CN1874993B - Modafinil compositions - Google Patents

Abstract

The present invention produces co-crystals and solvates of racemic, enantiomerically pure, and enantiomerically mixed modafinil and modulates several important physical properties. The solubility, dissolution, bioavailability, dose response and stability of modafinil can be adjusted to improve efficacy in pharmaceutical compositions.

Description

Composition of modafinil

Cross References to Related Applications

This application is a continuation-in-part of application PCT/US03/27772, filed September 4, 2003, which claims US application 10/378,956, filed March 3, 2003, April 18, 2003 Priority to US Provisional Application 60/463,962, filed February 28, 2003, US Provisional Application 60/451,213, and US Provisional Application 60/487,064, filed July 11, 2003. Said US application 10/378,956, filed March 3, 2003 claims priority to US provisional application 60/360,768, filed March 1, 2002.

This application is also a continuation-in-part of US Application 10/660,202, filed September 11,2003, which claims priority from PCT/US03/27772, filed September 4,2003. Said U.S. application 10/660,202, filed September 11, 2003 also claims priority to U.S. application 10/637,829, filed August 8, 2003, which is a U.S. application filed November 18, 2002 Divisional Application 10/295,995, U.S. Application 10/295,995 is a continuation of U.S. Application 10/232,589 filed September 3, 2002, U.S. Application 10/232,589 claims U.S. Provisional Application 60 filed August 30, 2002 /406,974, US Provisional Application 60/380,288, filed May 15, 2002, and US Provisional Application 60/356,764, filed February 15, 2002. Said U.S. application 10/660,202, filed September 11, 2003, is also a continuation-in-part of U.S. application 10/449,307, filed May 30, 2003, which claims U.S. Provisional Application 60/463,962, U.S. Provisional Application 60/444,315 filed January 31, 2003, U.S. Provisional Application 60/439,282 filed January 10, 2003, and U.S. Provisional Application 60/384,152 filed May 31, 2002 priority. Said US application 10/660,202, filed September 11, 2003, is also a continuation-in-part of US application 10/601,092, filed June 20, 2003. Said U.S. Application 10/660,202, filed September 11, 2003, also requires U.S. Provisional Application 60/451,213, filed February 28, 2003, U.S. Provisional Application 60/463,962, filed April 18, 2003, and 2003 7 Priority to U.S. provisional application 60/487,064, filed 11 March.

This application is also a continuation-in-part of application PCT/US04/06288, filed February 26, 2004, which claims U.S. Provisional Application 60/451,213, filed February 28, 2003, July 11, 2003 U.S. Provisional Application 60/487,064 filed on September 4, 2003, US Application 10/660,202, filed September 11, 2003, PCT/US03/27772, filed September 4, 2003, and PCT/US03/2003, filed March 3, 2003 US03/06662, U.S. Provisional Application 60/508,208 filed October 2, 2003, U.S. Provisional Application 60/542,752, filed February 6, 2004, U.S. Provisional Application 60/463,962, filed April 18, 2003, 2003 U.S. Application 10/449,307 filed May 30, 2003 U.S. Provisional Application 60/456,027 filed March 18, 2003 U.S. Application 10/601,092 filed June 20, 2003, June 20, 2003 Priority to application PCT/US03/19574 and application PCT/US03/41273, filed December 24, 2003.

This application also claims U.S. Provisional Application 60/508,208, filed October 2, 2003, U.S. Provisional Application 60/542,752, filed February 6, 2004, U.S. Provisional Application 60/560,411, filed April 6, 2004, 2004 U.S. Provisional Application 60/573,412 filed May 21, 2004, U.S. Provisional Application 60/579,176, filed June 12, 2004, U.S. Provisional Application 60/581,992, filed June 22, 2004, July 9, 2004 Priority to US Provisional Application 60/586,752 filed and US Provisional Application 60/588,236 filed July 15, 2004.

All of the above applications from which priority is claimed are hereby incorporated by reference in their entirety.

technical field

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

Background technique

The active pharmaceutical ingredient (API) in the pharmaceutical composition can be prepared in a variety of different forms. Such APIs can be prepared in a variety of different chemical forms including chemical derivatives, solvates, hydrates, co-crystals or salts. Such APIs can also be prepared with different shapes. For example, an API may be amorphous, may have different crystalline polymorphs, or may exist in different solvated or hydrated states. By changing the form of the API, it is possible to change its physical properties. For example, crystalline polymorphs typically have different solubilities from each other such that thermodynamically more stable polymorphs are less soluble than thermodynamically less stable polymorphs. Pharmaceutical polymorphs can also differ in many properties such as shelf-life, bioavailability, morphology, vapor pressure, density, color, and compressibility. Thus, variation in the crystalline state of an API is one of the many aspects in which its physical properties are modulated.

New forms of these APIs with improved properties are advantageous, especially as oral formulations. In particular, it is desirable to identify improved forms of APIs that exhibit significantly improved properties, including increased water solubility and stability. In addition, it is desirable to improve the processability or manufacture of pharmaceutical formulations. For example, the needle-like crystal form or crystal habit of the API can cause aggregation, even in compositions where the API is mixed with other substances, so that an inhomogeneous mixture results. The needle-like morphology can also cause filtration problems (see eg Mirmehrabi et al., J. Pharm. Sci. Vol. 93, No. 7, pp. 1692-1700, 2004). It would also be desirable to increase the dissolution rate of API-containing pharmaceutical compositions in water, increase the bioavailability of orally administered compositions and provide a faster onset of therapeutic effect. It would also be desirable to have a form of API which, when administered to a subject, reaches peak plasma concentration more quickly, has longer-lasting therapeutic plasma concentrations and higher global exposure than equivalent amounts of currently known forms of API.

Modafinil, an API for the treatment of subjects with narcolepsy, is practically insoluble in water. Modafinil (CAS registration number: 68693-11-8) is represented by structural formula (I):

Modafinil is a chiral molecule due to the chiral S=O group. Thus, modafinil exists as two isomers, R-(-)-modafinil and S-(+)-modafinil. New forms of modafinil with improved properties would be advantageous, especially as oral formulations. In particular, it is desirable to identify improved forms of modafinil that exhibit significantly increased aqueous solubility and chemical and form stability. It would also be desirable to increase the dissolution rate of API-containing pharmaceutical compositions in water, increase the bioavailability of orally administered compositions and provide a faster onset of therapeutic effect. It would also be desirable to have a form of API that, when administered to a subject, reaches peak plasma concentration more quickly and/or has a longer therapeutic plasma concentration and Higher full contact.

Contents of the invention

It has now been found that co-crystals and solvates of modafinil are available, many of which have different properties compared to the free form of the 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, nitrates, phosphates , phosphorothioate, ester, thioester, sulfate, carboxylic acid, phosphonic acid, phosphinic acid, sulfonic acid, amide, primary amine, secondary amine, ammonia, tertiary amine, sp2 amine, thiocyanate, cyanamide , oxime, nitrile, diazo, organic halide, nitro, S-heterocycle, thiophene, N-heterocycle, pyrrole, O-heterocycle, furan, epoxide, hydroxamic acid, imidazole or pyridine.

The present invention additionally provides pharmaceutical compositions comprising modafinil co-crystals. Typically, pharmaceutical compositions additionally include one or more pharmaceutically acceptable carriers, diluents or excipients. The pharmaceutical compositions of the present invention are described in more detail below.

In another aspect, the present invention provides a process for the preparation of co-crystals of modafinil comprising:

(a) providing modafinil;

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

(c) grinding, heating, co-subliming, co-melting or contacting modafinil with the co-crystal former under crystallization conditions such that a solid phase is formed; and

(d) Separation of co-crystals comprising modafinil and co-crystal formers.

