such embodiments can be used, for example, as controlled, sustained or extended release dosage forms. In another embodiment, the extended release dosage form comprises the free form modafinil, and the co-crystal or solvate of the present invention. Such extended release dosage forms contain forms of modafinil (eg, modafinil: malonic acid co-crystals) whose bioavailability is greater than free form modafinil. In addition, this form of C _max may be greater than the free form modafinil, thus facilitating a longer therapeutic effect than the free form modafinil alone.

In another embodiment, the pharmaceutical composition or drug comprises a modified release profile of one or more of racemic modafinil, R-(-)-modafinil and S-(+)-modafinil. Such modified release profiles may include, for example, two or more maximum plasma concentrations, eg, dual-release profiles. Such a modified release profile can help treat patients with loss of awakening in the afternoon with the compositions or drugs of the present invention. A second “collective release” or release of the API at least 2, 3, 4, 5 or 6 hours after administration may help to overcome this effect. In another embodiment, a pharmaceutical composition or drug can be used that comprises a small drop dose that is released immediately after administration, followed by use of an approximately zero-order release profile over subsequent 2, 3, 4, 5 or 6 hours. Can be. In such compositions, peak plasma levels can be reached at approximately noon.

In another embodiment, a pharmaceutical composition or drug comprising a modified release profile of modafinil may comprise R-(-)-modafinil and S-(+)-modafinil, such R-(-)- Modafinil provides an initial increase in plasma concentration (initial C _max due to R-(-)-modafinil, and S-(+)-modafinil provides a delayed increase in plasma concentration (S-(+ ) Gives subsequent C _max ) due to modafinil. The delayed increase in C _max due to S-(+)-modafinil is 2, 3, 4, 5, 6 hours after reaching the initial C _max due to R-(-)-modafinil have. In another embodiment, delay C _max is approximately equivalent to initial C _max . In another aspect, delay C _max is greater than initial C _max . In another aspect, delay C _max is smaller than initial C _max . In another embodiment, the delayed formula C _max is due to racemic modafinil instead of S-(+)-modafinil. In another embodiment, the delayed formula C _max is due to R-(-)-modafinil instead of S-(+)-modafinil. In another embodiment, the initial C _max is due to racemic modafinil instead of R-(-)-modafinil. In another embodiment, the initial C _max is due to S-(+)-modafinil instead of R-(-)-modafinil. In another embodiment, the modified release profile exhibits 3, 4, 5, or more "collective releases" in plasma concentration.

In another embodiment, the pharmaceutical composition or drug is co-crystal, solvate, free form or polymorph thereof, wherein at least one of racemic modafinil, R-(-)-modafinil or S-(+)-modafinil is Present in the form of a modified release profile of modafinil.

In another embodiment, the pharmaceutical composition or drug comprises a modified release profile in which R-(-)-modafinil is used in an oral formulation. Such compositions can minimize the first pass metabolic action of modafinil to sulfone. In another embodiment, the pharmaceutical composition or drug comprises a modified release profile in which racemic modafinil is used in an oral formulation. In another embodiment, the pharmaceutical composition or drug comprises a modified release profile in which S-(+)-modafinil is used in an oral formulation. In another embodiment, the pharmaceutical composition or drug comprises a modified release profile in which racemic modafinil and R-(-)-modafinil are used in oral formulations. In another embodiment, the pharmaceutical composition or drug comprises a modified release profile in which racemic modafinil and S-(+)-modafinil are used in oral formulations. In another embodiment, the pharmaceutical composition or drug comprises a modified release profile in which S-(+)-modafinil and R-(-)-modafinil are used in oral formulations. In another embodiment, the pharmaceutical composition or drug comprises a modified release profile in which racemic modafinil, S-(+)-modafinil and R-(-)-modafinil are used in oral formulations.

In another embodiment, a pharmaceutical composition or drug comprising a modified release profile of modafinil is administered transdermally. Such transdermal (TD) delivery can avoid first-pass metabolism. Additionally, a "pill-and-patch" strategy can be taken, where only a fraction of the daily dose is delivered through the skin to generate basal systemic levels, in addition to oral therapy, to ensure arousal effects.

Excipients used in the pharmaceutical compositions and drugs of the present invention may be solids, semi-solids, liquids or combinations thereof. Preferably the excipient is a solid. Compositions and drugs of the invention containing excipients may be prepared by techniques known in the art of pharmaceutics, including mixing excipients with APIs or therapeutic agents. The pharmaceutical composition or drug of the present invention contains a desired amount of API per dosage unit, and when intended for oral administration, for example, tablets, caplets, pills, hard or soft capsules, lozenges, khakis, powders Acidic powders, granules, suspensions, elixirs, dispersants, liquids, or any other form that is reasonably adapted for such administration. If it is intended for parenteral administration, it may be in the form of a suspending agent or a transdermal patch, for example. If it is intended for rectal administration, it may be in the form of suppositories, for example. Oral dosage forms, such as tablets or capsules, which are separate dosage units each containing a predetermined amount of API, are presently preferred.

Non-limiting examples of excipients that can be used to prepare the pharmaceutical compositions or drugs of the present invention are as follows:

Pharmaceutical compositions and drugs of the invention optionally comprise one or more pharmaceutically acceptable carriers or diluents as excipients. Examples of suitable carriers or diluents include lactose, including anhydrous lactose and lactose monohydrate; Starches, including directly compressible starch and hydrolyzed starches (eg Celutab ™ and Emdex ™); Mannitol; Sorbitol; Xylitol; Dextrose (eg Cerelose ™ 2000) and dextrose monohydrate; Divalent calcium phosphate dihydrate; Sucrose-based diluent; Refined sugar; Monovalent calcium sulfate monohydrate; Calcium sulfate dihydrate; Granular calcium lactate trihydrate; Dexrate; Inositol; Hydrolyzed cereal solids; Amylose; Cellulose including food grade sources of microcrystalline cellulose, alpha- and amorphous cellulose (eg RexdelJ), powdered cellulose, hydroxypropylcellulose (HPC) and hydroxypropylmethylcellulose (HPMC); Calcium carbonate; Glycine; Bentonite; Block copolymers; Polyvinylpyrrolidone and the like are included individually or in combination, but are not limited thereto. If such carriers or diluents are present, they comprise a total of about 5 to about 99%, preferably about 10% to about 85%, more preferably about 20% to about 80%, based on the total weight of the composition. . The carrier (s) or diluent (s) selected preferably exhibit suitable flow characteristics and compressibility when purification is desired.

Preferred diluents are lactose, mannitol, divalent sodium phosphate, and microcrystalline cellulose (particularly Avicel PH microcrystalline cellulose, eg Avicel PH 101), individually or in combination. These diluents are chemically compatible with APIs. Extragranular microcrystalline cellulose (ie microcrystalline cellulose added to the granular composition) may be used to improve hardness (hardness to tablets) and / or disintegration time. Especially preferred are lactose, in particular lactose monohydrate. Lactose typically provides compositions with suitable release rates, stability, pre-compressive fluidity, and / or drying properties under relatively low cost diluents of APIs. This assists in densification during granulation (when wet granulation is used), thus providing a high density substrate that improves blend flow and purification properties.

Pharmaceutical compositions and drugs of the invention optionally comprise one or more pharmaceutically acceptable disintegrants, in particular as excipients for tablet formulation. Suitable disintegrants include sodium starch glycolate (eg Explotab ™ from Pen West) and pregelled corn starch (eg National ™ 1551, National ™ 1550, and Colocorn ™ 1500 from National Starch and Chemical Company), clay (eg RT Vanderbilt's Veegum ™ HV), celluloses such as purified cellulose, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, and sodium carboxymethylcellulose, croscarmellose sodium (e.g. Ac-Di-Sol ™ from FMC ), Alginate, crospovidone, and gums such as, but not limited to, agar, guar, locust bean, karaya, pectin and tragacand gums, individually or in combination.

Disintegrants can be added at any suitable stage during the preparation of the compositions of the invention, in particular during the lubrication stage prior to granulation or prior to compression. When present, the disintegrant is present in an amount of about 0.2% to about 30%, preferably about 0.2% to about 10%, more preferably about 0.2% to about 5%, based on the total weight of the composition. do.

Croscarmellose sodium is a preferred disintegrant for tablet or capsule disintegration, where it is present, preferably from about 0.2% to about 10%, more preferably from about 0.2% to about 10% by weight of the composition 7%, even more preferably about 0.2% to about 5%. Croscarmellose sodium imparts excellent intragranular disintegration ability to the granular pharmaceutical compositions and drugs of the present invention.

Pharmaceutical compositions and drugs of the invention optionally comprise one or more pharmaceutically acceptable binders or adhesives, in particular as excipients for tablet formulation. Such binders and adhesives are preferably sufficient to allow the tablets to allow normal processing operations, such as sizing, lubrication, compression and packaging, but sufficient to allow the tablets to disintegrate and to allow the composition to be absorbed upon ingestion. Imparts cohesiveness to the powder. The binder may prevent or inhibit crystallization or recrystallization of the API of the present invention once the salt is dissolved in the solution. Suitable binders and adhesives include acacia; Tragacand; Sucrose; gelatin; Glucose; Starch such as pre-gelled starch (eg, National ™ 1511 and National ™ 1500), and the like; Celluloses such as methylcellulose and carmellose sodium (eg Tylose ™) and the like; Alginic acid and salts of alginic acid; Magnesium aluminum silicate; PEG; Guar gum; Polysaccharide acid; Bentonite; Povidones such as povidone K-15, K-30 and K-29 / 32; Polymethacrylates; HPMC; Hydroxypropylcellulose (eg Aqualon's Klucel ™); And ethylcellulose (eg, Ethocel ™ from the Dow Chemical Company), individually or in combination. If such binders and / or adhesives are present it is based on the total weight of the pharmaceutical composition or drug of the present invention in total from about 0.5% to about 25%, preferably from about 0.75% to about 15%, more preferably About 15 to about 10%.

Since many binders are polymers containing amide, ester, ether, alcohol or ketone groups, they are preferably included in the pharmaceutical compositions and drugs of the present invention. Particular preference is given to polyvinylpyrrolidone, for example povidone K-30. The polymeric binder can have various molecular weights, crosslinking degrees, and polymer grades. The polymeric binder may be a copolymer, for example a block copolymer containing a mixture of ethylene oxide and propylene oxide units. Variations in these unit ratios in certain polymers affect properties and performance. Examples of block copolymers involving block units of various compositions are Poloxamer 188 and Poloxamer 237 (BASF Corporation).

Pharmaceutical compositions and drugs of the invention optionally comprise one or more pharmaceutically acceptable wetting agents as excipients. Such humectants are preferably selected such that the API remains tightly associated with water, a condition that is believed to enhance the bioavailability of the composition.

Non-limiting examples of surfactants that can be used as wetting agents in the pharmaceutical compositions and drugs of the present invention include quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride, dioctyl sodium sulfostone Sinates, polyoxyethylene alkylphenyl ethers such as nonoxynol 9, nonoxynol 10 and octoxynol 9, poloxamers (polyoxyethylene and polyoxypropylene block copolymers), polyoxyethylene fatty acid glycerol Rides and oils such as polyoxyethylene (8) capryl / capric mono- and diglycerides (eg Labrasol ™ from Gattefosse), polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenation Castor oil; Polyoxyethylene alkyl ethers such as polyoxyethylene (20) cetostearyl ether, polyoxyethylene fatty acid esters such as polyoxyethylene (40) stearate, polyoxyethylene sorbitan esters such as , Polysorbate 20 and polysorbate 80 (eg Tween ™ 80 of ICI), propylene glycol fatty acid esters such as propylene glycol laurate (eg Lauroglycol ™ of Gattefosse), sodium lauryl sulfate, fatty acids and their Salts such as oleic acid, sodium oleate and triethanolamine oleate, glyceryl fatty acid esters such as glyceryl monostearate, sorbitan esters such as sorbitan monolaurate, sorbitan monoole Ate, sorbitan monopalmitate and sorbitan monostearate, tiloxapol, and mixtures thereof. If such a humectant is present, it is based on the total weight of the pharmaceutical composition or drug of the present invention in total from about 0.25% to about 15%, preferably from about 0.4% to about 10%, more preferably from about 0.5% to About 5%.

Preference is given to wetting agents which are anionic surfactants. Sodium lauryl sulfate is a particularly preferred humectant. If sodium lauryl sulfate is present, it is based on the total weight of the pharmaceutical composition or drug of the present invention in total from about 0.25% to about 7%, more preferably from about 0.4% to about 4%, even more preferably About 0.5% to about 2%.

Pharmaceutical compositions and drugs of the present invention optionally comprise one or more pharmaceutically acceptable lubricants, including anti-adhesives and / or lubricants, as excipients. Suitable lubricants include glyceryl behaate (eg Compritol ™ 888 from Gattefosse); Stearic acid and salts thereof, including magnesium, calcium and sodium stearate; Hydrogenated vegetable oils (eg, Abitec's Sterotex ™); Colloidal silica; Talc; Wax; Boric acid; Sodium benzoate; Sodium acetate; Sodium fumarate; Sodium chloride; DL-leucine; PEG (eg, Carbowax ™ 4000 and Carbowax ™ 6000 from the Dow Chemical Company); Sodium oleate; Sodium lauryl sulfate; And magnesium lauryl sulfate, including, but not limited to, individually. If such lubricants are present, they are based on the total weight of the pharmaceutical composition or drug of the present invention in total from about 0.1% to about 10%, preferably from about 0.2% to about 8%, more preferably from about 0.25% to About 5%.

Magnesium stearate is the preferred lubricant used to reduce the friction between the equipment and the granular mixture during compaction of the tablet formulation.

Suitable antiadhesives include, but are not limited to talc, corn starch, DL-leucine, sodium lauryl sulfate and metallic stearate. For example, preferred antiadhesives or lubricants for use in reducing formulation adhesion to the equipment surface and also in reducing static in the blend are talc. When talc is present, it is based on the total weight of the pharmaceutical composition or drug, in total from about 0.1% to about 10%, more preferably from about 0.25% to about 5%, even more preferably from about 0.5% to about 2%.

Glidants can be used to enhance powder flowability of solid formulations. Suitable glidants include, but are not limited to, colloidal silicon dioxide, starch, talc, trivalent calcium phosphate, powdered cellulose and magnesium trisilicate. Colloidal silicon dioxide is particularly preferred.

Other excipients such as colorants, flavors and sweeteners are known in the pharmaceutical art and can be used in the pharmaceutical compositions and drugs of the present invention. Tablets may or may not be coated with, for example, an enteric coating. The composition of the present invention may further comprise a buffer, for example.

Optionally, one or more blowing agents can be used as disintegrants and / or used to enhance the organoleptic properties of the pharmaceutical compositions and drugs of the present invention. When present in pharmaceutical compositions and drugs of the present invention to enhance dosage form disintegration, one or more blowing agents are preferably based on the total weight of the pharmaceutical compositions or drugs of the present invention, preferably in total from about 30% to about 75% , Preferably in an amount from about 45% to about 70%, for example about 60%.

According to particularly preferred embodiments of the present invention, the blowing agent present in the solid dosage form in an amount less than the amount effective to enhance the disintegration of the dosage form, improves the dispersibility of the API in the aqueous medium. While not wishing to be bound by any theory, it is believed that blowing agents are effective for accelerating the dispersion of APIs from dosage forms in the gastrointestinal tract, thus enhancing absorption and initiating a therapeutic effect quickly. If present in the pharmaceutical composition or drug of the present invention to enhance gastrointestinal dispersion but not to enhance disintegration, the blowing agent is preferably based on the total weight of such pharmaceutical composition or drug, preferably from about 1% to about 20 %, More preferably from about 2.5% to about 15%, even more preferably from about 5% to about 10%.

A "foaming agent" herein is an agent comprising one or more compounds that act together or separately to release a gas upon contact with water. The released gas is generally oxygen or most commonly carbon dioxide. Preferred blowing agents include bases and acids which react in the presence of water to generate carbon dioxide gas. Preferably, the base comprises an alkali metal or alkaline earth metal carbonate or bicarbonate, and the acid comprises an aliphatic carboxylic acid.