In one embodiment, the co-crystal former has at least one compound selected from the group consisting of ethers, thioethers, alcohols, thiols, aldehydes, ketones, thioketones, nitrates, phosphates, phosphorothioates, esters, thioesters, sulfuric acid Esters, carboxylic acids, phosphonic acids, phosphinic acids, sulfonic acids, amides, primary amines, secondary amines, ammonia, tertiary amines, sp2 amines, thiocyanates, cyanamides, oximes, nitriles, diazo, organic halides, Functional groups of nitro, S-heterocycle, thiophene, N-heterocycle, pyrrole, O-heterocycle, furan, epoxide, hydroxamic acid, imidazole or pyridine.

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

In another aspect, the present invention provides a method of increasing the solubility of modafinil in water, artificial gastric fluid (SGF) or artificial intestinal fluid (SIF) for use in a pharmaceutical composition or medicament, the method comprising:

(a) providing modafinil;

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

(c) grinding, heating, co-subliming, co-melting or contacting modafinil with the co-crystal former under crystallization conditions such that a solid phase is formed; and

(d) Separation of co-crystals comprising modafinil and co-crystal formers.

In another aspect, the present invention provides a method of modulating the dissolution rate of modafinil, thereby increasing its aqueous dissolution rate in artificial gastric or intestinal fluid or in a solvent or solvents, the method comprising:

(a) providing modafinil;

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

(c) grinding, heating, co-subliming, co-melting or contacting modafinil with the co-crystal former under crystallization conditions such that a solid phase is formed; and

(d) Separation of co-crystals comprising modafinil and co-crystal formers.

In another aspect, the invention provides methods of modulating the bioavailability of modafinil, thereby increasing AUC, shortening the time to Tmax, prolonging the duration of modafinil at concentrations above -Tmax, or increasing Cmax, which Methods include:

(a) providing modafinil;

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

(c) grinding, heating, co-subliming, co-melting or contacting modafinil with the co-crystal former under crystallization conditions such that a solid phase is formed; and

(d) Separation of co-crystals comprising modafinil and co-crystal formers.

In another aspect, the present invention provides a method of modulating the dose response of modafinil for use in a pharmaceutical composition or medicament, the method comprising:

(a) providing modafinil;

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

(c) grinding, heating, co-subliming, co-melting or contacting modafinil with the co-crystal former under crystallization conditions such that a solid phase is formed; and

(d) Separation of co-crystals comprising modafinil and co-crystal formers.

In another aspect of the invention, the invention provides a method of improving the stability of modafinil (compared to a reference form such as its free form), the method comprising:

(a) providing modafinil;

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

(c) grinding, heating, co-subliming, co-melting or contacting modafinil with the co-crystal former under crystallization conditions such that a solid phase is formed; and

(d) Separation of co-crystals comprising modafinil and co-crystal formers.

In another aspect, the present invention provides a method of altering the morphology of modafinil, the method comprising:

(a) providing modafinil;

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

(c) grinding, heating, co-subliming, co-melting or contacting modafinil with the co-crystal former under crystallization conditions such that a solid phase is formed; and

(d) Separation of co-crystals comprising modafinil and co-crystal formers.

In another aspect, the invention thus provides a method of screening co-crystallized compounds comprising

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

(b) screening for co-crystals of modafinil and co-crystal formers by subjecting each combination of modafinil and co-crystal formers to a process comprising the steps of:

(i) grinding, heating, co-subliming, co-melting or contacting modafinil with the co-crystal former under crystallization conditions such that a solid phase is formed; and

(ii) Separation of co-crystals including modafinil and co-crystal formers.

Alternative embodiments relate to methods of screening co-crystallized compounds comprising:

(a) providing (i) modafinil and (ii) a plurality of different co-crystal formers compatible with the functional groups of modafinil, such that the various co-crystal formers and modafinil can form co-crystals ;and

(b) screening for co-crystals of modafinil and co-crystal formers by subjecting each combination of modafinil and co-crystal formers to a process comprising the steps of:

(i) grinding, heating, co-subliming, co-melting or contacting modafinil with the co-crystal former under crystallization conditions such that a solid phase is formed; and

(ii) Separation of co-crystals including modafinil and co-crystal formers.

In another aspect, the present invention provides a co-crystal composition comprising a co-crystal, wherein the co-crystal comprises modafinil and a co-crystal former. In another embodiment, the co-crystal has improved properties compared to the free form (which includes hydrates and solvates). In another embodiment, the improved property is selected from: increased solubility, increased dissolution rate, increased bioavailability, increased dose response, or other properties described herein.

In another embodiment, the present invention provides a co-crystal 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, 2,5-dihydroxybenzoic 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 and Maleic Acids.

In another embodiment, the present invention provides the following co-crystals: modafinil: malonic acid, modafinil: glycolic acid, modafinil: maleic acid, modafinil: L-tartaric acid, modafinil: L-tartaric acid, modafinil: Dafinil: Citric Acid, Modafinil: Succinic Acid, Modafinil: DL-Tartrate, Modafinil: Fumaric Acid (Type I), Modafinil: Fumaric Acid (Type II), Modafinil: 2,5-dihydroxybenzoic 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-(-)-mo Dafinil: 1-hydroxy-2-naphthoic acid, R-(-)-modafinil: orotic acid, R-(-)-modafinil: glutaric acid, R-(-)-mo Dafinil: 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: 2,5-di Hydroxybenzoic 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 solvates of modafinil: acetic acid, tetrahydrofuran, 1,4-dioxane, methanol, nitromethane, acetone, o-xylene, benzene, ethanol, benzyl alcohol, Isopropanol, acetonitrile and toluene.

The methods of the invention may each comprise an additional step or steps in which the modafinil co-crystals thus produced are mixed into a pharmaceutical composition.

In another embodiment, the pharmaceutical composition comprises an altered release of one or more of racemic modafinil, R-(-)-modafinil and S-(+)-modafinil curve. An altered release profile may include, for example, two or more maximal plasma concentrations, such as a dual release profile.

The present invention further provides a co-crystallized drug comprising modafinil and a method for its production. Typically, the medicament additionally includes one or more pharmaceutically acceptable carriers, diluents or excipients. The medicaments of the present invention are described in more detail below.

The methods of the present invention may each comprise an additional step or steps in which the co-crystals of modafinil thus produced are mixed into a medicament.

In another aspect of the present invention there is provided the treatment of patients with excessive daytime sleepiness associated with narcolepsy, fatigue associated with multiple sclerosis, infertility, wherein modafinil is an effective active drug for said condition , a method for a subject, preferably a human subject, with an eating disorder, attention deficit hyperactivity disorder (ADHD), Parkinson's disease, incontinence, sleep apnea or myopathy. The method comprises administering to the subject a therapeutically effective amount of a co-crystal or solvate comprising modafinil or a polymorph of modafinil.

Description of drawings

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

Figure 2 - DSC thermogram including co-crystals of modafinil and malonic acid.

Figure 3 - TGA thermogram including co-crystals of modafinil and malonic acid.

Figures 4A and 4B - Raman spectra of co-crystals including modafinil and malonate (Figure 4A), and modafinil (lower spectrum), malonate (middle spectrum) and including modafinil Three Raman spectra (FIG. 4B) of co-crystals of nitric acid and malonic acid (upper spectrum).

Figures 5A and 5B - Infrared spectra of cocrystals including modafinil and malonate (Figure 5A), and modafinil (upper spectrum), malonate (middle spectrum) and including modafinil Three infrared spectra (Fig. 5B) of the co-crystal with malonic acid (upper spectrum).

Figure 6A - PXRD diffractogram of a co-crystal comprising modafinil and malonic acid.

Figure 6B - DSC thermogram including co-crystals of modafinil and malonate (obtained from grinding).

Figure 7 - Packing diagram of modafinil:malonate cocrystals.

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

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

Figure 10 - PXRD diffractogram of a co-crystal comprising modafinil and L-tartaric acid.

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

Figure 1 IB - DSC thermogram of co-crystals including modafinil and citric acid.

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

Figure 13 - DSC thermogram comprising co-crystals of modafinil and succinic acid.

Figure 14 - Packing diagram of co-crystals including modafinil and succinic acid.

Figure 15 - PXRD diffractogram of a co-crystal comprising modafinil and DL-tartaric acid.

Figure 16 - PXRD diffractogram of a co-crystal comprising modafinil and fumaric acid (Form I).

Figure 17 - Packing diagram of a co-crystal comprising modafinil and fumaric acid (Form I).

Figure 18 - PXRD diffractogram of a co-crystal comprising modafinil and fumaric acid (Form II).

Figure 19 - PXRD diffractogram of a co-crystal comprising modafinil and 2,5-dihydroxybenzoic acid.

Figure 20 - PXRD diffractogram of a co-crystal comprising modafinil and oxalic acid.

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

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

Figure 23 - DSC thermogram comprising co-crystals of R-(-)-modafinil and malonic acid.

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

Figure 25 - DSC thermogram comprising co-crystals of R-(-)-modafinil and succinic acid.

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

Figure 27 - DSC thermogram including co-crystallization of R-(-)-modafinil and citric acid.

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

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

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

Figure 31 - DSC thermogram comprising a co-crystal of R-(-)-modafinil and 1-hydroxy-2-naphthoic acid.

Figure 32 - PXRD diffractogram of a co-crystal comprising R-(-)-modafinil and 1-hydroxy-2-naphthoic acid from a high-throughput experiment.

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

Figure 34 - DSC thermogram including co-crystallization of R-(-)-modafinil and orotic acid.

Figure 35 - PXRD diffractogram of a solvate comprising modafinil and acetic acid.

Figure 36 - TGA thermogram of a solvate comprising modafinil and acetic acid.

Figure 37 - DSC thermogram of a solvate comprising modafinil and acetic acid.

Figure 38 - Raman spectrum of a solvate comprising modafinil and acetic acid.

Figure 39 - PXRD diffractogram of a solvate comprising modafinil and tetrahydrofuran.

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

Figure 41 - PXRD diffractogram of a solvate comprising modafinil and methanol.

Figure 42 - TGA thermogram of a solvate comprising modafinil and methanol.

Figure 43 - DSC thermogram of a solvate comprising modafinil and methanol.

Figure 44 - PXRD diffractogram of a solvate comprising modafinil and nitromethane.

Figure 45 - PXRD diffractogram of a solvate comprising modafinil and acetone.

Figure 46 - PXRD diffractogram of a solvate comprising modafinil and acetone.

Figure 47 - PXRD diffractogram comprising a solvate of modafinil and 1,2-dichloroethane.

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

Figure 49 - Stability graph of modafinil:malonate cocrystals over a 26 week period.

Figure 50 - Detailed view of the stability profile of modafinil:malonate cocrystals over a 26 week period.

Figure 51 - Comparison of PXRD diffractograms of modafinil:malonic acid cocrystals after subjecting to several environmental conditions.

Figure 52 - Dissolution profiles of several formulations of modafinil free form and modafinil:malonate.

Figure 53 - In vitro dissolution profiles of modafinil:malonate cocrystals in SGF and SIF.

Figure 54 - Dissolution profile of modafinil:malonic acid cocrystals in HCl.

Figure 55 - DVS plot of modafinil: malonate cocrystal.

Figure 56 - Pharmacokinetics of Modafinil:malonate in dogs.

Figure 57 - PXRD diffractogram of a co-crystal comprising R-(-)-modafinil and 2,5-dihydroxybenzoic acid.

Figure 58 - Packing diagram of the acetone channel solvate of modafinil.

Figure 59 - Additional packing diagram of the acetone channel solvate of modafinil.

Figure 60 - PXRD diffractogram of o-xylene solvate.

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

Figure 62 - TGA thermogram of o-xylene solvate.

Figure 63 - DSC thermogram of o-xylene solvate.

Figure 64 - PXRD diffractogram of benzene solvate.

Figure 65 - Raman spectrum of benzene solvate (middle spectrum).

Figure 66 - TGA thermogram of benzene solvate.

Figure 67 - DSC differential thermogram of benzene solvate.

Figure 68 - PXRD diffractogram of toluene solvate.

Figure 69 - Raman spectrum of toluene solvate (middle spectrum).

Figure 70 - TGA thermogram of toluene solvate.

Figure 71 - DSC differential thermogram of toluene solvate.

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

Figure 73 - TGA differential thermogram of R-(-)-modafinil ethanol solvate.

Figure 74 - PXRD diffractogram of R-(-)-modafinil benzyl alcohol solvate.

Figure 75 - DSC differential thermogram of R-(-)-modafinil benzyl alcohol solvate.

Figure 76 - TGA differential thermogram of R-(-)-modafinil benzyl alcohol solvate.

Figure 77 - PXRD diffractogram of R-(-)-modafinil isopropanol solvate.

Figure 78 - PXRD diffractogram of R-(-)-modafinil acetonitrile solvate.

Figure 79 - PXRD diffractogram of R-(-)-modafinil: glutaric acid cocrystal.

Figure 80 - PXRD diffractogram of R-(-)-modafinil:citric acid cocrystal.

Figure 81 - PXRD diffractogram of R-(-)-modafinil:L-tartaric acid cocrystal.

Figures 82A and 82B - PXRD diffractograms of R-(-)-modafinil: oxalic acid cocrystals.

Figure 83 - PXRD diffractogram of R-(-)-modafinil:palmitic acid cocrystal.

Figure 84 - PXRD diffractogram of R-(-)-modafinil:L-proline cocrystal.

Figure 85 - PXRD diffractogram of R-(-)-modafinil:salicylic acid cocrystal.

Figure 86 - PXRD diffractogram of R-(-)-modafinil:lauric acid cocrystal.

Figure 87 - PXRD diffractogram of R-(-)-modafinil:L-malic acid cocrystal.

Detailed Description of the Invention

The structure of modafinil includes a stereocenter, so it can exist as a racemate, as one of two pure isomers, or as a pair of two isomers in any ratio. The chemical name for racemic modafinil is (±)-2-[(benzhydryl)sulfinyl]acetamide. The isomer pair of racemic modafinil is R-(-)-2-[(diphenylmethyl)sulfinyl]acetamide or R-(-)-modafinil and S-(+ )-2-[(Benzhydryl)sulfinyl]acetamide or S-(+)-modafinil.

As used herein and unless otherwise specified, the term "enantiomerically pure" includes substantially enantiomerically pure compositions, including, for example, having at least about 90, 91, 92, 93, 94, Compositions in 95, 96, 97, 98 or 99% enantiomeric excess. Enantiomeric excess is defined as Enantiomer A % - Enantiomer B %, or by the formula:

ee%=100*([R]-[S]/([R]+[S]), where R is the mole number of R-(-)-modafinil, S is S-(+)-Mo The number of moles of Daphne.

As used herein, the term "modafinil" includes racemates, other mixtures of R- and S-isomers and individual enantiomers, but may be specifically stated as racemates, R-isomer, S-isomer or any mixture of R- and S-isomers.

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

As used herein and unless otherwise stated, the term "enantiomerically pure co-crystal" refers to a co-crystal consisting of modafinil and a stereoisomeric or non-stereomeric co-crystal former, Wherein the enantiomeric excess of the stereoisomeric material is at least about 90% ee (enantiomeric excess).