Non-limiting examples of bases suitable as components of the blowing agent useful in the present invention include carbonates such as calcium carbonate, bicarbonates such as sodium bicarbonate, sesqui-carbonates, and mixtures thereof. Calcium carbonate is the preferred base.

Non-limiting examples of acids and / or solid acids suitable as components of the blowing agent useful in the present invention include citric acid, tartaric acid (D-, L- or D / L-tartaric acid), malic acid, maleic acid, fumaric acid, adipic acid, succinic acid , Acid anhydrides of such acids, acid salts of these acids, and mixtures thereof. Citric acid is a preferred acid.

In a preferred embodiment of the invention, where the blowing agent comprises an acid and a base, the weight ratio of such acid to base is about 1: 100 to about 100: 1, more preferably about 1:50 to about 50: 1, even more preferred Preferably from about 1:10 to about 10: 1. In a further preferred embodiment of the invention, when the blowing agent comprises an acid and a base, the ratio of such acid to base is approximately stoichiometric.

Excipients that solubilize metal salts of APIs typically have both hydrophilic and hydrophobic regions, or preferably amphiphilic or amphiphilic regions. One type of amphipathic or partially amphiphilic excipient comprises an amphipathic polymer or is an amphipathic polymer. Specific amphiphilic polymers are polyalkylene glycols which are usually composed of ethylene glycol and / or propylene glycol subunits. Such polyalkylene glycols can be esterified at their ends by carboxylic acids, esters, acid anhydrides or other suitable moieties. Examples of such excipients include poloxamers (symmetric block copolymers of ethylene glycol and propylene glycol, such as poloxamer 237), polyalkylene glycolated esters of tocopherols, including di- or polyfunctional carboxylic acids. Esters formed are, for example, d-alpha-tocopherol polyethylene glycol-1000 succinate) and macrosolglycerides (mono-, di- and tri-glycerides and mixtures of mono- and di-esters are prepared) Formed by esterifying polyalkylene glycol and dialcoholizing oil; for example, stearoyl macrosol-32 glyceride). The pharmaceutical compositions and drugs are advantageously administered orally.

Pharmaceutical compositions and drugs of the present invention may comprise about 10 to about 50 weight percent, about 25 to about 50 weight percent, about 30 to about 45 weight percent, or about 30 to 35 weight percent API; About 10 to about 50 weight percent, about 25 to about 50 weight percent, about 30 to about 45 weight percent, or about 30 to about 35 weight percent of an excipient that inhibits crystallization; And about 5 to about 50 weight percent, about 10 to about 40 weight percent, about 15 to about 35 weight percent, or about 30 to about 35 weight percent binder. In one example, the weight ratio of excipient to binder that inhibits API to crystallization is about one to one.

Solid dosage forms of the invention may be prepared by any suitable method, including but not limited to the methods described herein.

The illustrated method comprises the steps of (a) blending a salt of the present invention with one or more excipients to form a blend; And (b) tableting or encapsulating these blends to form tablets or capsules, respectively.

In a preferred method, (a) blending an API salt of the invention with one or more excipients to form a blend; (b) granulating the blend to form granules; And (c) tableting or encapsulating the blend to form tablets or capsules, respectively, to produce a solid dosage form. Step (b) may be carried out by any dry or wet granulation technique known in the art, but is preferably carried out by a dry granulation step. Salts of the invention are advantageously granulated to form particles having a size of about 1 micrometer to about 100 micrometers, about 5 micrometers to about 50 micrometers, or about 10 micrometers to about 25 micrometers. For example, in the blending step, it is preferable to add one or more diluents, one or more disintegrants and one or more binders; For example, the granulating step may optionally add a humectant; After granulation, prior to tableting or encapsulation, it is preferred to add one or more disintegrants. It is preferable to add a lubricant before tableting. The blending and granulation steps can be performed independently under low shear or high shear. Easily disintegrates, flows easily enough to allow reliable control of weight fluctuations during capsule filling or tableting, and bulk for processing specific batches at individual doses and equipment selected for special capsules or tablet dies It is preferable to select a method of forming granules having a sufficiently dense, uniform API content in the state.

In another embodiment, the API is suspended together with one or more excipients in one or more sprayable liquids, preferably non-protic (e.g. non-aqueous or non-alcoholic) sprayable liquids, followed by rapid warming on the warmth. Solid dosage forms are prepared by a method comprising a spray drying step of spray drying.

Tablets may be prepared by compressing or molding the granules or spray-dried powders derived from any of the above-described methods, or capsules may be prepared by coating. Conventional tableting and encapsulation techniques known in the art can be used. If a coated tablet is to be prepared, conventional coating techniques are suitable.

Excipients for tablet compositions of the present invention provide a disintegration time of less than about 30 minutes, preferably up to about 25 minutes, more preferably up to about 20 minutes, even more preferably up to about 15 minutes, in a standard disintegration assay. It is preferable to select the one.

In another aspect of the invention, a pharmaceutical composition or drug can be prepared comprising modafinil and additional APIs. Modafinil and additional APIs may be in co-crystal form or may be included as a mixture or combination of active pharmaceutical ingredients. For example, the composition may include modafinil and caffeine as a combination. The composition comprising modafinil and caffeine can be used as a therapeutic agent for treating the same disease as modafinil. As such, in compositions comprising modafinil and caffeine, caffeine can yield a rapid release characteristic (smaller T _max compared to modafinil) for the solubility profile, while modafinil has a therapeutic effect that lasts for several hours after administration. Be sure to For example, the T _max 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 that of modafinil. Combination therapy includes administration of two or more APIs in the same formulation or in two or more co-administered formulations. APIs may be administered together at the same time, or may be administered separately at specified intervals.

Uses for modafinil are well known in the art and include treating paroxysmal sleep, multiple sclerosis-related fatigue, infertility, eating disorders, attention deficit hyperactivity disorder (ADHD), Parkinson's disease, incontinence, sleep apnea or myopathy It is included. In another embodiment, one or more of the modafinil compositions of the present invention can be used to treat one or more of the above diseases. Dosages and administrations for the modafinil compositions of the invention can be determined using routine methods in the art, but will generally fall within about 50 to about 700 mg per day.

In another embodiment, the compositions of the present invention can be administered to a mammal via injection. Injections include but are not limited to intravenous, subcutaneous and intramuscular injections. In another embodiment, the compositions of the invention are formulated for injection into a mammal in need of a therapeutic effect.

General Method for Making Co-crystals

a) High Throughput Crystallization Process Using CrystalMax® Platform

CrystalMax® includes an automated, integrated, high-throughput robotic station that allows rapid generation, identification, and characterization of polymorphs, salts, and co-crystals of APIs and API candidates. Using patented design software Architect ™, worksheet generation and combinatorial mixed design were performed. Typically, the API or API candidate was dispensed from the organic solvent into the tube and dried under a stream of nitrogen. Salts and / or co-crystal formers can also be dispensed and dried in the same way. Using a multi-channel distributor, water and organic solvents can be combined into tubes in combination. Each tube in the 96-tube array was then sealed within 15 seconds of the combined dispensing as above to prevent the solvent from evaporating. The mixture was then heated to 70 ° C. for 2 hours and then allowed to supersaturate by cooling to 5 ° C. with a ramp cooling 1 ° C. per minute. Then, optical inspection was performed to detect crystals and / or solid matter. Once solids were identified in the tubes, they were aspirated and dried to separate. Raman spectra for these solids were then obtained, and the patent software (Inquire ™) was used to group the spectral patterns by cluster.

b) crystallization process from solution

Co-crystals can be obtained by dissolving the separate components in a particular solvent and then adding one to the other. Then, as the solvent mixture is slowly evaporated, the co-crystals can precipitate or crystallize. Co-crystals may also be obtained by dissolving two components in the same solvent or solvent mixture. Co-crystals may also be obtained by seeding a two-component saturated solution and seeding together with the co-crystal polishing mixture.

c) crystallization process from the melt (co-melt)

Co-crystals can be obtained by melting the two components together (ie, co-melting) and then causing recrystallization to occur. In some cases, anti-solvents can be added to promote crystallization.

d) using a thermal microscope

Co-crystals can be obtained by melting the higher melting component on a glass slide and then recrystallizing it. The second component is then melted and it is also recrystallized. Co-crystals can be formed as bands between eutectic bands of separated phase / 2 original components.

e) mixing and / or polishing

Co-crystals can be obtained by mixing or polishing the two components together in a solid state. For example, Example 12 describes the synthesis of modafinil: 1-hydroxy-2-naphthoic co-crystals obtained by grinding (wet polishing) with addition of a small amount of a suitable solvent. Similarly, Example 5 describes the synthesis of modafinil: citric acid monohydrate co-crystals obtained by grinding with addition of a small amount of a suitable solvent or by grinding without addition of a solvent. In one embodiment, the co-crystals are prepared by grinding or polishing (dry polishing) modafinil with the co-crystal former. In another embodiment, co-crystals are prepared by grinding or grinding (wet polishing) modafinil, the co-crystal former and a small amount of solvent.

In another embodiment, co-crystals are prepared while adding a solvent, without adding a solvent, or both. Solvents used in such co-crystallization processes are, for example, acetone, methanol, ethanol, isopropyl alcohol, ethyl acetate, isopropyl acetate, nitromethane, dichloromethane, chloroform, toluene, propylene glycol, dimethyl sulfoxide (DMSO ), Dimethyl formamide (DMF), diethyl ether (ether), ethyl formate, hexane, acetonitrile, benzyl alcohol, water, or another organic solvent, including but not limited to alcohol.

f) co-sublimation

By heating or mixing the mixture of API and co-crystal former, or by placing the mixture under vacuum, the mixture of API and co-crystal former is co-sublimed as co-sublimation in the same sample cell as an intimate mixture. Crystals can be obtained. The API and co-crystal former are contained in separate sample cells connected to a single finger cooler, and each of these sample cells is kept under the same or different temperatures under vacuum atmosphere to form the desired co-crystals. Co-crystals may also be obtained by co-sublimation using a Kneudsen apparatus that allows co-sublimation of the two components on a finger cooler.

Analysis method

Differential Scanning Calorimetry (DSC) analysis of samples was performed using the Q1000 Differential Scanning Calorimeter (Advantage) [Version 1.0.0.78, Thermal Advantage Release 2.0 (2001 TA Instruments-Water LLC)]. TA Instruments, New Castle, DE, USA). In addition, the analytical software used is Universal Analysis 2000 for Windows 95/98/2000 / NT [Version 3.1E; Build 3.1.0.40 (2001 TA Instruments-Water LLC).

The purge gas used for DSC analysis was anhydrous nitrogen, the reference material was an empty aluminum pan crimped, and the sample spread was 50 mL per minute.

DSC analysis of the samples was performed by placing the modafinil sample in an aluminum pan with a crimped pan compartment. The starting temperature is typically 20 ° C., which is heated by 10 ° C. per minute and the ending temperature is 200 ° C. All reported DSC transitions exhibit endothermic or exothermic transition temperatures at their respective peaks, with an error of ± 2 ° C. unless otherwise indicated.

Thermogravimetric analysis (TGA) of samples was performed on the Q500 thermogravimetric analyzer (TA Instruments, New Castle) using Advantages for the QW-Series (version 1.0.0.78, Thermal Advantage Release 2.0 (2001 TA Instruments-Water LLC)). , DE, USA). In addition, the analytical software used was Universal Analyzes 2000 for Windows 95/98/2000 / NT [Version 3.1E; Build 3.1.0.40 (2001 TA Instruments-Water LLC).

The purge gas used for the TGA experiment was anhydrous nitrogen, balanced spread 40 mL N ₂ per minute and sample spread 60 mL N ₂ per minute.

TGA was performed on the sample by placing the modafinil sample in a platinum pan. The starting temperature is typically 20 ° C., which is heated by 10 ° C. per minute and the ending temperature is 300 ° C.

D / Max Rapid, Contact (Rigaku / MSC, The Woodlands, TX, USA) using the following software [RINT Rapid Control Software, Rigaku Rapid / XRD, version 1.0.0 (1999 Rigaku Co.)] as a control software. Was used to obtain a powder X-ray diffraction (PXRD) pattern for the sample. In addition, the analytical software used was RINT Rapid display software [version 1.18 (Rigaku / MSC)], and JADE XRD Pattern Processing [versions 5.0 and 6.0 (1995-2002, Materials Data, Inc.). Was.

For PXRD analysis, the acquisition parameters are as follows: the source is Cu with K line at 1.5406 kV; x-y stage is manual; Collimator size is 0.3 mm; Capillary (Charles Supper Company, Natick, MA, U. S. A.) is 0.3 mm ID; Reflection mode was used; The power for the X-ray tube is 46 kV; The current for the X-ray tube is 40 mA; The omega-axis vibrates in the range of 0-5 degrees at a rate of 1 degree per minute; The pi-axis radiates at a 360 degree angle at a rate of 2 degrees per second; 0.3 mm collimator; Collection time is 60 minutes; Temperature is room temperature; No heater was used. Samples were presented to X-ray sources in boron rich glass capillaries.

In addition, the analytical parameters are as follows: the integrated 2-theta range is 2 to 60 degrees; The integrated chi range is 0 to 360 degrees; The chi segment number is 1; The step size used is 0.02; The integration utility is cylint; Standardization was used; Dark count is 8; The omega offset is 180; The chi and pi offsets are zero.

PXRD diffractograms were also obtained via a Bruker AXS D8 Discover X-ray diffractometer. The instrument includes a GADDS ™ (General Area Diffraction Detection System), a Bruker AXS HI-STAR area detector with a 15.05 cm spacing according to system calibration, a copper source (Cu / K _α 1.54056 angstroms), an automated xyz stage, and a 0.5mm collimator Is equipped. The sample was densified to pellet form and placed on xyz stage. The powder was set to 40 kV and 40 mA in reflection mode while keeping the sample stationary and diffractograms were obtained under ambient conditions (25 ° C.). The exposure time for each sample was varied and specified. The diffractogram obtained is subjected to a spatial remapping process to reveal the reason of the geometric cushion deformation of the area detector, followed by 2-theta 2.1 to 37 degrees and chi at a step size of 0.02 degrees with a normalization process set up for normalization. As a result, it was integrated from -118.8 degrees to -61.8 degrees.

The relative intensity of the peak in the diffractogram does not necessarily limit the PXRD pattern, for example, because the peak intensity may vary from sample to sample due to crystalline impurities. In addition, each peak angle may vary from about ± 0.1 degrees, preferably ± 0.05. The entire pattern, or most of the pattern peaks, may vary from about ± 0.1 degrees to about ± 0.2 degrees because of differences in calibration, differences in settings, and device-specific and operator-specific variations. All PXRD peaks shown anywhere in the figures, examples, and specification herein are reported to have an error of about ± 0.1 degrees 2-theta.

Regarding the PXRD data herein, including the tables and figures, each composition of the present invention is defined as having any one, two, three, four, five, six, seven or eight or more of the two theta-angle peaks. Can be characterized. Any one, two, three, four, five or six DSC transitions may be used to characterize the compositions of the present invention. Different combinations of PXRD peaks and DSC transitions may be used to characterize the compositions of the present invention.

Thermal (microscopic) microscopy was completed on a Zeiss Axioplan 2 microscope equipped with a Mettler Toledo FP90 controller. The hot end used was METTLER TOLEDO FP82HT. All melting point measurements were completed by placing the sample on a microscope slide and covering it with a coverslip. The initial temperature was set at 30 ° C., which was raised by 10 ° C. per minute. Melting was observed through a 5x microscope objective.

HPLC method: See Donovan et al. Therapeutic Drug Monitoring 25: 197-202.

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

Mobile phase A: 20 mM sodium phosphate, pH 3.0

        B: 70:30 mobile phase A: acetonitrile

   Flow rate: 1.0 mL / min (about 1500 PSI)

Flow program: gradient

Run time: 35 minutes

Detection: UV @ 225 nm

Injection volume: 10 microliters

Column temperature: 30 ± 1 ℃

Standard Diluent: 90:10 (v / v) Mobile Phase A: Acetonitrile

Needle Wash Solution: Acetonitrile

Purge Solvent & Seal Wash: 90:10 (v / v) Water: Acetonitrile

Mobile phase manufacturing:

1. Preparation of 1 M monovalent sodium phosphate: 120 g of monovalent sodium phosphate is dissolved in water to 1000 mL and then filtered.