As used herein, the term "co-crystal" means a crystalline substance consisting of two or more distinct solids at room temperature (22° C.), each solid comprising unique physical properties such as structure, melting point, and heat of fusion, Unless specifically stated the API may be fluid at room temperature. Co-crystals of the present invention include co-crystal formers H-bonded with modafinil or a derivative thereof. The co-crystal former may be directly H-bonded to modafinil or may be H-bonded to another molecule that is bound to modafinil. Additional molecules can be H-bonded to modafinil or ionically bound to modafinil. Additional molecules can also be different APIs. Solvates of the modafinil compound which do not otherwise include co-crystal formers are not co-crystals of the present invention. However, co-crystals may include one or more solvate molecules in the crystal lattice. That is, solvates or co-crystals that additionally include solvents that are fluid at room temperature or co-crystals of compounds are co-crystals of the present invention, but consist only of modafinil and one or more fluids (at room temperature). ) composed of crystalline material is not a co-crystal of the present invention. Other modes of molecular recognition may also exist, including pi-stacking, guest-host complexation, and van der Waals interactions. For the above-mentioned interactions, hydrogen-bonding is the main interaction forming the co-crystal, (and is the interaction required by the present invention) so that between the hydrogen bond donor of one of the moieties and the hydrogen bond acceptor of the other form non-covalent bonds. Hydrogen bonding can produce several different intermolecular configurations. For example, hydrogen bonding can lead to dimer formation, linear or cyclic structure formation. These configurations may further include extended (two-dimensional) hydrogen bond networks and separated triplets. An alternative embodiment provides a co-crystal 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 co-crystalline forms of modafinil can be compared with reference compounds of different forms of modafinil. The reference compound may be designated as the free form, or more specifically, as the anhydrate or hydrate of the free form, or more specifically as, for example, the hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate of the free form substances, pentahydrates; or solvates. For example, a reference compound for free form modafinil co-crystallized with a co-crystal former may be free form modafinil. Reference compounds may also be designated as crystalline or amorphous. A reference compound can also be designated as the most stable known polymorph of the specified form of the reference compound.

According to the invention, the ratio of modafinil to co-crystal former may be stoichiometric or non-stoichiometric. Non-limiting examples of modafinil:cocrystal formers are ratios such as 1:1, 1:1.5, 1.5:1, 1:2 and 2:1 are acceptable. In addition, co-crystals having vacancies within the crystal lattice are included in the present invention. For example, having less than or about 0.01, 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, Co-crystals with 19 or 20% vacancies are included in the present invention. The vacancies may result from missing modafinil molecules or missing co-crystal former molecules, or both, in the crystal lattice.

It has been surprisingly found that when modafinil and selected co-crystal formers are allowed to form co-crystals, the resulting co-crystals often result in improved properties of modafinil compared to the free form of modafinil, in particular with respect to: solubility , dissolution rate, bioavailability, stability, Cmax, Tmax, processability (including compressibility), longer-lasting therapeutic plasma concentrations, and the like. For example, co-crystalline forms of modafinil are particularly advantageous due to the low solubility of modafinil in water. Additionally, conferring co-crystalline properties to modafinil is also useful in that it can improve the bioavailability of modafinil and can improve the plasma and/or serum concentrations of modafinil. This is particularly advantageous for orally administrable formulations. In addition, the dose response of modafinil can be improved, for example by increasing the maximum achievable response and/or by increasing the potency of modafinil by increasing the biological activity per dose equivalent.

Accordingly, in a first aspect, the present invention provides a pharmaceutical composition (or medicament) comprising a co-crystal of modafinil and a co-crystal former such that modafinil and the co-crystal former can be obtained from The liquid phase or co-crystallized from the solid state by, for example, grinding or heating. In another aspect, the co-crystal former has at least one member selected from the group consisting of ethers, thioethers, alcohols, thiols, aldehydes, ketones, thioketones, nitrates, phosphates, phosphorothioates, esters, thioesters, sulfuric acid Esters, carboxylic acids, phosphonic acids, phosphinic acids, sulfonic acids, amides, primary amines, secondary amines, ammonia, tertiary amines, sp2 amines, thiocyanates, cyanamides, oximes, nitriles, diazo, organic halides, Functional groups of nitro, S-heterocycle, thiophene, N-heterocycle, pyrrole, O-heterocycle, furan, epoxide, hydroxamic acid, imidazole, and pyridine, or the functional groups in the tables herein, such that moda Finney and co-crystal formers are capable of co-crystallization from the liquid phase under crystallization conditions.

In another embodiment, an excess (more than 1 molar equivalent for a 1:1 co-crystal) of the co-crystal former may be used to drive the formation of the stoichiometric co-crystal. For example, by adding 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100 times or more than the stoichiometric amount for a given co-crystal Large amounts of co-crystal formers produce co-crystals with a stoichiometry of 1:1, 2:1 or 1:2. This excess of co-crystal former used to form the co-crystal can be employed either in solution or when grinding modafinil and co-crystal former to induce co-crystal formation.

In another embodiment of the present invention, the modafinil co-crystal further comprises a co-crystal former bonded by hydrogen bonding through preferred interactions between two or more functional groups. For example, modafinil and malonic acid co-crystallize through the interaction of the carboxylic acid functional groups of the co-crystal former with the sulfoxide and amide functional groups of modafinil.

In another embodiment of the present invention, the co-crystal comprises modafinil wherein modafinil forms a dimeric primary amide structure through hydrogen bonding with the R ² ₂ (8) moiety. See, e.g., J.Bernstein, Polymorphism in Molecular Crystals , Oxford University Press, 2002, pp.55-59; or MCEtter, Acct.Chem.Res., 1990, 23, 120; or MCEtter, J.Phys.Chem., 1991 , 95, 4601. In this structure, the _NH2 moiety can also participate in hydrogen bonding with a donor or acceptor moiety from, for example, a co-crystal former or an additional (third) molecule; Hydrogen bonding of the donor moiety of a former or another molecule. In another embodiment, the dimeric primary amide structure (formed from two modafinil molecules) additionally includes one, two, three or four hydrogen bond donors (from one, two, three or four co-crystal formers). In another embodiment, the dimeric primary amide structure additionally includes one or two hydrogen bond acceptors (from one or two co-crystal formers). In another embodiment, the dimeric primary amide structure additionally includes a combination of hydrogen bond donors and acceptors. For example, a dimeric primary amide structure may additionally include a hydrogen bond donor and a hydrogen bond acceptor, a hydrogen bond donor and two hydrogen bonds, two hydrogen bond donors and a hydrogen bond acceptor, two hydrogen bond acceptors, bond donor and two hydrogen bond acceptors or three hydrogen bond donors and one hydrogen bond acceptor.

The co-crystals of the present invention are formed in which modafinil and the co-crystal former are hydrogen bonded together. Other non-covalent interactions may also exist, including pi-stacking and van der Waals interactions.

In one embodiment, the co-crystal former is selected from the co-crystal formers of Table I and Table II. In other embodiments, the co-crystal formers of Table I are designated as Class 1, Class 2, or Class 3 co-crystal formers (see column labeled "Classification" in Table I). Table I lists various pKa values for co-crystal formers with multiple functionalities. It will be apparent to those skilled in the art that a particular functional group corresponds to a particular pKa value.

In another embodiment, specific functional groups of co-crystal formers that interact with modafinil are specified (see, e.g., Table I, columns labeled "Functionality" and "Molecular Structure" and Table II values labeled column "co-crystal former functional group").

In another embodiment, the co-crystal comprises more than one co-crystal former. For example, two, three, four, five or more co-crystal formers may be combined in a co-crystal with modafinil. A co-crystal comprising two or more co-crystal formers and an API is hydrogen bonded together. In one embodiment, the associated 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 the combined co-crystal former.

In each of the methods of the present invention, it is necessary to contact modafinil with the co-crystal former. This may involve grinding two solids together or melting one or both components and allowing them to recrystallize. This may also involve dissolving modafinil and adding the co-crystal former, or dissolving the co-crystal former and adding modafinil. Crystallization conditions were applied to modafinil and co-crystal formers. This may involve changing properties of the solution such as pH or temperature, and may require concentration of the solute, usually by removal of the solvent, typically by drying the solution. Removal of the solvent causes the concentration of modafinil and co-crystal former to increase over time, facilitating crystallization. For example, co-crystals can be crystallized using evaporation, cooling, or the addition of antisolvents. In another embodiment, a co-crystal is formed using a slurry comprising modafinil and a co-crystal former. Once a solid, including any crystals, is formed, it can be tested as described herein.

The co-crystals obtained by this process step can be easily mixed into pharmaceutical compositions (or medicaments) by conventional methods. Pharmaceutical compositions and medicaments in general are discussed in further detail below, and may further comprise pharmaceutically acceptable diluents, excipients or carriers.

In another aspect, the present invention provides a method of preparing co-crystals of modafinil comprising:

(a) providing modafinil;

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

(c) grinding, heating, co-subliming, co-melting or contacting modafinil with the co-crystal former under crystallization conditions such that a solid phase is formed; and

(d) Separation of co-crystals comprising modafinil and co-crystal formers.

In one embodiment, the co-crystal former has at least one compound selected from the group consisting of ethers, thioethers, alcohols, thiols, aldehydes, ketones, thioketones, nitrates, phosphates, phosphorothioates, esters, thioesters, sulfuric acid Esters, carboxylic acids, phosphonic acids, phosphinic acids, sulfonic acids, amides, primary amines, secondary amines, ammonia, tertiary amines, sp2 amines, thiocyanates, cyanamides, oximes, nitriles, diazo, organic halides, Functional groups of nitro, S-heterocycle, thiophene, N-heterocycle, pyrrole, O-heterocycle, furan, epoxide, hydroxamic acid, imidazole or pyridine.

In another aspect, the present invention provides a method of producing a pharmaceutical composition or medicament, the method comprising:

(a) providing modafinil;

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

(c) grinding, heating, co-subliming, co-melting or contacting modafinil with the co-crystal former under crystallization conditions;

(d) isolating the co-crystals thus formed; and

(e) Incorporating the co-crystal into a pharmaceutical composition or medicament.

In another embodiment, the method of forming the co-crystal comprises a metastable form of modafinil, a co-crystal former, or both. Metastable forms may be, for example but not limited to, polymorphs, solvates or hydrates of modafinil or co-crystal formers. While not being bound by theory, binding metastable forms may promote co-crystal formation by increasing the thermodynamic driving force.

The solids can be analyzed by routine methods known in the art to determine the presence of co-crystals of modafinil and the co-crystal former. For example, it is convenient and routine to assess the presence of co-crystals using powder X-ray diffraction techniques. This can be done by comparing the diffractograms of modafinil, crystal formers and putative co-crystals to determine if a true co-crystal has formed. Other techniques used in a similar manner include differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), infrared spectroscopy (IR) and Raman spectroscopy. Single crystal X-ray diffraction is particularly useful for identifying co-crystal structures.

In another aspect, the present invention thus provides a method of screening co-crystallized compounds comprising:

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

(b) screening for co-crystals of modafinil and co-crystal formers by subjecting each combination of modafinil and co-crystal formers to a process comprising the steps of:

(i) grinding, heating, co-subliming, co-melting or contacting modafinil with the co-crystal former under crystallization conditions such that a solid phase is formed; and

(ii) Separation of co-crystals including modafinil and co-crystal formers.

Alternative embodiments relate to methods of screening co-crystallized compounds comprising:

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

(b) screening for co-crystals of modafinil and co-crystal formers by subjecting each combination of modafinil and co-crystal formers to a process comprising the steps of:

(i) grinding, heating, co-subliming, co-melting or contacting modafinil with various co-crystal formers under crystallization conditions such that a solid phase is formed; and

(ii) Separation of co-crystals including modafinil and co-crystal formers.

The present invention includes several co-crystals comprising modafinil and a carboxylic acid co-crystal former. Some examples include modafinil with malonic acid, tartaric acid (L- and DL-), succinic acid, citric acid, fumaric acid, 2,5-dihydroxybenzoic acid, oxalic acid, and 1-hydroxy-2-naphthalene Co-crystals formed by formic acid. These examples represent mono-, di- and tricarboxylic acid co-crystal formers. Other acids, including carboxylic acids, can be used as co-crystal formers with modafinil, including but not limited to palmitic acid, orotic acid, and adipic acid, among others. These co-crystal formers may include one, two, three or more carboxylic acid functional groups. Co-crystal formers may also include non-carboxylic acid molecules such as, but not limited to, urea, saccharin, and caffeine.

In another embodiment, the co-crystal comprises modafinil and a carboxylic acid as a co-crystal former. In another embodiment, the carboxylic acid co-crystal former has one, two, three or more carboxylic acid functional groups.

Several co-crystals may exhibit one or more specific interactions between modafinil and the carboxylic acid co-crystal former. For example, the carboxylic acid functionality can interact with the primary amide and/or S=O functionality of modafinil via hydrogen bonding. In another embodiment, the carboxylic acid functionality from the co-crystal former can interact with the primary amide functionality or the S=O functionality of modafinil via hydrogen bonding. In another embodiment, the carboxylic acid functionality from the co-crystal former can interact with the periphery of the amide dimer of modafinil via hydrogen bonding. In another embodiment, the carboxylic acid functionality from the co-crystal former can interact with the amide dimer or S=O functionality of modafinil via hydrogen bonding. In another embodiment, the carboxylic acid functional group from the co-crystal former can interact with the two amide dimers of modafinil via hydrogen bonding.

Modafinil and some of the co-crystal formers of the present invention possess one or more chiral centers and can exist in various stereoisomeric configurations. Due to these chiral centers, modafinil and several co-crystal formers of the present invention as racemates, enantiomeric mixtures and as individual enantiomers, as well as diastereomers and Diastereomeric mixtures exist. All such racemates, enantiomers and diastereomers are within the scope of the invention, including for example cis and trans isomers, R- and S-enantiomers and (D)- and (L)-isomers. The co-crystals of the present invention may comprise isomeric forms of modafinil or the co-crystal former 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 include 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 may comprise about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40 %, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, greater than 99% or any intermediate enantiomeric excess of modafinil or co-crystal former. A few 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 may comprise a polymorph having 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%, Enantiomeric excess of modafinil of 99%, greater than 99%, or any intermediate value.

"Enriched" modafinil of the present invention includes amounts greater than or equal to about 5, 6, 7, 8, 9, or 10% by weight and less than or equal to about 90, 91, 92, 93, 94, or 95% by weight R-(-)- and S-(+)-isomers of modafinil. For example, a composition comprising 67% by weight R-(-)-modafinil and 33% by weight S-(+)-modafinil is an enriched modafinil composition. In such instances, the composition is neither racemic nor enantiomerically pure. The term "R-(-)-modafinil enriched" can be used to describe modafinil with greater than 50% R-(-)-modafinil and less than 50% S-(+)-modafinil Finney composition. Likewise, the term "enriched in S-(+)-modafinil" may be used to describe a protein having greater than 50% S-(+)-modafinil and less than 50% R-(-)-modafinil Modafinil composition.

The terms "R-(-)-modafinil" and "S-(+)-modafinil" can be used to describe enriched modafinil, enantiomerically pure modafinil or substantially Enantiomerically pure modafinil, but enriched modafinil, enantiomerically pure modafinil and/or substantially enantiomerically pure modafinil may also be specifically excluded Modafinil.