2. Preparation of Mobile Phase A (20 mM Sodium Phosphate, pH 3.0): Using water, dilute 20 mL 1 M sodium phosphate per liter to 1000 mL; The pH is adjusted to 3.0 using phosphoric acid.

3. Preparation of mobile phase B (70:30 (v / v) 20 mM sodium phosphate, pH 3.0: acetonitrile): For each liter, mix 700 mL mobile phase A with 300 mL of acetonitrile.

Sample preparation:

1. Dissolve the sample in 90:10 (v / v) 20 mM sodium phosphate, pH 3.0: acetonitrile to a concentration of approximately 20 micrograms / mL.

Raman Acquisition:

Samples were left in glass vials and processed therein, or aliquots of samples were transferred to glass slides. This glass vial or slide was placed in the sample chamber. Measurements were made using an Almega ™ Dispersive Raman (Almega ™ Dispersive Raman, Thermo-Nicolet, 5225 Verona Road, Madison, WI 53711-4495) system with a fixed 785 nm laser source. Using the microscope portion of the device equipped with a 10 × magnification objective (unless otherwise specified), the laser was directed towards the sample surface by manually focusing the sample. Spectra were acquired using the parameters summarized in Table A (exposure time and number of exposures may vary; changes to the parameters will be described for each acquisition):

Raman spectrum acquisition parameters parameter Settings used Exposure time (s) 2.0 Impressions 10 Laser source wavelength (nm) 785 Laser power (%) 100 Caliber Pinhole Aperture size (㎛) 100 Spectral range 104-3428 Grid position single Temperature at acquisition (℃) 24.0

IR acquisition:

The following instruments [NexusTM 470 FT-IR, Thermo-Nicolet, 5225 Verona Road, Madison, WI 53711-4495] were used to obtain IR spectra, and software for control and analysis [OMNIC, version 6.0a, (C) Thermo- Nicolet, 1995-2004].

Data for the co-crystals are presented in Table IV and the figures.

Example 1

Racemic modafinil: malonic acid co-crystal

Malonic acid (114.9 mg, 1.104 mmol) was added to a solution containing racemic modafinil (150 mg, 0.549 mmol) in acetic acid (600 microliters). The mixture was then heated on a hotplate at 67 ° C. until all material dissolved. The solution was dried under nitrogen flow to give 1: 1 modafinil: malonic acid co-crystals as colorless solids. This solid material was characterized by PXRD. The material was then dried overnight under additional nitrogen flow to yield the same material with a slight excess of malonic acid. Colorless solids were characterized by PXRD (Bruker), DSC, TGA, IR and Raman spectroscopy. PXRD data for modafinil: malonic acid (1: 1) co-crystals are described in Table IV, the diffractograms of which are shown in FIG. 1 (data as collected / accepted), DSC at about 106 ° C. An endothermic transition was shown and its temperature record is shown in FIG. 2. TGA thermograms are shown in FIG. 3. 4A and 4B show Raman spectra of modafinil: malonic acid co-crystals and three Raman spectra of modafinil, malonic acid and co-crystal, respectively. 5A and 5B show the IR spectra of modafinil: malonic acid co-crystals and the three IR spectra of modafinil, malonic acid and co-crystals, respectively. Modafinil: malonic acid co-crystals include, but are 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-theta It can be characterized by any one, two, three, four, five or six or more of the peaks.

Modafinil: malonic acid co-crystals were also prepared by polishing the API and the co-crystal former together. Racemic modafinil (2.50 g, 0.009 mol) and malonic acid (1.01 g, 0.0097 mmol) were mixed in a large mortar and pestle over 7 days (malonic acid was added in 7 days increments, about 1: A 1.05 ratio was made and added over the next 7 days increasing to a 1: 2 modafinil: malonic acid ratio). The mixture was initially ground for 45 minutes and further malonic acid was added every 20 minutes. On day 7, the mixture of co-crystals and starting component was heated in a sealed 20 ml vial at 80 ° C. for about 35 minutes to complete co-crystal formation. PXRD analysis (Bruker) of the resulting material was completed and the results are shown in FIG. 6A (data as accepted). Modafinil: malonic acid co-crystals include but are 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-theta Any one of two, three, four, five or six or more. DSC thermograms for the co-crystals showed an endothermic transition at about 116 ° C. in FIG. 6B. Single crystal data of modafinil: malonic acid co-crystals were obtained and reported next. 7 shows a packing diagram of modafinil: malonic acid.

Determination data: C ₁₈ H ₁₉ NO ₆ S, M = 377.40, monoclinic C2 / c; a = 18.728 (8) angstroms, b = 5.480 (2) angstroms, c = 33.894 (13) angstroms, alpha = 90 °, beta = 91.864 (9) °, gamma = 90 °, T = 100 (2) K, Z = 8, D _c = 1.442 Mg / m 3, V = 3477 (2) cubic angstroms, λ = 0.71073 angstroms, 6475 measured reflections, 3307 unique (R _int = 0.1567). The final residual is as follows: for I> 2 sigma (I), R ₁ = 0.1598, wR ₂ = 0.3301; For all 3307 data, R _l = 0.2544, wR ₂ = 0.3740.

Other methods have also been used to prepare modafinil: malonic acid co-crystals. A third preparation method was performed by placing modafinil (30 mg, 0.0001 mol) and excess malonic acid in stainless steel vials. 20 microliters of acetone were added to the vial. The vial was then placed in a grinder (wig-l-bug, Bratt Technologies, 115 V / 60 Hz) and then the solid mixture was ground for 5 minutes. The powder thus produced was collected and characterized by PXRD and DSC. In another method for producing modafinil: malonic acid co-crystal, the third method of production was completed without adding a solvent. All of these methods with malonic acid were found to produce identical co-crystals via PXRD and DSC analysis.

Example 2

Racemic modafinil: glycolic acid co-crystal

Racemic modafinil (1 mg, 0.0037 mmol) and glycolic acid (0.30 mg, 0.0037 mmol) were dissolved in acetone (400 microliters). This solution was evaporated to dryness and the resulting solids were characterized by PXRD (Rigaku). PXRD data for modafinil: glycolic acid co-crystals are described in Table IV (see FIGS. 8A and 8B). 8A shows the PXRD diffractogram after subtracting background noise. 8B shows the PXRD raw data as collected.

Another method for preparing modafinil: glycolic acid co-crystals was also completed. To a solution of modafinil (1 mg, 0.0037 mmol) dissolved in a mixture of acetone and methanol (3: 1, 100 microliters) was added glycolic acid (0.28 mg, 0.0037 mmol) dissolved in methanol (500 microliters). . The solvent was then evaporated to dryness under nitrogen flow to give a mixture of the two starting components. Acetone (200 microliters) was then added to the mixture, which was heated to 70 ° C. and then held under 70 ° C. for 2 hours. The sample was then cooled to 5 ° C. and kept at this temperature for 1 day. After 1 day, the lid was removed from the vial and the solvent was evaporated to dryness to afford modafinil: glycolic acid co-crystals as a colorless solid. Modafinil: glycolic acid co-crystals were characterized by PXRD. Modafinil: glycolic acid co-crystals include any one or two of the peaks in FIG. 8A, including but not limited to 9.51, 14.91, 15.97, 19.01, 20.03, 21.59, 22.75, 25.03, and 25.71 ° 2-theta Can be characterized as three, four, five or six or more. Modafinil: glycolic acid co-crystals also include any one of two peaks in FIG. 8B, including but not limited to 9.53, 14.93, 15.99, 19.05, 20.05, 21.61, 22.77, and 25.05 ° 2-theta. Can be characterized as three, four, five or six or more.

Example 3

Racemic Modafinil: Maleic Acid Co-crystal

Maleic acid (30.7 mg, 0.264 mmol) was added to a solution of modafinil (150 mg, 0.549 mmol) in acetic acid (600 microliters). This mixture was then heated on a hotplate at 67 ° C. until all material dissolved. The solution was then dried under nitrogen flow to yield a clean amorphous material. This amorphous material was stored in sealed vials at room temperature. After 2 days, a solid material began to form, which was collected and identified as being modafinil: maleic acid co-crystal using PXRD (Rigaku), as shown in FIGS. 9A and 9B. 9A shows a PXRD diffractogram after subtracting background noise. 9B shows the PXRD raw material. PXRD data for modafinil: maleic acid co-crystals are shown in Table IV. Modafinil: maleic acid co-crystals include any of the peaks in FIG. 9A, including 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-theta It can be characterized as one, two, three, four, five or six or more. Modafinil: maleic acid co-crystal also includes, but is not limited to, the peaks in FIG. 9B including, 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-theta. Any one of two, three, four, five or six or more.

Example 4

Racemic modafinil: L-tartaric acid co-crystal

To a solution of racemic modafinil (10.12 mg, 0.037 mmol) in methanol (2 mL) was added L-tartaric acid (5.83 mg, 0.039 mmol). This solution was then evaporated at room temperature to yield a clear viscous material. This material was dried under additional nitrogen flow for 2 days, then placed in a vial and the lid closed. After 6 days, a small amount of colorless solid formed. One day after the first solid was observed, approximately 60% of the remaining clear amorphous volume was converted to solid form. Samples of this material were analyzed by PXRD (Bruker) as shown in FIG. 10. Modafinil: L-tartaric acid co-crystals include, but are 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-theta It can be characterized as any one, two, three, four, five or six or more.

Example 5

Racemic modafinil: citric acid co-crystal

Racemic modafinil (25.3 mg, 93 mmol) and citric acid monohydrate (26.8 mg, 128 mmol) were ground together for 3 minutes. Subsequently, 1 mg of the resulting mixture was dissolved in acetone (100 microliters), heated to 70 ° C. and held at this temperature for 2 hours. The solution was then cooled to 5 ° C. and left at this temperature for 2 days. After 2 days, the lid was removed from the vial and 1 drop of water was added. The solvent was then evaporated to give modafinil: citric acid monohydrate co-crystals as a colorless solid. Modafinil: citric acid monohydrate co-crystals were characterized by PXRD (Rigaku), as shown in FIG. 11A (background deducted). Modafinil: citric acid co-crystals include any one of the peaks in FIG. 11A, including 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-theta Can be characterized as three, four, five or six or more.

Other methods have also been used to prepare modafinil: citric acid monohydrate co-crystals. A second preparation process was performed by placing modafinil (30 mg, 0.0001 mol) and excess citric acid monohydrate in stainless steel vials. 20 microliters of acetone were added to the vial. The vial was then placed in a grinder (wig-l-bug, Bratt Technologies, 115 V / 60 Hz) and then the solid mixture was ground for 5 minutes. The powder thus produced was collected and characterized by PXRD and DSC. DSC thermograms are shown in FIG. 11B. In another method for producing modafinil: citric acid monohydrate co-crystal, the second method of preparation was completed without adding a solvent. All of the above methods with citric acid monohydrate were found to produce the same co-crystals via PXRD and DSC analysis.

Example 6

Racemic modafinil: succinic acid co-crystal

Racemic modafinil (25 mg, 90 mmol) and succinic acid (10.6 mg, 90 mmol) were placed in glass vials and dissolved in methanol (20 microliters). The resulting solution was heated at 70 ° C. for 2 hours and then cooled to 5 ° C. and maintained at this temperature for 2 days. After 2 days, the lid was removed from the vial and the solvent was evaporated under 65 ° C. to give 2: 1 modafinil: succinic acid co-crystals as a colorless solid. This co-crystal was a 2: 1 co-crystal comprising 2 moles of modafinil per mole of succinic acid. Modafinil: Succinic acid co-crystals were characterized by PXRD (Rigaku) and DSC, as shown in FIGS. 12A, 12B and 13. 12A shows the PXRD diffractogram after subtracting background noise. 12B shows the PXRD raw material. Figure 13 shows a DSC thermogram.

Another method for preparing modafinil: succinic acid co-crystals was also completed. To racemic modafinil (49.7 mg, 0.182 mmol) and succinic acid (21.6 mg, 0.182 mmol) in a round bottom flask was added methanol (1.5 mL). This mixture was then dissolved on a hotplate at 65 ° C. Subsequently, seed crystals of modafinil: succinic acid co-crystal from the preparation method were added to the flask. The methanol was then evaporated using a rotary evaporator and a 65 ° C. hot water bath to give modafinil: succinic acid co-crystals as a colorless solid. The collected solids were analyzed by PXRD (Rigaku) to confirm that modafinil: succinic acid co-crystals were synthesized. Modafinil: Succinic acid co-crystals include any of the peaks in FIG. 12A, including 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-theta Can be characterized as three, four, five or six or more. Modafinil: Succinic acid co-crystals also include any one of the peaks in FIG. Can be characterized as three, four, five or six or more. Single crystal data of modafinil: succinic acid co-crystals were obtained and reported next. FIG. 14 shows a packing diagram of modafinil: succinic acid co-crystal.

Decision Data: C ₁₇ H ₁₈ NO ₄ S, triclinic P-1; a = 5.672 (4) angstroms, b = 8.719 (6) angstroms, c = 16.191 (11) angstroms, alpha = 93.807 (14) °, beta = 96.471 (17) °, gamma = 92.513 (13) °, T = 100 (2) K, Z = 2, D _c = 1.392 Mg / m 3, V = 792.8 (9) cubic angstroms, λ = 0.71073 angstroms, 2448 measured reflectivity, 1961 unique (R _int = 0.0740). The final residual is as follows: for I> 2 sigma (I), R ₁ = 0.1008, wR ₂ = 0.2283; For all 1961 data R _l = 0.1593, w R ₂ = 0.2614.

Modafinil: succinic acid co-crystals have also been prepared using a third method. This method was performed by placing modafinil (30 mg, 0.0001 mol) and excess succinic acid in stainless steel vials. 20 microliters of acetone were added to the vial. The vial was then placed in a grinder (wig-l-bug, Bratt Technologies, 115 V / 60 Hz) and then the solid mixture was ground for 5 minutes. The powder thus produced was collected and characterized by PXRD and DSC. All of these methods with succinic acid were found to produce the same co-crystals via PXRD and DSC analysis.

Example 7

Racemic modafinil: DL-tartaric acid co-crystal

A suspension of racemic modafinil (162 mg; 0.591 mmol) and DL-tartaric acid (462 mg; 3.08 mmol) in acetone (10 mL) was heated to reflux for 1 minute. Undissolved DL-tartaric acid was filtered off through a 0.2 micron PTFE filter while the suspension was still heated. The remaining solution was cooled to room temperature and then cooled to 0 ° C. for 1 hour. After 1 hour, large colorless crystals were observed. The mother liquor was decanted and the solids were air dried and then characterized by PXRD (Rigaku) as shown in FIG. 15. Modafinil: DL-tartaric acid co-crystals include, but are 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-theta (as collected). It can be characterized by any one, two, three, four, five or six or more of the peaks within.

Example 8

Racemic Modafinil: Fumaric Acid Co-crystal (Form I)

Racemic modafinil (30 mg, 0.0001 mol) and fumaric acid (2.3 mg, 0.0002 mol) were placed in stainless steel vials. 20 microliters of acetone were added to the vial. The vial was then placed in a grinder (wig-l-bug, Bratt Technologies, 115 V / 60 Hz) and then the solid mixture was ground for 5 minutes. The resulting powder was collected and characterized as modafinil: fumaric acid co-crystal (form I) using PXRD (Rigaku) as shown in FIG. 16. This co-crystal was a 2: 1 co-crystal comprising 2 moles of modafinil per mole of fumaric acid. Modafinil: Fumaric acid co-crystals (Form I) include but are 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-theta (as collected) It can be characterized by any one, two, three, four, five or six or more of the peaks in FIG. 16, without limitation. Single crystal data of modafinil: fumaric acid co-crystal (form I) was obtained and reported next. FIG. 17 shows a packing diagram of modafinil: fumaric acid co-crystal (form I).