Co-crystals, solvates and polymorphs comprising enantiomerically pure and/or enantiomerically enriched components (e.g., modafinil or co-crystal formers) can result in relative Those comprising the corresponding co-crystals of the racemic components give adjusted chemical and/or physical properties. For example, the modafinil:malonate cocrystal obtained in 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 may result in modulation of, for example, activity, bioavailability or solubility of corresponding co-crystals comprising racemic components. For example, the cocrystal R-(-)-modafinil:malonic acid has modulated properties compared to the racemic modafinil:malonic acid cocrystal.

Modafinil can also be prepared from racemic modafinil, enantiomerically pure modafinil or from any mixture of R-(-)- and S-(+)-modafinil according to the invention Polymorphs and solvates of Finney.

In another embodiment, the present invention includes a pharmaceutical composition or medicament comprising enantiomerically pure modafinil wherein the bioavailability is adjusted relative to the racemic co-crystal and/or co-crystal formation co-crystallization. In another embodiment, the present invention includes a pharmaceutical composition or medicament comprising enantiomerically pure modafinil and/or a co-crystal former wherein the co-crystal activity relative to racemic is modulated. co-crystallization. In another embodiment, the present invention includes a pharmaceutical composition or medicament comprising enantiomerically pure modafinil and/or a co-crystal former wherein the solubility relative to the racemic co-crystal is adjusted. co-crystallization.

In another embodiment, a pharmaceutical composition or medicament can be formulated to comprise modafinil as a co-crystal form of micronized particles or nanoparticles. More specifically, another embodiment combines a process from pure modafinil to a co-crystal form with a process to produce controlled particle sizes for use in pharmaceutical dosage forms. This embodiment combines two process steps into one by techniques such as but not limited to grinding, fusing or sintering (ie heating the powder mixture). The combination of these processes overcomes a series of disadvantages such as having to separate or store the bulk drug required for the formulation, which can be difficult to separate under the same circumstances (eg polymorphism, chemical or physical instability).

Solubility adjustment

In another aspect, the present invention provides a method of increasing the solubility of modafinil in water, artificial gastric fluid (SGF) or artificial intestinal fluid (SIF) for use in a pharmaceutical composition or medicament, the method comprising:

(a) providing modafinil;

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

(c) grinding, heating, co-subliming, co-melting or contacting modafinil with the co-crystal former in the crystalline state such that a solid phase is formed; and

(d) Separation of co-crystals comprising modafinil and co-crystal formers.

In one embodiment, the solubility of modafinil is adjusted such that the aqueous solubility (mg/mL) is increased by at least 1.1, 1.2, 1.3, 1.5, 2.0, 5.0, 10.0, 20.0, 25.0, 50.0, 75.0, or 100.0 over the free form times or more. The solubility of modafinil can be measured by any conventional method, such as chromatography (e.g., HPLC) or spectroscopic determination of the amount of modafinil in a saturated solution, such as UV-spectroscopy, IR-spectroscopy, Raman spectroscopy method, quantitative mass spectrometry, or gas chromatography.

In another embodiment, compositions or medicaments comprising co-crystals, solvates and polymorphs of the present invention are comparable to the free form of modafinil available as PROVIGIL® (Cephalon, Inc.). (seeing US Reissued Patent No. RE37,516). For example, the bioavailability of a composition or drug of the invention can be compared to that of PROVIGIL. As an embodiment of the present invention, solubility can be increased by 2, 3, 4, 5, 7, 10, 15 by producing co-crystallization of a reference form (e.g., crystalline or amorphous free form, hydrate or solvate) , 20, 25, 50, 75 or 100 times. Additional water solubility can be measured in artificial gastric fluid (SGF) or artificial intestinal fluid (SIF) instead of water. SGF (undiluted) of the present invention was produced by combining 1 g/L Triton X-100 and 2 g/L NaCl in water and adjusting the pH with 20 mM HCl to obtain a final pH=1.7 solution. SIF is 0.68% potassium monobasic phosphate, 1% trypsin and sodium hydroxide where the pH of the final solution is 7.5. The pH of the solvent used can also be specified as 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.

Examples of embodiments include: a co-crystal composition having an at least 5-fold increase in water solubility at 37°C and pH 7.0 over the reference form, a co-crystal composition having an at least 5-fold increase in solubility in SGF over the reference form, a solubility ratio in SIF The co-crystallized composition increased at least 5-fold for the reference form.

Dissolution Rate Modulation

In another aspect of the invention, the dissolution rate profile of modafinil is adjusted to increase its dissolution rate in water or in artificial gastric or intestinal fluid or a solvent or solvents. The dissolution rate is the rate at which the API solid dissolves in the dissolution medium. For APIs for which the rate of absorption is faster than the rate of dissolution (eg, steroids), the rate-limiting step in the absorption process is often the rate of dissolution. API that remains undissolved before being removed from the site of intestinal absorption is considered ineffective due to the limited residence time at the site of absorption. Therefore, the dissolution rate has a significant impact on the performance of poorly soluble APIs. Therefore, the dissolution rate of an API in solid dosage forms is an important, routine quality control parameter used in the API manufacturing process. The following equations are approximate,

Dissolution rate = KS(C _s -C)

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

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

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

An increase in the dissolution rate of the cocrystal over the reference form (e.g., free form) in the same solution, such as 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% times, or 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200 , 250, 300, 350, 400, 500, 1000, 10,000 or 100,000 times. The conditions for measuring the dissolution rate were as discussed above. The increase in dissolution rate is further illustrated by the time the composition remains supersaturated before reaching equilibrium solubility.

In another aspect, the present invention provides a method for modulating the dissolution of modafinil to increase its aqueous dissolution rate in artificial gastric or intestinal fluid or in a solvent or solvents, the method comprising:

(a) providing modafinil;

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

(c) grinding, heating, co-subliming, co-melting or contacting modafinil with the co-crystal former in the crystalline state such that a solid phase is formed; and

(d) Separation of co-crystals comprising modafinil and co-crystal formers.

Examples of the above embodiments include: co-crystallized compositions that have an increased dissolution rate in aqueous solution at 37°C and pH 7.0 at least 5-fold compared to the reference form, co-crystallized compositions that have an increased dissolution rate in SGF by at least 5-fold compared to the reference form . A co-crystallized composition having an increase in dissolution rate in SIF of at least 5-fold compared to a reference form.

bioavailability regulation

The method of the present invention is used to produce pharmaceutical modafinil formulations with greater solubility, dissolution and bioavailability. Bioavailability can be improved by increasing AUC, shortening time to Tmax (time to reach peak serum concentration), or increasing Cmax. The present invention can produce higher plasma concentrations of modafinil compared to the free form (reference form).

AUC is the area under the curve of plasma concentration (not logarithm of concentration) of API versus time after API administration. This area is conveniently determined by the "trapezoidal rule": connect the data points with straight line segments, the perpendicular being the perpendicular from the abscissa to each data point, and calculate the sum of the areas of the triangles and trapezoids thus constructed. When the last measured concentration (Cn, at time tn) is not zero, the AUC from time tn to infinity is estimated from Cn/ _kel .

AUC is particularly useful in estimating the bioavailability of the API and in estimating the total clearance (Cl _T ) of the API. After a single intravenous dose, for a one-compartment system subject to first-order elimination kinetics, AUC=D/Cl _T , where D is the dose; alternatively, AUC=C ₀ / _kel , where _kel is API elimination rate constant. For routes of administration other than intravenous administration, AUC = F·D/Cl _T , where F is the absolute bioavailability of the API.