Decision data: C ₁₇ H ₁₇ NO ₄ S, M = 331.38, Samsa P-1; a = 5.7000 (15) angstroms, b = 8.735 (2) angstroms, c = 16.204 (4) angstroms, alpha = 93.972 (6) °, beta = 99.024 (6) °, gamma = 93.119 (7) °, T = 100 (2) K, Z = 2, D _c = 1.381 Mg / m 3, V = 797.2 (4) cubic angstroms, λ = 0.71073 angstroms, 4047 measured reflections, 2615 unique (R _int = 0.0475). The final residual is as follows: for I> 2 sigma (I), R ₁ = 0.0784, wR ₂ = 0.1584; For all 2615 data, R _l = 0.1154 and wR ₂ = 0.1821.

Example 9

Racemic Modafinil: Fumaric Acid Co-crystal (Form II)

Racemic modafinil (30 mg, 0.0001 mol) and fumaric acid (1.2 mg, 0.0001 mol) were placed in stainless steel vials. 20 microliters of acetone were added to the vial. The vial was then placed in a grinder (wig-l-bug, Bratt Technologies, 115 V / 60 Hz) and then the solid mixture was ground for 5 minutes. The resulting powder was collected and characterized as modafinil: fumaric acid co-crystal (form II) using PXRD (Rigaku) as shown in FIG. 18. Modafinil: Fumaric acid co-crystals (Form II) include 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-theta (as collected) However, without limitation, any one, two, three, four, five or six or more of the peaks in FIG. 18 may be characterized.

Example 10

Racemic Modafinil: Genticinic Acid Co-crystal

Racemic modafinil (30 mg, 0.0001 mol) and gentisic acid (1.5 mg, 0.0001 mol) were placed in stainless steel vials. 20 microliters of acetone were added to the vial. The vial was then placed in a grinder (wig-l-bug, Bratt Technologies, 115 V / 60 Hz) and then the solid mixture was ground for 5 minutes. The powder thus produced was collected and characterized by PXRD (Rigaku) as shown in FIG. 19. Modafinil: Gentisinic acid co-crystals include, but are not limited to, 6.96, 12.92, 14.76, 17.40, 18.26, 20.10, 20.94, 23.46, and 24.36 ° 2-theta (as collected) Any one of two, three, four, five or six or more.

Example 11

Racemic Modafinil: Oxalic Acid Co-crystal

The process for preparing modafinil: oxalic acid co-crystals was carried out by placing racemic modafinil (30 mg, 0.0001 mol) and oxalic acid (1-2 mg, 0,0001-0.0002 mol) in stainless steel vials. 20 microliters of acetone were added to the vial. The vial was then placed in a grinder (wig-l-bug, Bratt Technologies, 115 V / 60 Hz) and then the solid mixture was ground for 5 minutes. The powder thus produced was collected and characterized by PXRD (Bruker) as shown in FIG. 20. In another process for preparing modafinil: oxalic acid co-crystals, the process was completed without adding a solvent. Both methods were found to produce identical co-crystals through PXRD analysis. Modafinil: Oxalic acid co-crystals include any of the peaks in FIG. 20, including but not limited to 5.98, 13.68, 14.80, 17.54, 19.68, 21.12, 21.86, and 28.90 ° 2-theta (as collected) , Two, three, four, five or six or more.

Example 12

Racemic modafinil: 1-hydroxy-2-naphthoic acid co-crystal

Racemic modafinil (30 mg, 0.0001 mol) and 1-hydroxy-2-naphthoic acid (21 mg, 0.0001 mol) were placed in stainless steel vials. 20 microliters of acetone were added to the vial. The vial was then placed in a grinder (wig-l-bug, Bratt Technologies, 115 V / 60 Hz) and then the solid mixture was ground for 5 minutes. The powder thus produced was collected and characterized by PXRD (Bruker) as shown in FIG. 21. Modafinil: 1-hydroxy-2-naphthoic acid co-crystals are 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-theta (as collected) It can be characterized as any one, two, three, four, five or six or more of the peaks in Figure 21, including but not limited to. PXRD peaks under 10.05 and 26.36 ° 2-theta may be from excess co-crystal formers.

Example 13

R-(-)-modafinil: malonic acid co-crystal

R-(-)-modafinil: malonic acid co-crystal by grinding R-(-)-modafinil (29.7 mg, 0.109 mmol, 82.2% R-isomer) with malonic acid (11.9 mg, 0.114 mmol) Was prepared. The thus ground mixture was then heated to 80 ° C. for 10 minutes. Powders were analyzed by PXRD (Bruker) and DSC, as shown in FIGS. 22 and 23, respectively. The PXRD pattern confirmed that co-crystals were made and appeared to be much similar to the PXRD pattern for racemic modafinil: malonic acid co-crystals. R-(-)-modafinil: malonic acid co-crystals include, but are not limited to, 5.04, 9.26, 16.73, 18.23, 19.37, 21.90, 22.74, 24.44, and 25.67 ° 2-theta (as collected) , Any one, two, three, four, five or six or more of the peaks in FIG. 22. DSC indicated a melting range of 111.5-114.7 ° C. with a heat of fusion of 112.9 J / g.

Example 14

R-(-)-modafinil: succinic acid co-crystal

R-(-)-modafinil: succinic acid co-crystal was prepared by polishing R-(-)-modafinil (30.9 mg, 0.113 mmol, 82.2% R-isomer) with succinic acid (14.8 mg, 0.125 mmol). It was. The thus ground mixture was then heated to 145 ° C. for 5 minutes. Powders were analyzed by PXRD (Bruker) and DSC, as shown in FIGS. 24 and 25, respectively. The PXRD pattern confirmed that co-crystals were made and appeared to be much similar to the PXRD pattern for racemic modafinil: succinic acid co-crystals made from solution. R-(-)-modafinil: succinic acid co-crystals include, but are not limited to, 5.36, 9.83, 15.80, 17.88, 18.70, 19.87, 21.21, 21.85, and 25.96 ° 2-theta (as collected) Any one, two, three, four, five or six or more of the peaks in FIG. 24 may be characterized. DSC indicated a melting point range of 143.3-145.2 ° C. with a heat of fusion of 140.7 J / g.

Example 15

R-(-)-modafinil: citric acid co-crystal

R-(-)-modafinil: citrate co-crystal by grinding R-(-)-modafinil (30.0 mg, 0.110 mmol, 82.2% R-isomer) with citric acid monohydrate (27.1 mg, 0.129 mmol) Was prepared. Powders were analyzed by PXRD (Bruker) and DSC, as shown in FIGS. 26 and 27, respectively. The PXRD pattern confirmed that co-crystals were made, and appeared to be very similar to the PXRD pattern for racemic modafinil: citric acid co-crystals. R-(-)-modafinil: citric acid co-crystals include but are 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-theta (as collected) It can be characterized by any one, two, three, four, five or six or more of the peaks in FIG. 26, which are not limited. DSC showed a melting point range of 83.5-89.0 ° C. with a heat of fusion of 39.8 J / g.

Example 16

R-(-)-modafinil: DL-tartaric acid co-crystal

R-(-)-modafinil: DL-tartaric acid co-crystals were revealed from dichloromethane via high throughput crystallization equipment. The vial contained a 1: 2 mixture of R-(-)-modafinil (more than 98% R-isomer) and DL-tartaric acid. Co-crystals were also found from a 1: 1 mixture of R-(-)-modafinil (more than 98% R-isomer) and DL-tartaric acid in nitromethane. Solid material was collected and characterized using PXRD (Bruker) and DSC, as shown in FIGS. 28 and 29, respectively. R-(-)-modafinil: DL-tartaric acid co-crystals include, but are not limited to, 4.67, 15.41, 17.97, 19.46, 20.50, 22.91, and 24.63 ° 2-theta (as collected) It can be characterized by any one, two, three, four, five or six or more of the peaks within. Endothermic transitions were present at about 107, 152 and 187 ° C.

Example 17

R-(-)-modafinil: 1-hydroxy-2-naphthoic acid co-crystal

O-xylene (4.5 mL) in a solid mixture of R-(-)-modafinil (98.6 mg; 0.361 mmol, more than 98% R-isomer) and 1-hydroxy-2-naphthoic acid (71.2 mg; 0.378 mmol) Was added. The mixture was heated to reflux for less than 1 minute, at which time both solids dissolved. The solution was then slowly cooled to room temperature where the solids crystallized. The solid was collected by filtration and air dried. The powder was characterized by PXRD (Bruker) as shown in FIG. 30. Using this procedure, the same material was prepared from benzene, toluene and acetone. R-(-)-modafinil: 1-hydroxy-2-naphthoic acid co-crystal is 5.27, 8.85, 10.60, 12.11, 14.47, 17.80, 18.80, 21.20, 23.03, and 25.61 ° 2-theta (as collected May be characterized as any one, two, three, four, five or six or more of the peaks in FIG. 30, including but not limited to.

R-(-)-modafinil: 1-hydroxy-2-naphthoic acid co-crystal also contains R-(-)-modafinil (more than 98% R-isomer) and 1-hydroxy-2 in nitromethane. Obtained under high throughput crystallization equipment from a vial containing a 1: 1 mixture of naphthoic acid. Solid materials were obtained and characterized using DSC and PXRD (Bruker) as shown in FIGS. 31 and 32, respectively. R-(-)-modafinil: 1-hydroxy-2-naphthoic acid co-crystals include 5.34, 8.99, 10.68, 12.15, 14.51, 21.28, 23.14, and 24.50 ° 2-theta (as collected) However, without limitation, it may be characterized as any one, two, three, four, five or six or more of the peaks in FIG. 32. DSC showed endothermic transitions under about 118 and 179 ° C.

Example 18

R-(-)-modafinil: Orotic acid co-crystal

The R-(-)-modafinil: orotic acid co-crystal is composed of R-(-)-modafinil (1 mg, 0.0036 mmol, more than 98% R-isomer) and orotic acid (in acetone (100 microliters)). 1.14 mg, 0.0073 mmol) was obtained under high throughput crystallization equipment from a vial. The solid material obtained was visualized using PXRD (Bruker) and DSC, as shown in FIGS. 33 and 34, respectively. R-(-)-modafinil: orotic acid co-crystals include, but are not limited to, peaks in FIG. 33 including, but not limited to, 9.77, 17.85, 20.52, 20.95, 24.03, and 26.80 ° 2-theta (as collected) Any one, two, three, four, five or six or more. PXRD peaks under 14.61 and 28.60 may correspond to excess co-crystal formers. Endothermic transitions were present at about 116, 130 and 169 ° C.

Example  19

Acetic acid solvate of racemic modafinil

To racemic modafinil (12.9 mg, 0.047 mmol) was added acetic acid (40 microliters). The mixture was heated at 50 ° C. to completely dissolve the solids. When the solution was cooled to room temperature and left to stand overnight, no precipitate formed. The solution was then evaporated under nitrogen flow until precipitation was observed. The resulting solid was further dried under nitrogen flow. As shown in FIGS. 35 to 38, respectively, the identification of the product was achieved through PXRD (Rigaku), TGA, DSC, and Raman spectroscopy. Another method for preparing acida solvate of modafinil was also completed. Modafinil acetic acid solvate samples by dissolving racemic modafinil (12.9 mg, 0.047 mmol) in acetic acid (40 microliters), incubating at 65 ° C. for 30 minutes, then incubating overnight at 25 ° C. Was prepared. The sample was then evaporated to approximately 1/3 volume. After centrifugation of the sample, rapid nucleation and crystal growth were observed. Then 20 microliters of acetic acid was further added. The sample was heated at 50 ° C. until partial dissolution of the crystals was observed. The sample was then allowed to cool to room temperature over 1 hour and then to 5 ° C. for 3 hours to induce crystal growth. The sample was then dried under nitrogen gas. The rapid appearance of crystals was observed. Modafinil acetic acid solvate includes any one, two, or three of the peaks in FIG. 35, including but not limited to 6.17, 9.63, 15.69, 17.97, 19.99, and 21.83 ° 2-theta (data as collected). Can be characterized as dogs, four, five or six or more.

Example 20

Tetrahydrofuran Solvate of Racemic Modafinil

The tetrahydrofuran (THF) solvate of modafinil was prepared by placing racemic modafinil (10.4 mg, 0.038 mmol) in tetrahydrofuran (1 mL). The powder was not completely dissolved in THF and was converted to long, thin needle-shaped crystals overnight, which were collected and analyzed by PXRD (Rigaku) as shown in FIG. 39. Modafinil tetrahydrofuran solvates include, but are not limited to, 6.97, 9.79, 10.97, 16.19, 19.03, 19.71, 20.59, 22.25, and 25.13 ° 2-theta (data as collected) Any one of two, three, four, five or six or more.

Example 21

1,4-dioxane solvate of racemic modafinil

To racemic modafinil (11.6 mg, 0.042 mmol) was added 1,4-dioxane (1 mL). The mixture was then left to stand overnight to convert to long thin needle-like crystals which were collected and analyzed by PXRD (Rigaku) as shown in FIG. 40. Modafinil 1,4-dioxane solvate includes, but is not limited to, 6.93, 9.85, 10.97, 16.19, 18.97, 19.61, 20.33, 20.65, and 22.07 ° 2-theta (data as collected). It can be characterized by any one, two, three, four, five or six or more of the peaks within. The PXRD pattern also contained some spikes that resulted from instrument error, which could not be removed.

Example 22

Methanol Solvate of Racemic Modafinil

Methanol solvate of modafinil was obtained by evaporating 2 mL of a 30 mg / mL racemic modafinil solution in methanol overnight under nitrogen flow. Methanol solvates were characterized by PXRD (Rigaku), TGA, and DSC, as shown in FIGS. 41, 42, and 43, respectively. Modafinil methanol solvate includes any of the peaks in FIG. 41, including but not limited to 6.15, 9.89, 12.25, 15.69, 17.97, 20.07, 21.85, and 22.73 ° 2-theta (data as collected), Can be characterized as two, three, four, five or six or more.

Example 23

Nitromethane Solvate Of Racemic Modafinil

To racemic modafinil (12.9 mg, 0.047 mmol) was added nitromethane (1 mL). The mixture, which was not completely dissolved, was left overnight to convert to large square crystals. Solids were collected and analyzed by PXRD (Rigaku) as shown in FIG. 44. Modafinil nitromethane solvates include, but are not limited to, 6.17, 9.77, 15.89, 18.11, 20.07, 22.17, 22.91, 25.31, and 25.83 ° 2-theta (data as collected) among the peaks in FIG. 44. It can be characterized as any one, two, three, four, five or six or more.

Example 24

Acetone Solvate of Racemic Modafinil

A solution containing racemic modafinil (300 mg, 0.001 mol) and glutaric acid (150 mg, 0.001 mol) in acetone (3 mL) was heated until it boiled to dissolve all solid material. Once the solids dissolved, the solution was placed on an aluminum block at 5 ° C. After 15 minutes of leaving at 5 ° C., crystals began to form on the bottom of the vial. The solution was then decanted, single crystals collected, and analyzed using PXRD (Rigaku), as shown in FIG. 45. This crystal was determined to be the acetone solvate of modafinil. Acetone solvates of modafinil include, but are 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-theta (as collected). Any one, two, three, four, five or six or more of the peaks within 45 may be characterized. Acetone solvates may also be obtained according to this process using several other co-crystal formers, including adipic acid, lactobionic acid, maleic acid and glycolic acid.

Example 25

Racemic modafinil (1 mg, 0.0037 mmol) and mandelic acid (0.55 mg, 0.0037 mmol) were dissolved in acetone (400 microliters). The solution was evaporated to dryness and the resulting solids were characterized by PXRD (Rigaku), as shown in FIG. 46. The solid thus obtained was a mixture of acetone solvate and another product of modafinil. This form includes any one, two, three, four, five of the peaks in FIG. 46, including but not limited to 6.11, 9.53, 15.77, 18.03, 20.01, and 21.61 ° 2-theta (background removed). Can be characterized as dogs or six or more. Other peaks, including 6.75, 10.31, 14.77, and 23.27, may correspond to modafinil polymorphs.

Example 26

Racemic modafinil (1 mg, 0.0037 mmol) and fumaric acid (0.42 mg, 0.0037 mmol) were dissolved in 1,2-dichloroethane (400 microliters). The solution was evaporated to dryness and the resulting solids were characterized by PXRD (Rigaku), as shown in FIG. 47. The solid thus obtained may be a solvate of modafinil. Such forms include, but are not limited to, any of the peaks in FIG. 47, including, but not limited to, 5.87, 8.95, 12.49, 13.99, 18.19, 19.99, 21.57, and 25.01 ° 2-theta (background removed). It can be characterized as four, five or six or more.

Example 27

Novel forms of racemic modafinil

Racemic modafinil was dispensed from a stock solution containing 50 mg of modafinil in 20 mL of 15: 5 acetone / methanol mixture. The solution was then evaporated to dryness under nitrogen flow. The benzoic acid was partitioned from the acetone solution and the mixture was evaporated to dryness again. Then 200 microliters of isopropyl alcohol or methanol were added and the vial was capped. After standing at room temperature for 1 day, the lid was removed and the solvent was evaporated. As shown in FIG. 48, PXRD (Rigaku) was performed on the sample. A new form of racemic modafinil, which may be polymorph or co-crystal, is designated as Form VII. Form VII includes any one of the peaks in FIG. 48, including 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-theta (data as collected). , Two, three, four, five or six or more.

Example 28

From dog Racemic  Pharmacokinetic Study of Modafinil: Malonic Acid Co-crystal

Racemic modafinil: malonic acid co-crystals (obtained from Example 1) were administered to dogs in pharmacokinetic studies. Modafinil: malonic acid co-crystal particles having an average particle size of about 16 micrometers were administered in this study. As reference, micronized modafinil with an average particle size of about 2 microns was also administered in this study. The AUC of modafinil: malonic acid co-crystal was determined to be 40-60% higher than pure modafinil. This higher bioavailability illustrates that important pharmacokinetic parameters have been adjusted due to aspects of the present invention. A compilation of important pharmacokinetic parameters measured in animal studies is presented in Table V below:

Pharmacokinetic Parameters of Modafinil: Malonic Acid Co-crystal and Pure Modafinil in Dogs parameter Pure modafinil Modafinil: Malonic Acid Co-crystal Average particle size 2 micrometer 16 micrometer C _max (ng / ml) 11.0 ± 5.9 10.3 ± 3.4 T _max (hr) 1.3 ± 0.6 1.7 ± 0.6 AUC (relative) 1.0 1.4-1.6 Half-life (hr) 2.1 ± 0.7 5.1 ± 2.4

Example 29

Racemic modafinil: malonic acid co-crystal solid-state stability

The stability of the racemic modafinil: malonic acid co-crystals was measured over four weeks under various temperatures and relative humidity. No decomposition was found at 20 or 40 ° C. Under 60 ° C., about 0.14% degradation per day was measured based on a single index model. At 80 ° C., about 8% degradation per day was measured.

The stability of the modafinil: malonic acid co-crystal was also measured under various temperatures and relative humidity over 26 weeks. 49 and 50 show 25 ° C., 60% RH; 40 ° C., 75% RH; 40 ° C., ambient RH; 60 ° C., ambient RH; 80 ° C., ambient RH; And percent impurity area as measured through HPLC vs. time (Note) for samples stored under various conditions including -20 ° C. These data suggest that the compound was stable when stored below 40 ° C. for at least 26 weeks. FIG. 51 compares the PXRD patterns of early and 26-week-old samples of modafinil: malonic acid co-crystals for several temperatures and RH levels.

Example 30

Formulation of Racemic Modafinil: Malonic Acid Co-crystal

Lactose was used to complete the formulation of the racemic modafinil: malonic acid co-crystals. Two mixtures, a mixture of modafinil and lactose, and a second mixture of modafinil: malonic acid co-crystal and lactose were polished together in the mortar. The mixture targeted a 1: 1 weight ratio of modafinil to lactose. In a mixture of modafinil and lactose, 901.2 mg of modafinil and 901.6 mg of lactose were ground together. In a mixture of modafinil: malonic acid co-crystal and lactose, 1221.6 mg of co-crystal and 871.4 mg of lactose were polished together. The resulting powder was analyzed by PXRD and DSC. The PXRD pattern and DSC thermogram of the mixture showed little change as a result of comparing both individual components. DSC of the co-crystal mixture showed a co-crystal melting peak under 113.6 ° C. with a heat of fusion of only 75.9 J / g. This heat of fusion is 59.5% of that found for co-crystals alone (127.5 J / g). This result was consistent with the 58.4 wt% ratio of co-crystals in the mixture. DSC of the modafinil and lactose mixture had a melting point of 165.7 ° C. This is slightly lower than the melting point (168.7 ° C.) measured for modafinil. The heat of fusion of the mixture (59.3 J / g) is 46.9% of the heat of fusion of modafinil alone (126.6 J / g), which is consistent with the figure estimated at 50%.

In vitro solubility of both modafinil: malonic acid co-crystals and pure modafinil was tested in capsules. Both gelatin and hydroxypropylmethyl cellulose (HPMC) capsules were used in this solubility study. The capsules were formulated with and without lactose. Prior to transfer all formulations to capsules, they were ground in weak mortar. The solubility of the capsules was tested in 0.01 M HCl (see FIG. 52).

In 0.11 H HCl, sieved and ground material was used in gelatin capsules:

Modafinil and modafinil: malonic acid co-crystals were passed through 38 micron sieves. 200.0 mg of sieved modafinil, 280.4 mg of sieved modafinil: malonic acid co-crystal, 200.2 mg of polished modafinil or 280.3 mg of grinding in gelatin capsules (Size 0, B & B Pharmaceuticals, Lot # 15-01202) Modafinil: malonic acid co-crystal was charged. Solubility studies were performed in a Vankel VK 7000 Benzsaver solubility test apparatus equipped with a VK750D heater / circulator set at 37 ° C. At 0 minutes, the capsules were put down in a vessel containing 900 mL 0.01 M HCl and stirred by paddle.

Absorbance was read using a Cary 50 spectrophotometer (wavelength set under 260 nm) at the following time points: 0, 5, 10, 15, 20, 25, 30, 40, 50, and 60 minutes. This absorbance was compared to the standard and the modafinil concentration of the solution was calculated.

O. O1  N HCl In, with or without lactose, the ground material was used in gelatin or HPMC capsules:

Modafinil and modafinil: malonic acid co-crystals were mixed with an equivalent amount of lactose (Spectrum, Lot QV0460) for approximately 5 minutes. 400.2 mg of modafinil and lactose (approx. 200 mg modafinil), or 561.0 mg of modafinil: malonic acid co-crystal and lactose (approx. 200 mg modal) in gelatin capsules (Size 0, B & B Pharmaceuticals, Lot # 15-01202) Finyl) was charged. 399.9 mg of modafinil and lactose, 560.9 mg of modafinil: malonic acid co-crystals and lactose, 199.9 mg of modafinil, or 280.5 mg of modafinil: malonic acid in HPMC capsules (Size 0, Shionogi, Lot # A312A6) Co-crystals were charged. Solubility studies were performed as previously described.

Example 31

In vitro solubility

FIG. 53 shows in vitro solubility data of undifferentiated racemic modafinil: malonic acid co-crystals and undifferentiated modafinil in mock gastric juice (SGF) and mock intestinal fluid (SIF). Both samples were blended with lactose and filled into HPMC capsules. The co-crystals released modafinil into solution more rapidly in both SGF and SIF than in the free form of modafinil. FIG. 54 compares the solubility of HPV capsules filled with modafinil: malonic acid co-crystals blended with lactose and the solubility of PROVIGIL tablets. FIG. 55 shows a dynamic vapor sorption (DVS) isothermal plot of modafinil: malonic acid co-crystal. This plot suggests that there was no appreciable level of water adsorption at up to 40% RH at 26 ° C.

Example 32

In vivo research

Pharmacokinetic studies were completed in dogs using both racemic modafinil: malonic acid and PROVIGIL tablets (200 mg) formulated with lactose. Seven capsules were filled with modafinil: malonic acid co-crystals and lactose to 476.24 ± 2 mg (each containing 200 mg of modafinil). FIG. 56 shows that co-crystal formulations showed increased C _max and increased bioavailability. Some important pharmacokinetic parameters are listed in Table VI. In Table VI, "C _max " is the maximum blood plasma concentration, "AUC (inf)" is the extrapolated area under the curve, and "t _1/2 " is the blood plasma level from the time of administration to be half of the C _max level. The time taken to decrease, "T _max " is the time to reach the maximum blood plasma concentration from the time of administration, "CL" is the clearance rate of modafinil and "F%" is the percent bioavailability (%).

Modafinil: Malonic Acid Co-crystal and PK Parameters of PROVIGIL from In Vivo Studies PROVIGIL (200 mg) C _max AUC (inf) t _1/2 T _max CL F% 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 Modafinil: Malonic Acid (200 mg Modafinil) C _max AUC (inf) t _1/2 T _max CL F% 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

Example 33

R-(-)-modafinil: gentisic acid co-crystal

R-(-)-modafinil (50 mg, 0.183 mmol, more than 98% R-isomer) and gentic acid (28.2 mg, 0.183 mmol) were placed in stainless steel vials. Ten microliters of acetone were added to the vial. This vial was then placed in a grinder (wig-l-bug, Bratt Technologies, 115 V / 60 Hz) and the solid mixture was ground for 5 minutes. The powder thus produced was then collected and characterized by PXRD (Rigaku) as shown in FIG. 57. R-(-)-modafinil: gentisic acid co-crystals include, but are not limited to, 7.07, 9.07, 12.31, 13.03, 14.09, 18.93, 19.83, and 21.27 ° 2-theta (as collected) Any one, two, three, four, five or six or more of the peaks at 57 can be characterized. Other PXRD peaks at 7.51, 16.03, 17.63, 18.39, 23.57, 26.93, and 28.85 ° 2-theta correspond to excess co-crystal formers.

Example 34

Channel Solvate of Racemic Modafinil

Channel solvates of modafinil were unexpectedly found. Channel solvates were made from a solution of racemic modafinil (97.9 mg, 0.358 mmol) and 1-hydroxy-2-naphthoic acid (68.8 mg, 0.366 mmol) in acetone (3.15 mL) dissolved on a 60 ° C. hotplate. . This solution was then evaporated under nitrogen flow while heating to a total volume of 1.6 ml. Once cooled, the solution was seeded with polishing racemic modafinil: 1-hydroxy-2-naphthoic acid co-crystals. Single crystals were obtained and characterized by single x-ray analysis. Single crystal x-ray parameters: P2 (1) / n, a = 12.737 (3) angstroms, b = 5.5945 (11) angstroms, c = 22.392 (5) angstroms, alpha = 90 °, beta = 104.140 (4) °, Gamma = 90 °, V = 1547.3 (5) Cubic Angstroms, Z = 2. FIGS. 58 and 59 show packing diagrams of acetone channel solvates of modafinil. This packing diagram shows acetone showing variable positions in the channel structure. Ethyl acetate channel solvates were also prepared according to the above method using ethyl acetate instead of acetone.

Example 35

O-xylene anti-solvate of racemic modafinil

o-xylene half- was prepared by preparing a 1: 2 solution of racemic modafinil (49.6 mg, 0.181 mmol) and 1-hydroxy-2-naphthoic acid (68.3 mg, 0.363 mmol) in o-xylene (4.5 ml). Solvate was formed. This mixture was heated on a hotplate while vortexing until all solids dissolved. The solution was then left to crystallize in a sealed vial. The powder thus produced was collected on a filter for centrifugation and analyzed by PXRD (Bruker) as shown in FIG. 60. Raman spectroscopy (FIG. 61), TGA (FIG. 62), and DSC (FIG. 63) were also used to analyze and characterize the anti-solvate. o-xylene solvate includes any one, two, three of the peaks in FIG. 60, including but not limited to 5.31, 6.53, 6.96, 10.68, 14.20, 17.64, 19.93, 25.69, and 26.79 ° 2-theta Can be characterized as four, five or six or more. The o-xylene solvate also includes, but is not limited to, any one, two, three, of the peaks (central spectrum) in FIG. 61, including but not limited to 1641, 1407, 1379, 1211, 1024, and 721 cm ⁻¹ . It can be characterized as four, five or six or more.

Example 36

Benzene semi-solvate of racemic modafinil

A benzene semi-solvate was formed by preparing a 1: 2 solution of racemic modafinil (50.6 mg, 0.181 mmol) and 1-hydroxy-2-naphthoic acid (70.1 mg, 0.373 mmol) in benzene (1.8 ml). I was. This mixture was heated on a hotplate while vortexing until all solids dissolved. The solution was then left to crystallize in a sealed vial. The powder thus produced was collected on a centrifugal filter and analyzed by PXRD (Bruker) as shown in FIG. 64. Raman spectroscopy (FIG. 65), TGA (FIG. 66), and DSC (FIG. 67) were also used to analyze and characterize the anti-solvate. Benzene solvate includes any of the peaks in FIG. 64, including 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-theta , Two, three, four, five or six or more. Benzene solvates also include, but are not limited to, any of the peaks in the FIG. 65 (central spectrum), including, but not limited to, 1637, 1600, 1409, 1380, 1214, 1025, 998, and 721 cm ⁻¹ . Can be characterized as dogs, four, five or six or more.

Example 37

Toluene anti-solvate of racemic modafinil

Toluene semi-solvate was formed by preparing a 1: 2 solution of racemic modafinil (37.3 mg, 0.136 mmol) and 1-hydroxy-2-naphthoic acid (51.3 mg, 0.273 mmol) in toluene (1 ml). I was. This mixture was heated on a hotplate while vortexing until all solids dissolved. The solution was then left to crystallize in a sealed vial. The powder thus produced was collected on a filter for centrifugation and analyzed by PXRD (Bruker) as shown in FIG. 68. Raman spectroscopy (FIG. 69), TGA (FIG. 70), and DSC (FIG. 71) were also used to analyze and characterize the anti-solvate. Toluene solvates include any one, two, three, four, five of the peaks in FIG. 68, including but not limited to 5.30, 5.96, 10.65, 12.90, 14.51, 17.60, and 18.15 ° 2-theta Or as six or more. Toluene solvates also include, but are not limited to, any one, two, or three of the peaks (central spectrum) in FIG. 69, including but not limited to 1640, 1581, 1408, 1380, 1209, 1024, 1001, and 722 cm ⁻¹ . Can be characterized as dogs, four, five or six or more.

Example 38

Pharmacokinetics of Modafinil Isomers

Dog pharmacokinetic studies (N = 6) of a single intravenous dose of R-(-)-modafinil were completed. The purity of R-(-)-modafinil in the administered formulation was about 80%. This formulation was compared to the formulation of racemic modafinil, which was also administered by the intravenous route to the same dog in a crossover design. The results are reported in Table VII. In Table VII, "C _max " is the maximum blood plasma concentration, "AUC (inf)" is the extrapolated area under the curve, and "t _1/2 " is such that blood plasma levels are half of the C _max levels from the time of administration. The time taken to reduce, "V _d " is the distribution capacity, and "CL" is the clearance rate of modafinil.

PK parameters of racemic modafinil and R-(-)-modafinil from in vivo studies Racemic Modafinil (5 mg / kg IV) C _max
(ng / ml) AUC (inf)
(ng / ml x hr) t _1/2
(hr) V _d
(ml / kg) CL
(ml / hr x kg) 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-(-)-modafinil (5 mg / kg IV) 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 suggest that there was no significant difference (significant difference) between the pharmacokinetics of R-(-)-modafinil and racemic modafinil after intravenous administration.

These results were in contrast to the pharmacokinetics of the isomers when administered by the oral route (see US Pat. No. 4,927,855, which is incorporated herein by reference in its entirety). In the study, four dogs received 30 mg of R-(-)-modafinil (40-982), S-(+)-modafinil (40-983), or racemic modafinil (40-476). / kg oral dose. AUC was calculated from the plasma concentrations of both forms (40-476) and sulfone metabolites were measured 2-9 hours after dose administration. Table VIII shows the pharmacokinetic data.