In another aspect, the invention provides methods of modulating the bioavailability of modafinil to increase AUC, shorten the time to Tmax, increase the duration of modafinil concentrations above one-half Tmax, or increase Cmax , the method includes:

(a) providing modafinil;

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

(c) grinding, heating, co-subliming, co-melting or contacting modafinil with the co-crystal former in the crystalline state such that a solid phase is formed; and

(d) Separation of co-crystals comprising modafinil and co-crystal formers.

Examples of the above embodiments include: a co-crystal composition having a time to Tmax increase of at least 5% compared to a reference form, a co-crystal composition having a time to Tmax increase of at least 10% compared to a reference form, a time to Tmax being increased by at least 10% compared to a reference form A co-crystal composition with an increase of at least 15%, a co-crystal composition with a time to Tmax increase of at least 20% over the reference form, a co-crystal composition with a time to Tmax increase of at least 25% over the reference form, a time to Tmax over the reference Co-crystal composition with at least 30% increase in form, co-crystal composition with at least 35% increase in time to Tmax over reference form, at least 40% increase in time to Tmax over reference form, co-crystal composition with at least 40% increase in AUC over reference form A co-crystal composition of at least 5%, a co-crystal composition with an AUC increase of at least 10% over a reference form, a co-crystal composition with an AUC increase of at least 15% over a reference form, a co-crystal composition with an AUC increase of at least 20% over a reference form A co-crystal composition with an increase in AUC of at least 25% over the reference form A co-crystal composition with an increase in AUC of at least 30% over the reference form A co-crystal composition with an increase in AUC of at least 35% over the reference form AUC over the reference form increased by at least 40% % co-crystal composition. Other examples include where the reference form is crystalline, where the reference form is amorphous, or where the reference form is an anhydrous crystalline form of modafinil.

dose response modulation

In another aspect, the present invention provides a method of modulating the dose response of modafinil for use in a pharmaceutical composition or medicament, the method comprising:

(a) providing modafinil;

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

(c) grinding, heating, co-subliming, co-melting or contacting modafinil with the co-crystal former in the crystalline state such that a solid phase is formed; and

(d) Separation of co-crystals comprising modafinil and co-crystal formers.

A dose response is a quantitative relationship between a measure of response and the dose that induces a response, which can be measured by routine methods known in the art. A curve involving the relative effect (as dependent variable) on dose (as independent variable) of the API-cell system is a "dose-response curve". Typically, a dose-response curve is the measured response to the API plotted against a given API dose (mg/kg). A dose response curve can also be a curve of AUC versus a given dose of API.

In an embodiment of the invention, the co-crystals of the invention have an increased dose response curve or a more linear dose response curve than the corresponding reference compound.

increased stability

In another aspect of the present invention, the present invention provides a method of improving the stability of modafinil (compared to a reference form such as its free form), the method comprising:

(a) providing modafinil;

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

(c) grinding, heating, co-subliming, co-melting or contacting modafinil with the co-crystal former in the crystalline state such that a solid phase is formed; and

(d) Separation of co-crystals comprising modafinil and co-crystal formers.

In a preferred embodiment, the compositions of the invention comprising modafinil co-crystals, solvates and formulations comprising modafinil have suitable stability for pharmaceutical use. Preferably, modafinil or a formulation thereof of the invention is stable such that less than 0.2% of any degradant is formed when stored at 30°C for 2 years. Herein the term degradant refers to the product of a single chemical reaction. For example, if a hydrolysis phenomenon occurs that splits the molecule into two products, it is considered a single degradant for the purposes of the present invention. More preferably, less than 0.2% of either degradation product is formed when stored at 40°C for 2 years. Alternatively, less than 0.2% or 0.15% or 0.1% of either degradation product is formed when stored at 30°C for 3 months; or less than 0.2% or 0.15% is formed when stored at 40°C for 3 months % or 0.1% of any degradation product. Or when stored at 60°C for 4 weeks, less than 0.2 or 0.15% or 0.1% of either degradation product is formed. Relative humidity (RH) may be specified as ambient RH, 75% RH, or any integer between 1 and 99% RH. In another embodiment, a single dose of the invention comprises less than 0.5%, 0.2%, or 0.1% of degradants when administered to a subject.

Morphological regulation

In another aspect, the present invention provides a method of altering the morphology of modafinil, the method comprising:

(a) providing modafinil;

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

(c) grinding, heating, co-subliming, co-melting or contacting modafinil with the co-crystal former in the crystalline state such that a solid phase is formed; and

(d) Separation of co-crystals comprising modafinil and co-crystal formers.

In one embodiment, the co-crystal comprises or comprises modafinil and a co-crystal former, wherein between the amino group of modafinil and the co-crystal former having the corresponding interacting group in Table III occurs between the two interactions, such as H-bonding. In another embodiment, the co-crystal comprises modafinil and a co-crystal former of Table I or II. In one aspect of the invention, the invention includes only co-crystals having an H-bond acceptor on a first molecule and an H-bond donor on a second molecule, wherein the first and second molecules are co-crystal formers and Modafinil, or modafinil and co-crystal formers, are encompassed by the present invention.

A co-crystal can include more than two chemical entities within its co-crystal structure. For example, co-crystals may additionally include solvent molecules, water molecules, salts, and the like. Additionally, a co-crystal may comprise one API and two or more co-crystal formers, one co-crystal former and two or more APIs, two or more APIs, or two or more co-crystal formers.

As defined herein, a ternary co-crystal is a co-crystal comprising three different chemical entities in stoichiometric ratios, each of which is solid at room temperature (except that the API may be fluid at room temperature). Specifically, a ternary co-crystal includes three different chemical entities such as API: co-crystal former (1): co-crystal former (2), wherein the ratio of the components may be, for example but not limited to, 1:1:1, 2:1:1, 2:1:2, 2:1:0.5, 2:2:1, etc. Ternary co-crystals may also include other combinations of components such as, but not limited to, API(1):API(2):co-crystal former, API(1):API(2):API(3) and co-crystal former Product (1): Co-crystal former (2): Co-crystal former (3).

In another embodiment, the present invention provides a co-crystal 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, 2,5-dihydroxybenzoic 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 and Maleic Acids.

In another embodiment, the present invention provides the following co-crystals: modafinil: malonic acid, modafinil: glycolic acid, modafinil: maleic acid, modafinil: L-tartaric acid, modafinil: L-tartaric acid, modafinil: Dafinil: Citric Acid, Modafinil: Succinic Acid, Modafinil: DL-Tartrate, Modafinil: Fumaric Acid (Type I), Modafinil: Fumaric Acid (Type II), Modafinil: 2,5-dihydroxybenzoic 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-(-)-mo Dafinil: 1-hydroxy-2-naphthoic acid, R-(-)-modafinil: orotic acid, R-(-)-modafinil: glutaric acid, R-(-)-mo Dafinil: 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: 2,5-di Hydroxybenzoic 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 solvates of modafinil: acetic acid, tetrahydrofuran, 1,4-dioxane, methanol, nitromethane, acetone, o-xylene, benzene, and toluene.

Pharmaceutically acceptable co-crystals can be administered by controlled release or extended release methods. Controlled release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled release counterparts. Ideally, the use of an optimally designed controlled release formulation in medical treatment is characterized by treating or controlling a condition with the least amount of drug substance in the shortest period of time. The advantages of controlled release formulations include: 1) prolonged drug activity; 2) reduced dosing frequency; 3) increased patient compliance; 4) less total dose; 5) reduced local or systemic side effects; 7) reduced blood level fluctuations; 8) improved therapeutic efficacy; 9) reduced enhancement or loss of drug activity; and 10) improved speed of controlling the 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 fluctuations in the concentration of the drug in the blood and other tissues of the patient. These fluctuations can affect many parameters such as dosing frequency, 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 drug action, duration of action, plasma levels within the therapeutic window, and peak blood concentration. In particular, controlled-release or extended-release dosage forms or formulations can be used to ensure that the maximum effectiveness of the drug is achieved, while minimizing potential side effects and safety concerns that can arise from underdosing of the drug (i.e., in the below the minimum therapeutic level) and when the toxic level of the drug is exceeded.