PK parameters of racemic modafinil, R-(-)-modafinil and S-(+)-modafinil from in vivo studies Administered compound
(30 mg / kg) Average AUC (racemate)
(mg / L x hr) Average AUC (Sulfone)
(mg / L x hr) 40-476 (racemate) 46.76 ± 6.95 35.12 ± 6.93 40-982 (R-(-)-modafinil) 97.22 ± 12.58 8.69 ± 1.22 40-983 (S-(+)-modafinil) 50.94 ± 8.77 83.12 ± 21.66

These results show significant differences between the metabolism of both isomers of modafinil, resulting in differences in the formation of inactive sulfone metabolites, resulting in exposure to API when administered as R-(-)-modafinil. Suggests more. The different profiles observed between the intravenous and oral routes are the fact that the formation of sulfone metabolites is mainly catalyzed by cytochrome CYP3A4, which is present at both intestinal and liver levels, and the affinity of CYP3A4 for S-(+)-modafinil. It could be explained by the fact that the degree is higher than the affinity for R-(-)-modafinil (stereoselective metabolism).

Example 39

R-(-)-modafinil ethanol solvate

A solution containing R-(-)-modafinil (100 mg, 0.366 mmol, 85.4% R-isomer) and racemic modafinil (40 mg, 0.146 mmol) in ethanol (3 ml) was prepared. The mixture was heated to reflux to dissolve the entire solid and then cooled to room temperature (25 ° C.). After keeping at room temperature for 15 minutes, the solution was left at 5 ° C. overnight. A solid precipitate was observed after 1 day, which was collected, dried and characterized by PXRD and TGA (FIGS. 72 and 73). This solid was determined to be the ethanol solvate of R-(-)-modafinil.

R-(-)-modafinil ethanol solvates include, but are not limited to, 6.13, 9.59, 15.69, 17.97, 20.05, 21.55, 22.35, 25.77, and 29.07 ° 2-theta (Rigaku PXRD, data as collected) Can be characterized as any one, two, three, four, five or six or more of the peaks in FIG. 72.

The TGA of the R-(-)-modafinil ethanol solvate identified in FIG. 73 showed about 5.4% weight loss between about 25 ° C and about 140 ° C.

Example 40

R-(-)-modafinil benzyl alcohol solvate

R-(-)-modafinil (100 mg, 0.366 mmol) was triturated with benzyl alcohol (40 microliters) for 5 minutes. The powders thus milled were then analyzed by PXRD, DSC, and TGA (Figures 74, 75 and 76). This powder was determined to be the benzyl alcohol solvate of R-(-)-modafinil.

R-(-)-modafinil benzyl alcohol solvates include, but are not limited to, 5.77, 7.76, 10.48, 15.78, 17.80, 18.57, 21.53, 22.97, and 27.73 ° 2-theta (Bruker PXRD, data as collected) Can be characterized as any one, two, three, four, five or six or more of the peaks in FIG. 74.

DSC of the R-(-)-modafinil benzyl alcohol solvate identified in FIG. 75 showed an endothermic transition under about 83 ° C.

The TGA of the R-(-)-modafinil benzyl alcohol solvate identified in FIG. 76 showed about 28.5% weight loss between about 25 ° C and about 125 ° C.

Example 41

R-(-)-modafinil isopropanol solvate

R-(-)-modafinil was slurried overnight in isopropanol. The liquid was filtered on a centrifugal filter and then dried under flowing nitrogen gas at 5 ° C. The resulting solids were analyzed by PXRD.

R-(-)-modafinil isopropanol solvates include, but are not limited to, 5.76, 7.77, 10.49, 15.79, 18.58, 21.53, 25.76, and 27.74 ° 2-theta (Bruker PXRD, data as collected) It may be characterized as any one, two, three, four, five or six or more of the peaks in FIG. 77.

Example 42

R-(-)-modafinil acetonitrile solvate

100 mg of R-(-)-modafinil was slurried in acetonitrile for 2 days. Solid was filtered out of suspension and analyzed by PXRD.

R-(-)-modafinil acetonitrile solvates include, but are not limited to, 5.29, 6.17, 8.16, 10.19, 11.19, and 21.86 ° 2-theta (Bruker PXRD, data as collected) It can be characterized by any one, two, three, four, five or six or more of the peaks.

Example 43

R-(-)-modafinil: glutaric acid co-crystal

R-(-)-modafinil (20-30 mg, more than 98% R-isomer) and glutaric acid (15-20 mg) were polished together in the presence of 1 drop of benzyl alcohol.

The resulting solids were characterized by PXRD (see FIG. 79), which may include co-crystals. R-(-)-modafinil: glutaric acid co-crystals are 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 ° 2-theta (Bruker PXRD, Data as collected), but may be characterized as any one, two, three, four, five or six or more of the peaks in FIG. 79.

Wet polishing was also used with acetone and water (co-crystals formed from both).

Example 44

R-(-)-modafinil: citric acid co-crystal

R-(-)-modafinil (20-30 mg, more than 98% R-isomer) and citric acid (15-20 mg) were polished together in the presence of 1 drop of benzyl alcohol.

The resulting solids were characterized by PXRD (see FIG. 80), which may include co-crystals. R-(-)-modafinil: citric acid co-crystals are 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 ° 2-theta (Bruker PXRD, Data as collected), but may be characterized as any one, two, three, four, five or six or more of the peaks in FIG. 80.

Wet polishing was also used with acetone (co-crystals formed).

Example 45

R-(-)-modafinil: L-tartaric acid co-crystal

R-(-)-modafinil (20-30 mg, more than 98% R-isomer) and L-tartaric acid (15-20 mg) were polished together in the presence of 1 drop of benzyl alcohol.

The resulting solids were characterized by PXRD (see FIG. 81), which may include co-crystals. R-(-)-modafinil: L-tartaric acid co-crystals include 4.56, 10.33, 14.45, 17.29, 19.91, 21.13, 23.10, 24.10, and 26.76 ° 2-theta (Bruker PXRD, data as collected) However, without limitation, it may be characterized as any one, two, three, four, five or six or more of the peaks in FIG. 81.

Wet polishing was also used with acetone and water (co-crystals formed from both).

Example 46

R-(-)-modafinil: oxalic acid co-crystal

R-(-)-modafinil (20-30 mg, more than 98% R-isomer) and oxalic acid (15-20 mg) were polished together in the presence of 1 drop of benzyl alcohol.

The resulting solids were characterized by PXRD (see FIGS. 82A and 82B), which may include one or more co-crystals. R-(-)-modafinil: oxalic acid (form I) co-crystals include but are not limited to 5.99, 14.73, 16.59, 17.38, 18.64, 25.66, and 28.85 ° 2-theta (Bruker PXRD, data as collected) It may be characterized by any one, two, three, four, five or six or more of the peaks in FIG. 82A, without limitation. R-(-)-modafinil: oxalic acid (form II) co-crystals include but are not limited to 5.66, 14.76, 17.20, 17.63, 19.60, 24.90, and 28.84 ° 2-theta (Bruker PXRD, data as collected) It can be characterized by any one, two, three, four, five or six or more of the peaks in FIG. 82B, which are not limited.

Wet polishing was also used with acetone and water (co-crystals formed from both).

Example 47

R-(-)-modafinil: palmitic acid co-crystal

R-(-)-modafinil (20-30 mg, more than 98% R-isomer) and palmitic acid (15-20 mg) were polished together in the presence of 1 drop of benzyl alcohol.

The resulting solids were characterized by PXRD (see FIG. 83), which may include co-crystals. R-(-)-modafinil: palmitic acid co-crystals are 3.80, 6.55, 7.66, 10.24, 11.49, 19.48, 21.09, 21.74, 22.20, 22.97, and 23.99 ° 2-theta (Bruker PXRD, as collected) Data) can be characterized as any one, two, three, four, five or six or more of the peaks in FIG. 83, including but not limited to.

Example 48

R-(-)-modafinil: L-proline co-crystal

R-(-)-modafinil (20-30 mg, more than 98% R-isomer) and L-proline (15-20 mg) were polished together in the presence of 1 drop of benzyl alcohol.

The resulting solids were characterized by PXRD (see FIG. 84), which may include co-crystals. R-(-)-modafinil: L-proline co-crystals are 6.52, 8.53, 10.25, 14.69, 19.06, 19.71, 20.75, 22.29, 22.75, 25.08, and 26.27 ° 2-theta (Bruker PXRD, as collected) Data) can be characterized as any one, two, three, four, five or six or more of the peaks in FIG. 84, including but not limited to.

Wet polishing was also used with acetone and methanol (co-crystals formed from both).

Example 49

R-(-)-modafinil: salicylic acid co-crystal

R-(-)-modafinil (20-30 mg, more than 98% R-isomer) and salicylic acid (15-20 mg) were polished together in the presence of one drop of benzyl alcohol.

The resulting solids were characterized by PXRD (see FIG. 85), which may include co-crystals. R-(-)-modafinil: salicylic acid co-crystals are 8.92, 10.85, 12.18, 14.04, 17.07, 17.59, 18.81, 21.24, 23.32, 25.22, and 28.59 ° 2-theta (Bruker PXRD, data as collected) It may be characterized as any one, two, three, four, five or six or more of the peaks in Figure 85, including but not limited to.

Example 50

R-(-)-modafinil: lauric acid co-crystal

R-(-)-modafinil (20-30 mg, more than 98% R-isomer) and lauric acid (15-20 mg) were polished together in the presence of 1 drop of benzyl alcohol.

The resulting solids were characterized by PXRD (see FIG. 86), which may include co-crystals. R-(-)-modafinil: lauric acid co-crystals are 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 ° 2-theta (Bruker PXRD, collected Data such as, but not limited to, any one, two, three, four, five or six or more of the peaks in FIG. 86.

Wet polishing was also used with acetone and methanol (co-crystals formed from both).

Example 51

R-(-)-modafinil: L-malic acid co-crystal

R-(-)-modafinil (20-30 mg, more than 98% R-isomer) and L-malic acid (15-20 mg) were polished together in the presence of 1 drop of acetone.

The resulting solids were characterized by PXRD (see FIG. 87), which may include co-crystals. R-(-)-modafinil: L-malic acid co-crystals are 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 ° 2-theta (Bruker PXRD, collected Data such as, but not limited to, any one, two, three, four, five or six or more of the peaks in FIG. 87.

Example 52

Preparation of Benzhydrylthioacetic Acid from Benzhydrol

Thioglycolic acid (50 g, 0.542 mol) was added dropwise over 20 minutes to a solution of benzhydrol (100 g, 0.542 mol) in trifluoroacetic acid (300 ml) at room temperature (about 22 ° C.). The reaction progress was monitored by thin layer chromatography (TLC). The reaction was completed within 1 hour, at which time water (1000 ml) was slowly added into the reaction mixture to precipitate the product. The resulting precipitate was filtered, washed with water and then dried under high vacuum overnight to yield benzhydrylthioacetic acid (139.3 g, 99.3%) as a pale yellow solid. See Prisinzano, T. et al, Tetrahedron Asymm. , 2004, 15, 1053-1058.

Example 53

Preparation of Benzhydrylthioacetic Acid from Bromodiphenylmethane (One Pot Process)

To a solution of thiourea (30.4 g, 0.399 mol) in water (200 ml) was added bromodiphenylmethane (98.8 g, 0.399 mol) at 42 ° C. The mixture was gradually heated to reflux for 10 minutes. The reaction mixture was then cooled to 50 ° C. and 5 N NaOH (200 mL) was added successively. The reaction mixture was then heated to reflux (101-102 ° C.) for 30 minutes and then cooled to 60 ° C. continuously. To this reaction mixture was slowly added a solution of chloroacetic acid (53.4 g, 0.565 mol) and NaOH (22.2 g) in water (150 ml) over 45 minutes. The reaction mixture was stirred for another 30 minutes. The reaction was then cooled to room temperature and washed with t-butylmethylether (200 ml) to remove all non-carboxylic acid impurities. Concentrated HCl (50 ml) was used to acidify the aqueous layer (pH 2.0). The resulting precipitate was filtered, washed with water (2 × 200 mL) and then with heptane (200 mL) and air dried to give benzhydrylthioacetic acid (116.8 g, 100%) as a colorless solid. : US Pat. No. 4,066,686].

Example 54

Benzhydrylthioacetic acid was prepared from benzhydrol using trifluoroacetic acid in dichloromethane.

To a solution of benzhydryl (90 g, 0.488 mol) and trifluoroacetic acid (90 ml) in dichloromethane (300 ml) was added thioglycolic acid (40 g, 0.488 mol) in dichloromethane (60 ml) in 20 minutes. Dropwise over. This reaction was completed in 1 hour. The solvent was removed in vacuo to afford a crude solid which was dried overnight under high vacuum. The solid was treated with 2 N NaOH (1.0 L) and washed with t-butylmethylether (200 ml) to remove non-carboxylic acid impurities. The aqueous solution was then acidified with concentrated HCl, and the resulting precipitate was collected, washed with water and dried to give benzhydrylthioacetic acid (128.5 g) as a colorless solid.

Example 55

Benzhydrylsulfinylacetic acid is prepared from benzhydrylthioacetic acid.

To a suspension of benzhydrylthioacetic acid (63.7 g, 0.246 mol) in methanol (250 ml) was added a solution of concentrated H ₂ SO ₄ (1.6 mL) in isopropyl alcohol (65 ml) at room temperature (about 22 ° C.). To this suspension 30% H ₂ 0 ₂ (65 ml) in water was added dropwise over 25 minutes. The reaction was monitored by TLC and completed within 2 hours. This solution was diluted with a solution of NaHS0 ₃ (125 mg) in water (700 ml). The resulting precipitate was filtered off, washed with water and then with methanol: water (1: 1) and dried to give benzhydrylsulfinylacetic acid (47.6 g). ¹ H-NMR indicated that the desired product was obtained with approximately 10% starting material and some impurities. The compound was triturated with ethanol (100 ml), filtered and dried to give pure benzhydrylsulfinylacetic acid (33.4 g, 49.4%) as a colorless solid. Prisinzano, T. et al, Tetrahedron Asymm. , 2004, 15, 1053-1058.

Example 56

Oxidation of Benzhydrylthioacetic Acid

In a 50 L three-necked round bottom flask equipped with a mechanical stirrer, a 2 L dropping funnel, a nitrogen inlet and an internal temperature probe, benzhydrylthioacetic acid (3.5 kg, 13.54 mol) in isopropyl alcohol (6.5 L), Methanol (14 L) and H ₂ SO ₄ (72 g) solution was charged. 30% H ₂ O ₂ solution (3.75 L) in water was added dropwise over 80 minutes while maintaining the temperature below 30 ° C. The reaction mixture was further stirred for 7 hours, resulting in crystalline solids. The reaction was monitored using TLC and HPLC. The resulting solid was filtered and washed with water (4.0 L) to give benzhydrylsulfinylacetic acid (2.5 kg) as a colorless solid. Peroxide was quenched with NaHSO ₃ solution.

Example 57

S-(-)-α- Methylbenzylamine  using Benzhydrylsulfinylacetic acid  Separated

To a solution of (±) -benzhydrylsulfinylacetic acid (62.4 g, 0.227 mol) in water (300 ml) at 80 ° C. was added S-(−)-α-methylbenzyl amine (30 ml, 0.236 mol), 10 Stirred to reflux (101-102 ° C.) for minutes. The solution was gradually cooled to 40 ° C. and the resulting precipitate was filtered off, washed with water and dried to give a colorless solid (71.4 g). The salt was recrystallized in water (500 ml) to give another colorless solid (53.5 g). The salt was then suspended in water (200 ml), acidified with concentrated HCl (50 mL) and stirred for 10 minutes. The resulting suspension was filtered and washed with water to give R-(-)-benzhydrylsulfinylacetic acid (21.5 g) as a colorless solid. Chiral purity as measured by HPLC was> 99.9% ee (see US Pat. No. 4,927,855).

Example 58

Amidation of R-(-)-benzhydrylsulfinylacetic acid with N, N-carbonyl diimidazole to afford R-(-)-modafinil

In a 50 L three-necked round bottom flask equipped with a mechanical stirrer, nitrogen inlet and internal temperature probe, R-(-)-benzhydrylsulfinylacetic acid (1.32 kg, 4.81 mol) and tetrahydrofuran (7.0 L) Charged. To this slurry was added N, N-carbonyl diimidazole (1.215 kg, 7.49 mol) in tetrahydrofuran (7 L) to obtain a clear solution. This solution was then stirred for 30 minutes and then NH ₃ gas (191 g, 2.5 equiv) was bubbled into the reaction mixture for 3.5 h. After this time the volatiles were removed in vacuo to afford a crude solid which was ground overnight with a 20% methanol solution (7.0 L) in t-butylmethylether. The solid material was then collected and this solid was further purified by refluxing in a 1: 1 mixture of ethanol and t-butylmethylether (3 L). The reaction was then cooled to room temperature, the solid material was filtered off and dried to give R-(-)-modafinil (501 g, 99.6% chemical purity and 100% ee) as a colorless solid.

Example 59

Preparation of racemic modafinil through activation using N, N-carbonyl diimidazole (CDI)

N, N-carbonyl diimidazole (7.1 g, 0.043 mol) was added to a suspension of (±) -benzhydrylsulfinylacetic acid (10.0 g, 0.036 mol) in tetrahydrofuran (100 ml) to give a clear solution. Generated. The solution was stirred for 10 minutes, when a precipitate formed upon CO ₂ release. Subsequently, NH ₃ gas was bubbled into the reaction mixture for 10 minutes while the reaction temperature was raised from 16 ° C. to 33 ° C. The reaction mixture was then diluted with water and extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, washed with water and then brine and dried over Na ₂ SO ₄ . The organic layer was then concentrated in vacuo to afford crude modafinil (11.5 g). Recrystallization from 60% aqueous methanol gave pure modafinil (6.0 g) as a colorless solid.

Example 60

Synthesis of (±) -modafinil from benzhydrol

To a solution of benzhydrol (30 g, 0.162 mol) and trifluoroacetic acid (15 ml) in dichloromethane (120 ml) was added a solution of methyl thioglycolate (0.178 mol) in dichloromethane (30 ml) in 20 minutes. Dropwise over. The reaction was stirred for 1 h at room temperature and saturated NaHCO ₃ solution was added slowly. The organic layer was separated and concentrated in vacuo to afford crude benzhydrylthioacetate (38.2 g, 89%).

To a solution of NH ₄ Cl (0.29 mol, 2.0 equiv) and NH ₄ 0H (300 ml) in methanol (200 ml) while maintaining the temperature below 20 ° C., benzhydrylthioacetate (38.2 g) in methanol (50 ml) , 0.145 mol) solution was added. The reaction was stirred for 1 hour and diluted with water (100 ml) to form a precipitate. This precipitate was collected, washed with water and dried to give benzhydrylthioacetamide (31 g) as a colorless solid.

In the preparation of R-(-)-modafinil, racemic modafinil is obtained by oxidation of benzhydrylthioacetamide using H ₂ O ₂ according to the same method as used for the oxidation reaction of benzhydrylthioacetic acid. Obtained.

Claims (85)

delete delete delete delete delete delete delete Malonic acid, fumaric acid, tartaric acid, citric acid, succinic acid, gentisic acid, oxalic acid, 1-hydroxy-2-naphthoic acid, orotic acid, glutaric acid, L-tartaric acid, palmitic acid, L-proline, salicylic acid, lauric A co-crystal consisting of modafinil and a co-crystal former selected from the group consisting of acids, L-malic acid and maleic acid. 9. The method of claim 8, (a) The co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein   (i) the co-crystal is modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.08, 9.28 and 16.81 degrees;   (ii) the co-crystal is modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises peaks at 16.81, 18.27 and 19.45 degrees;   (iii) the co-crystal is modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises peaks at 9.28, 19.45 and 22.83 degrees;   (iv) the co-crystal is modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.08 and 9.28 degrees;   (v) the co-crystal is modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises peaks at 16.81 and 19.45 degrees;   (vi) the co-crystal is modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises peaks at 18.27 and 22.83 degrees;   (vii) the co-crystal is modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises a peak at 5.08 degrees;   (viii) the co-crystal is modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises a peak at 9.28 degrees; or   (ix) the co-crystal is modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises a peak at 16.81 degrees; (b) the co-crystal is characterized by a DSC thermogram, wherein the co-crystal is modafinil: malonic acid co-crystal and the DSC thermogram comprises an endothermic transition at 116 ± 2 ° C .; or (c) the co-crystal is characterized by a Raman spectrum containing a peak expressed in cm ⁻¹ , where   (i) the co-crystal is modafinil: malonic acid co-crystal and the Raman spectrum comprises peaks at 1004, 633, and 265;   (ii) the co-crystal is modafinil: malonic acid co-crystal and the Raman spectrum comprises peaks at 1032, 1601 and 767;   (iii) the co-crystal is modafinil: malonic acid co-crystal and the Raman spectrum comprises peaks at 1004 and 633;   (iv) the co-crystal is modafinil: malonic acid co-crystal and the Raman spectrum comprises peaks at 1183 and 767; or   (v) the co-crystal is modafinil: malonic acid co-crystal and the Raman spectrum comprises peaks at 1601 and 718 Ball-crystal. delete 9. The method of claim 8, (a) The co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein   (i) the co-crystal is modafinil: maleic acid co-crystal and the X-ray diffraction pattern comprises peaks at 4.69, 6.15 and 9.61 degrees;   (ii) the co-crystal is modafinil: maleic acid co-crystal and the X-ray diffraction pattern comprises peaks at 10.23, 19.97 and 21.83 degrees;   (iii) the co-crystal is modafinil: maleic acid co-crystal and the X-ray diffraction pattern comprises peaks at 4.69, 10.23 and 21.83 degrees;   (iv) the co-crystal is modafinil: maleic acid co-crystal and the X-ray diffraction pattern comprises peaks at 4.69 and 19.97 degrees;   (v) the co-crystal is modafinil: maleic acid co-crystal and the X-ray diffraction pattern comprises peaks at 6.15 and 9.61 degrees;   (vi) the co-crystal is modafinil: maleic acid co-crystal and the X-ray diffraction pattern comprises peaks at 4.69 and 6.15 degrees;   (vii) the co-crystal is modafinil: maleic acid co-crystal and the X-ray diffraction pattern comprises a peak at 4.69 degrees;   (viii) the co-crystal is modafinil: maleic acid co-crystal and the X-ray diffraction pattern comprises a peak at 9.61 degrees; or   (ix) the co-crystal is modafinil: maleic acid co-crystal and the X-ray diffraction pattern comprises a peak at 19.97 degrees; or (b) the co-crystal is characterized by a DSC thermogram, wherein the co-crystal is modafinil: maleic acid co-crystal and the DSC thermogram includes an endothermic transition at 168 ± 2 ° C. Ball-crystal. The method of claim 8, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein (a) the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 6.10, 14.33 and 20.71 degrees; (b) the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 16.93, 20.15 and 22.49 degrees; (c) the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 16.93, 20.71 and 29.72 degrees; (d) the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 6.10 and 20.15 degrees; (e) the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 14.33 and 20.71 degrees; (f) the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 7.36 and 25.04 degrees; (g) the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises a peak at 6.10 degrees; (h) the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises a peak at 16.93 degrees; or (i) the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises a peak at 20.71 degrees Ball-crystal. The method of claim 8, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein (a) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.29, 7.29 and 9.31 degrees; (b) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises peaks at 12.41, 13.29 and 14.61 degrees; (c) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises peaks at 17.29, 17.97 and 21.37 degrees; (d) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.29 and 17.29 degrees; (e) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises peaks at 7.29 and 9.31 degrees; (f) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises peaks at 12.41 and 21.37 degrees; (g) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises a peak at 5.29 degrees; (h) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises a peak at 7.29 degrees; or (i) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises a peak at 12.41 degrees Ball-crystal. 9. The method of claim 8, (a) The co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein   (i) the co-crystal is modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.45, 9.93 and 17.99 degrees;   (ii) the co-crystal is modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises peaks at 19.95, 21.95 and 25.07 degrees;   (iii) the co-crystal is modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.45, 17.99 and 21.35 degrees;   (iv) the co-crystal is modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.45 and 9.93 degrees;   (v) the co-crystal is modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises peaks at 17.99 and 21.95 degrees;   (vi) the co-crystal is modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises peaks at 9.93 and 19.95 degrees;   (vii) the co-crystal is modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises a peak at 5.45 degrees;   (viii) the co-crystal is modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises a peak at 9.93 degrees; or   (ix) the co-crystal is modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises a peak at 17.99 degrees; or (b) the co-crystal is characterized by a DSC thermogram, wherein the co-crystal is modafinil: succinic acid co-crystal and the DSC thermogram comprises an endothermic transition at 149 ± 2 ° C. Ball-crystal. The method of claim 8, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein (a) the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 4.75, 9.53 and 15.83 degrees; (b) the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 17.61, 20.25 and 22.55 degrees; (c) the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 10.07, 17.61 and 21.53 degrees; (d) the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 4.75 and 15.83 degrees; (e) the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 9.53 and 17.61 degrees; (f) the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 21.53 and 22.55 degrees; (g) the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises a peak at 4.75 degrees; (h) the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises a peak at 9.53 degrees; or (i) the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises a peak at 15.83 degrees Ball-crystal. The method of claim 8, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein (a) the co-crystal is modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.45, 9.95 and 18.03 degrees; (b) the co-crystal is modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 15.93, 18.81 and 21.95 degrees; (c) the co-crystal is modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 9.95, 19.93 and 23.09 degrees; (d) the co-crystal is modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.45 and 9.95 degrees; (e) the co-crystal is modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.45 and 18.03 degrees; (f) the co-crystal is modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 15.93 and 21.95 degrees; (g) the co-crystal is modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises a peak at 5.45 degrees; (h) the co-crystal is modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises a peak at 9.95 degrees; or (i) the co-crystal is modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises a peak at 18.03 degrees Ball-crystal. 17. The co-crystal of claim 16 which is modafinil: fumaric acid form I. The method of claim 8, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein (a) the co-crystal is modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 6.47, 8.57 and 9.99 degrees; (b) the co-crystal is modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 13.89, 14.53 and 20.79 degrees; (c) the co-crystal is modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 16.45, 18.39 and 20.05 degrees; (d) the co-crystal is modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 6.47 and 20.79 degrees; (e) the co-crystal is modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 9.99 and 14.53 degrees; (f) the co-crystal is modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 13.89 and 20.05 degrees; (g) the co-crystal is modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises a peak at 6.47 degrees; (h) the co-crystal is modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises a peak at 13.89 degrees; or (i) the co-crystal is modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises a peak at 20.79 degrees Ball-crystal. 19. The co-crystal of claim 18 which is modafinil: fumaric acid form II. The method of claim 8, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein (a) the co-crystal is modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises peaks at 6.96, 12.92 and 14.76 degrees; (b) the co-crystal is modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises peaks at 14.76, 18.26 and 20.10 degrees; (c) the co-crystal is modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises peaks at 6.96, 17.40 and 20.94 degrees; (d) the co-crystal is modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises peaks at 6.96 and 14.76 degrees; (e) the co-crystal is modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises peaks at 12.92 and 17.40 degrees; (f) the co-crystal is modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises peaks at 6.96 and 18.26 degrees; (g) the co-crystal is modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises a peak at 6.96 degrees; (h) the co-crystal is modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises a peak at 14.76 degrees; or (i) the co-crystal is modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises a peak at 18.26 degrees Ball-crystal. The method of claim 8, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein (a) the co-crystal is modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.98, 17.54 and 19.68 degrees; (b) the co-crystal is modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises peaks at 13.68, 14.80 and 21.12 degrees; (c) the co-crystal is modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises peaks at 17.54, 19.68 and 21.86 degrees; (d) the co-crystal is modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.98 and 19.68 degrees; (e) the co-crystal is modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises peaks at 13.68 and 14.80 degrees; (f) the co-crystal is modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.98 and 17.54 degrees; (g) the co-crystal is modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises a peak at 5.98 degrees; (h) the co-crystal is modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises a peak at 19.68 degrees; or (i) the co-crystal is modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises a peak at 17.54 degrees Ball-crystal. The method of claim 8, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein (a) the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.72, 7.10 and 14.16 degrees; (b) the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises peaks at 11.48, 15.66 and 20.26 degrees; (c) the co-crystal is modafinil: 1-hydroxy-2-naphthoic co-crystal and the X-ray diffraction pattern comprises peaks at 5.72, 7.10 and 20.26 degrees; (d) the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.72 and 7.10 degrees; (e) the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises peaks at 14.16 and 20.26 degrees; (f) the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.72 and 14.16 degrees; (g) the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises a peak at 5.72 degrees; (h) the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises a peak at 7.10 degrees; or (i) the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises a peak at 14.16 degrees Ball-crystal. 9. The method of claim 8, (a) The co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein   (i) the co-crystal is modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.04, 9.26 and 16.73 degrees;   (ii) the co-crystal is modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises peaks at 18.23, 19.37, and 22.74 degrees;   (iii) the co-crystal is modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.04, 16.73 and 19.37 degrees;   (iv) the co-crystal is modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.04 and 9.26 degrees;   (v) the co-crystal is modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises peaks at 16.73 and 19.37 degrees;   (vi) the co-crystal is modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises peaks at 9.26 and 18.23 degrees;   (vii) the co-crystal is modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises a peak at 5.04 degrees;   (viii) the co-crystal is modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises a peak at 9.26 degrees; or   (ix) the co-crystal is modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises a peak at 19.37 degrees; or (b) the co-crystal is characterized by a DSC thermogram, wherein the co-crystal is modafinil: malonic acid co-crystal and the DSC thermogram includes an endothermic transition at 115 ± 2 ° C. Ball-crystal. 24. The co-crystal of claim 23 wherein the modafinil is R-(-)-modafinil. 9. The method of claim 8, (a) The co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein   (i) the co-crystal is modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.36, 9.83 and 17.88 degrees;   (ii) the co-crystal is modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises peaks at 15.80, 19.87 and 21.85 degrees;   (iii) the co-crystal is modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.36, 9.83 and 21.85 degrees;   (iv) the co-crystal is modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.36 and 9.83 degrees;   (v) the co-crystal is modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises peaks at 17.88 and 19.87 degrees;   (vi) the co-crystal is modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises peaks at 9.83 and 15.80 degrees;   (vii) the co-crystal is modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises a peak at 5.36 degrees;   (viii) the co-crystal is modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises a peak at 9.83 degrees; or   (ix) the co-crystal is modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises a peak at 17.88 degrees; or (b) the co-crystal is characterized by a DSC thermogram, wherein the co-crystal is modafinil: succinic acid co-crystal and the DSC thermogram includes an endothermic transition at 145 ± 2 ° C. Ball-crystal. 26. The co-crystal of claim 25, wherein modafinil is R-(-)-modafinil. 9. The method of claim 8, (a) The co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein   (i) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.18, 7.23 and 9.23 degrees;   (ii) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises peaks at 12.32, 13.23 and 17.25 degrees;   (iii) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises peaks at 9.23, 17.92 and 21.30 degrees;   (iv) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.18 and 9.23 degrees;   (v) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises peaks at 7.23 and 13.23 degrees;   (vi) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises peaks at 17.25 and 17.92 degrees;   (vii) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises a peak at 5.18 degrees;   (viii) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises a peak at 7.23 degrees; or   (ix) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises a peak at 9.23 degrees; or (b) the co-crystal is characterized by a DSC thermogram, wherein the co-crystal is modafinil: citric acid co-crystal and the DSC thermogram includes an endothermic transition at 89 ± 2 ° C. Ball-crystal. The co-crystal of claim 27, wherein modafinil is R-(-)-modafinil. The method of claim 8, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein (a) the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.27, 8.85 and 10.60 degrees; (b) the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises peaks at 10.60, 14.47 and 21.20 degrees; (c) the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.27, 14.47 and 23.03 degrees; (d) the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.27 and 8.85 degrees; (e) the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises peaks at 10.60 and 23.03 degrees; (f) the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises peaks at 14.47 and 21.20 degrees; (g) the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises a peak at 5.27 degrees; (h) the co-crystal is modafinil: 1-hydroxy-2-naphthoic co-crystal and the X-ray diffraction pattern comprises a peak at 8.85 degrees; or (i) the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises a peak at 14.47 degrees Ball-crystal. 30. The co-crystal of claim 29 wherein modafinil is R-(-)-modafinil. The method of claim 8, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein (a) the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 4.67, 15.41 and 19.46 degrees; (b) the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 17.79, 19.46 and 22.91 degrees; (c) the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 4.67, 22.91 and 24.63 degrees; (d) the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 4.67 and 19.46 degrees; (e) the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 17.97 and 22.91 degrees; (f) the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 15.41 and 24.63 degrees; (g) the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises a peak at 4.67 degrees; (h) the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises a peak at 19.46 degrees; or (i) the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises a peak at 22.91 degrees Ball-crystal. 32. The co-crystal of claim 31 wherein the modafinil is R-(-)-modafinil. The method of claim 8, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein (a) the co-crystal is modafinil: orotic acid co-crystal and the X-ray diffraction pattern comprises peaks at 9.77, 17.85 and 20.52 degrees; (b) the co-crystal is modafinil: orotic acid co-crystal and the X-ray diffraction pattern comprises peaks at 17.85, 24.03 and 26.80 degrees; (c) the co-crystal is modafinil: orotic acid co-crystal and the X-ray diffraction pattern comprises peaks at 9.77, 20.52 and 24.03 degrees; (d) the co-crystal is modafinil: orotic acid co-crystal and the X-ray diffraction pattern comprises peaks at 9.77 and 17.85 degrees; (e) the co-crystal is modafinil: orotic acid co-crystal and the X-ray diffraction pattern comprises peaks at 17.85 and 24.03 degrees; (f) the co-crystal is modafinil: orotic acid co-crystal and the X-ray diffraction pattern comprises peaks at 9.77 and 26.80 degrees; (g) the co-crystal is modafinil: orotic acid co-crystal and the X-ray diffraction pattern comprises a peak at 9.77 degrees; (h) the co-crystal is modafinil: orotic acid co-crystal and the X-ray diffraction pattern comprises a peak at 17.85 degrees; or (i) the co-crystal is modafinil: orotic acid co-crystal and the X-ray diffraction pattern comprises a peak at 24.03 degrees Ball-crystal. 34. The co-crystal of claim 33, wherein modafinil is R-(-)-modafinil. delete delete delete delete delete delete delete delete delete delete delete delete delete The co-crystal of claim 8, wherein modafinil is R-(-)-modafinil. The co-crystal of claim 8, wherein the modafinil is S-(+)-modafinil. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete The method of claim 8, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein (a) the co-crystal is modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises peaks at 7.07, 9.07 and 12.31 degrees; (b) the co-crystal is modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises peaks at 9.07, 18.39 and 21.27 degrees; (c) the co-crystal is modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises peaks at 17.63, 23.57 and 26.93 degrees; (d) the co-crystal is modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises peaks at 9.07 and 16.03 degrees; (e) the co-crystal is modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises peaks at 7.51 and 21.27 degrees; (f) the co-crystal is modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises peaks at 7.07 and 7.51 degrees; (g) the co-crystal is modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises a peak at 9.07 degrees; (h) the co-crystal is modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises a peak at 7.07 degrees; (i) the co-crystal is modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises a peak at 16.03 degrees; (j) the co-crystal is modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises peaks at 7.07, 9.07, 16.03, 18.39, 21.27 and 23.57 degrees; or (k) the co-crystal is modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises peaks at 7.51, 12.31, 14.09, 16.03, 17.63 and 23.57 degrees Ball-crystal. The method of claim 8, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein (a) the co-crystal is modafinil: glutaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 9.78, 18.92 and 21.36 degrees; (b) the co-crystal is modafinil: glutaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 20.50, 22.25, and 23.87 degrees; (c) the co-crystal is modafinil: glutaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 8.67, 19.74 and 27.16 degrees; (d) the co-crystal is modafinil: glutaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 8.67 and 18.92 degrees; (e) the co-crystal is modafinil: glutaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 9.78 and 20.50 degrees; (f) the co-crystal is modafinil: glutaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 21.36 and 23.87 degrees; (g) the co-crystal is modafinil: glutaric acid co-crystal and the X-ray diffraction pattern comprises a peak at 23.87 degrees; (h) the co-crystal is modafinil: glutaric acid co-crystal and the X-ray diffraction pattern comprises a peak at 8.67 degrees; (i) the co-crystal is modafinil: glutaric acid co-crystal and the X-ray diffraction pattern comprises a peak at 9.78 degrees; (j) the co-crystal is modafinil: glutaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 8.67, 9.78, 18.92, 20.50 and 23.87 degrees; or (k) the co-crystal is modafinil: glutaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 18.92, 20.50, 21.36, 22.25 and 23.87 degrees Ball-crystal. The method of claim 8, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein (a) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises peaks at 7.06, 9.10 and 17.95 degrees; (b) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises peaks at 12.43, 13.18 and 20.85 degrees; (c) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.23, 7.06 and 9.10 degrees; (d) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.23 and 12.43 degrees; (e) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises peaks at 9.10 and 17.95 degrees; (f) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises peaks at 9.10 and 12.43 degrees; (g) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises a peak at 7.06 degrees; (h) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises a peak at 9.10 degrees; (i) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises a peak at 17.95 degrees; (j) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises peaks at 7.06, 12.43, 13.18, 17.95 and 20.85 degrees; or (k) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises peaks at 7.06, 9.10, 17.95, 21.39 and 22.96 degrees Ball-crystal. The method of claim 8, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein (a) the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 4.56, 10.33 and 17.29 degrees; (b) the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 17.29, 19.91 and 21.13 degrees; (c) the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 4.56, 14.45 and 19.91 degrees; (d) the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 4.56 and 10.33 degrees; (e) the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 17.29 and 19.91 degrees; (f) the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 19.91 and 21.13 degrees; (g) the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises a peak at 4.56 degrees; (h) the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises a peak at 10.33 degrees; (i) the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises a peak at 19.91 degrees; or (j) the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 4.56, 10.33, 17.29, 19.91 and 21.13 degrees Ball-crystal. The method of claim 8, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein (a) the co-crystal is modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.99, 14.73 and 17.38 degrees; (b) the co-crystal is modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises peaks at 17.38, 18.64 and 28.85 degrees; (c) the co-crystal is modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises peaks at 14.73, 18.64 and 25.66 degrees; (d) the co-crystal is modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.99 and 14.73 degrees; (e) the co-crystal is modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises peaks at 17.38 and 18.64 degrees; (f) the co-crystal is modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.99 and 28.85 degrees; (g) the co-crystal is modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises a peak at 5.99 degrees; (h) the co-crystal is modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises a peak at 14.73 degrees; (i) the co-crystal is modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises a peak at 28.85 degrees; or (j) the co-crystal is modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.99, 14.73, 17.38, 18.64 and 28.85 degrees Ball-crystal. The method of claim 8, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein (a) the co-crystal is modafinil: palmitic acid co-crystal and the X-ray diffraction pattern comprises peaks at 3.80, 6.55 and 7.66 degrees; (b) the co-crystal is modafinil: palmitic acid co-crystal and the X-ray diffraction pattern comprises peaks at 10.24, 19.48 and 21.09 degrees; (c) the co-crystal is modafinil: palmitic acid co-crystal and the X-ray diffraction pattern comprises peaks at 3.80, 19.48 and 23.99 degrees; (d) the co-crystal is modafinil: palmitic acid co-crystal and the X-ray diffraction pattern comprises peaks at 3.80 and 6.55 degrees; (e) the co-crystal is modafinil: palmitic acid co-crystal and the X-ray diffraction pattern comprises peaks at 6.55 and 7.66 degrees; (f) the co-crystal is modafinil: palmitic acid co-crystal and the X-ray diffraction pattern comprises peaks at 19.48 and 23.99 degrees; (g) the co-crystal is modafinil: palmitic acid co-crystal and the X-ray diffraction pattern comprises a peak at 3.80 degrees; (h) the co-crystal is modafinil: palmitic acid co-crystal and the X-ray diffraction pattern comprises a peak at 6.55 degrees; (i) the co-crystal is modafinil: palmitic acid co-crystal and the X-ray diffraction pattern comprises a peak at 7.66 degrees; (j) the co-crystal is modafinil: palmitic acid co-crystal and the X-ray diffraction pattern comprises peaks at 3.80, 7.66, 10.24 and 19.48 degrees; or (k) the co-crystal is modafinil: palmitic acid co-crystal and the X-ray diffraction pattern comprises peaks at 3.80, 6.55, 7.66, 10.24, 19.48 and 23.99 degrees Ball-crystal. The method of claim 8, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein (a) the co-crystal is modafinil: L-proline co-crystal and the X-ray diffraction pattern comprises peaks at 6.52, 8.53 and 10.25 degrees; (b) the co-crystal is modafinil: L-proline co-crystal and the X-ray diffraction pattern comprises peaks at 19.06, 22.75 and 25.08 degrees; (c) the co-crystal is modafinil: L-proline co-crystal and the X-ray diffraction pattern comprises peaks at 6.52, 10.25 and 19.06 degrees; (d) the co-crystal is modafinil: L-proline co-crystal and the X-ray diffraction pattern comprises peaks at 6.52 and 8.53 degrees; (e) the co-crystal is modafinil: L-proline co-crystal and the X-ray diffraction pattern comprises peaks at 6.52 and 10.25 degrees; (f) the co-crystal is modafinil: L-proline co-crystal and the X-ray diffraction pattern comprises peaks at 19.06 and 22.29 degrees; (g) the co-crystal is modafinil: L-proline co-crystal and the X-ray diffraction pattern comprises a peak at 6.52 degrees; (h) the co-crystal is modafinil: L-proline co-crystal and the X-ray diffraction pattern comprises a peak at 8.53 degrees; (i) the co-crystal is modafinil: L-proline co-crystal and the X-ray diffraction pattern comprises a peak at 19.06 degrees; (j) the co-crystal is a modafinil: L-proline co-crystal and the X-ray diffraction pattern comprises peaks at 6.52, 10.25, 19.06, 22.75 and 25.08 degrees; or (k) the co-crystal is modafinil: L-proline co-crystal and the X-ray diffraction pattern comprises peaks at 8.53, 10.25, 19.06, 22.29 and 25.08 degrees Ball-crystal. The method of claim 8, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein (a) the co-crystal is modafinil: salicylic acid co-crystal and the X-ray diffraction pattern comprises peaks at 8.92, 10.85 and 17.07 degrees; (b) the co-crystal is modafinil: salicylic acid co-crystal and the X-ray diffraction pattern comprises peaks at 12.18, 21.24 and 23.32 degrees; (c) the co-crystal is modafinil: salicylic acid co-crystal and the X-ray diffraction pattern comprises peaks at 8.92, 18.81 and 25.22 degrees; (d) the co-crystal is modafinil: salicylic acid co-crystal and the X-ray diffraction pattern comprises peaks at 8.92 and 10.85 degrees; (e) the co-crystal is modafinil: salicylic acid co-crystal and the X-ray diffraction pattern comprises peaks at 17.07 and 21.24 degrees; (f) the co-crystal is modafinil: salicylic acid co-crystal and the X-ray diffraction pattern comprises peaks at 23.32 and 25.22 degrees; (g) the co-crystal is modafinil: salicylic acid co-crystal and the X-ray diffraction pattern comprises a peak at 8.92 degrees; (h) the co-crystal is modafinil: salicylic acid co-crystal and the X-ray diffraction pattern comprises a peak at 10.85 degrees; (i) the co-crystal is modafinil: salicylic acid co-crystal and the X-ray diffraction pattern comprises a peak at 21.24 degrees; (j) the co-crystal is modafinil: salicylic acid co-crystal and the X-ray diffraction pattern comprises peaks at 8.92, 12.18, 17.07, 21.24 and 23.32 degrees; or (k) the co-crystal is modafinil: salicylic acid co-crystal and the X-ray diffraction pattern comprises peaks at 10.85, 14.04, 21.24 and 23.32 degrees Ball-crystal. The method of claim 8, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein (a) the co-crystal is modafinil: lauric acid co-crystal and the X-ray diffraction pattern comprises peaks at 3.12, 6.55 and 10.24 degrees; (b) the co-crystal is modafinil: lauric acid co-crystal and the X-ray diffraction pattern comprises peaks at 6.55, 13.97 and 17.62 degrees; (c) the co-crystal is modafinil: lauric acid co-crystal and the X-ray diffraction pattern comprises peaks at 3.12, 21.38 and 23.81 degrees; (d) the co-crystal is modafinil: lauric acid co-crystal and the X-ray diffraction pattern comprises peaks at 3.12 and 6.55 degrees; (e) the co-crystal is modafinil: lauric acid co-crystal and the X-ray diffraction pattern comprises peaks at 10.24 and 17.62 degrees; (f) the co-crystal is modafinil: lauric acid co-crystal and the X-ray diffraction pattern comprises peaks at 21.38 and 23.81 degrees; (g) the co-crystal is modafinil: lauric acid co-crystal and the X-ray diffraction pattern comprises a peak at 3.12 degrees; (h) the co-crystal is modafinil: lauric acid co-crystal and the X-ray diffraction pattern comprises a peak at 6.55 degrees; (i) the co-crystal is modafinil: lauric acid co-crystal and the X-ray diffraction pattern comprises a peak at 21.38 degrees; (j) the co-crystal is modafinil: lauric acid co-crystal and the X-ray diffraction pattern comprises peaks at 3.12, 10.24, 16.40, 19.02 and 21.38 degrees; or (k) the co-crystal is modafinil: lauric acid co-crystal and the X-ray diffraction pattern comprises peaks at 3.12, 6.55, 10.24, 21.38 and 23.81 degrees Ball-crystal. The method of claim 8, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein (a) the co-crystal is modafinil: L-malic acid co-crystal and the X-ray diffraction pattern comprises peaks at 4.62, 9.32 and 19.30 degrees; (b) the co-crystal is modafinil: L-malic acid co-crystal and the X-ray diffraction pattern comprises peaks at 9.32, 10.32, and 21.48 degrees; (c) the co-crystal is modafinil: L-malic acid co-crystal and the X-ray diffraction pattern comprises peaks at 19.30, 21.48 and 24.26 degrees; (d) the co-crystal is modafinil: L-malic acid co-crystal and the X-ray diffraction pattern comprises peaks at 4.62 and 9.32 degrees; (e) the co-crystal is modafinil: L-malic acid co-crystal and the X-ray diffraction pattern comprises peaks at 9.32 and 10.32 degrees; (f) the co-crystal is modafinil: L-malic acid co-crystal and the X-ray diffraction pattern comprises peaks at 19.30 and 21.48 degrees; (g) the co-crystal is modafinil: L-malic acid co-crystal and the X-ray diffraction pattern comprises a peak at 4.62 degrees; (h) the co-crystal is modafinil: L-malic acid co-crystal and the X-ray diffraction pattern comprises a peak at 9.32 degrees; (i) the co-crystal is modafinil: L-malic acid co-crystal and the X-ray diffraction pattern comprises a peak at 19.30 degrees; (j) the co-crystal is modafinil: L-malic acid co-crystal and the X-ray diffraction pattern comprises peaks at 4.62, 15.83, 17.38, 19.30 and 21.48 degrees; or (k) Co-crystals wherein said co-crystals are modafinil: L-malic acid co-crystals and said X-ray diffraction pattern comprises peaks at 9.32, 10.32, 17.38, 19.30, 21.48 and 24.26 degrees.

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