Most controlled-release formulations are used to initially release the amount of drug (active ingredient) that rapidly produces the desired therapeutic effect, and to gradually and continuously release other amounts of the drug to maintain this level of therapeutic or prophylactic effect over an extended period of time . In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that replaces the amount of drug being metabolized and excreted from the body. Controlled release of the active ingredient is 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.

There are a variety of known controlled release or extended release dosage forms, formulations and devices that may be suitable for use with the co-crystals and compositions of the present invention.其例子包括但不限于在美国专利3,845,770、3,916,899、3,536,809、3,598,123、4,008,719、5,674,533、5,059,595、5,591,767、5,120,548、5,073,543、5,639,476、5,354,556、5,733,566和6,365,185B1中所述的那些。 Each of which is incorporated herein by reference. These dosage forms can be used to provide slow or controlled release of one or more active ingredients using, for example, hypromellose, other polymeric matrices, gels, osmotic membranes, osmotic systems (such as OROS® (Alza Corporation, Mountain View, Calif.USA)), multilayer coatings, microparticles, liposomes or microspheres or combinations thereof to provide the desired release profile in varying proportions. Additionally, ion-exchange materials can be used to prepare immobilized adsorbed co-crystals and thereby enable controlled delivery of drugs. Examples of specific anion exchangers include, but are not limited to, Duolite_A568 and Duolite_AP143 (Rohm & Haas, Spring House, PA. USA).

One embodiment of the invention includes a unit dosage form comprising a pharmaceutically acceptable co-crystal or a solvate, hydrate, anhydrate, anhydrate, amorphous form thereof, and one or more pharmaceutically acceptable excipients An agent or diluent wherein the pharmaceutical composition, medicament or dosage form is formulated for controlled release. Particular dosage forms employ osmotic drug delivery systems.

A specific and well-known osmotic drug delivery system is called OROS® (Alza Corporation, Mountain View, Calif. USA). Such techniques can be readily adapted to deliver the compounds and compositions of the invention. Aspects of this technology are disclosed in US Pat. Specific OROS® modifications that can be used to administer the compounds and compositions of the invention include, but are not limited to, OROS_Push-Pull ^™ , Delayed Push-Pull ^™ , Multi-Layer Push-Pull ^™ , and Push-Stick ^™ Systems, which are all well known. See, eg, http://www.alza.com . Additional OROS® systems useful for controlled oral delivery of compounds and compositions of the invention include OROS_-CT and L-OROS_.Id. See also Delivery Times, vol. II, issue II (Alza Corporation).

Conventional OROS® oral dosage forms are produced by compressing drug powders (e.g. co-crystals) into hard tablets, coating the tablets with a cellulose derivative to form a semipermeable membrane, and then drilling holes in the coating (e.g. , 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 drug delivery is not affected by physiological or experimental conditions. Even drugs with pH-dependent solubility can be delivered at a constant rate regardless of the pH of the delivery medium. But because these advantages are provided by the build-up of osmotic pressure within the dosage form after administration, conventional OROS® drug delivery systems cannot be used to effectively deliver drugs with low water solubility. Id. at 234. Because the co-crystals of the present invention are more soluble in water than modafinil itself, they are well suited for osmotic-based delivery to patients. However, the present invention includes the incorporation of conventional crystalline modafinil (eg, pure modafinil without co-crystal formers) and its isomers and mixtures of isomers into OROS® dosage forms.

Particular dosage forms of the invention include: a wall defining a cavity, the wall having an outlet formed therein, and at least a portion of the wall being semipermeable; A layer; a drug layer in a dry or substantially dry state positioned in the cavity adjacent to the outlet and in direct or indirect contact with the expandable layer; and inserted between the inner surface of the wall and at least the outer surface of the drug layer in the cavity The flow-promoting layer between them, wherein the drug layer comprises co-crystal or its solvate, hydrate, dehydrate, anhydrate or amorphous. See US Patent 6,368,626, which is hereby incorporated by reference in its entirety.

Another specific dosage form of the invention includes: a wall defining a cavity, the wall having an outlet formed therein, and at least a portion of the wall being semipermeable; Expandable layer; drug layer located within the cavity adjacent to the outlet and in direct or indirect contact relationship with the expandable layer; the drug layer includes a fluid, active agent formulation absorbed in porous particles suitable for resisting enough to form a compact drug Compressive force of layers without significant exudation of fluid, active agent formulation, dosage form optionally has placebo layer between outlet and drug layer, wherein active agent formulation comprises co-crystal or solvate, hydrate, dehydrate thereof , Anhydrous or amorphous. See US Patent 6,342,249, which is hereby incorporated by reference in its entirety.

In another embodiment, the pharmaceutical composition or medicament comprises a mixture of the novel forms of modafinil of the invention (eg, co-crystals) and the free form of modafinil. Such embodiments are useful, for example, as controlled-release, sustained-release or extended-release dosage forms. In another embodiment, the extended release dosage form comprises modafinil in free form and a co-crystal or solvate of the invention. Such extended release dosage forms comprise a form of modafinil that has greater bioavailability than the free form of modafinil (eg, modafinil: malonate cocrystal). Additionally, the Cmax of this form may be greater than that of the free form of modafinil, contributing to a longer duration of therapeutic effect than free form modafinil alone.

In another embodiment, the pharmaceutical composition or medicament comprises a modification of one or more of racemic modafinil, R-(-)-modafinil and S-(+)-modafinil release curve. An altered release profile can include, for example, two or more maximal plasma concentrations, such as a dual release profile. This altered release profile may aid in the treatment of patients experiencing, for example, a loss of wakefulness in the afternoon with the compositions or medicaments of the invention. A second "burst" 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 medicament comprising a small loading dose immediately after administration followed by a near zero order release profile within 2, 3, 4, 5 or 6 hours may be employed. In this composition, peak plasma levels can be reached around noon.

In another embodiment, the pharmaceutical composition or medicament comprising a modified release profile of modafinil comprises R-(-)-modafinil and S-(+)-modafinil, wherein R-(- )-modafinil provides an initial increase in plasma concentration (due to the Cmax of R-(-)-modafinil), while S-(+)-modafinil provides a delayed increase in plasma concentration (due to S - Subsequent Cmax of (+)-modafinil). The delayed increase in Cmax due to S-(+)-modafinil can be 2, 3, 4, 5, 6 hours or more after the initial Cmax due to R-(-)-modafinil. In another embodiment, the delayed Cmax is approximately equal to the original Cmax. In another embodiment, the delayed Cmax is greater than the initial Cmax. In another embodiment, the delayed Cmax is less than the original Cmax. In another embodiment, the delayed Cmax is due to racemic modafinil rather than S-(+)-modafinil. In another embodiment, the delayed Cmax is due to R-(-)-modafinil rather than S-(+)-modafinil. In another embodiment, the initial Cmax is due to racemic modafinil, not R-(-)-modafinil. In another embodiment, the initial Cmax is due to S-(+)-modafinil instead of R-(-)-modafinil. In another embodiment, the altered release profile has 3, 4, 5 or more "bursts" of plasma concentration.

In another embodiment, the pharmaceutical composition or medicament comprises an altered release profile of modafinil, wherein racemic modafinil, R-(-)-modafinil or S-(+)-modafinil One or more of Dafenil exists in the form of co-crystals, solvates, free forms or polymorphs.

In another embodiment, the pharmaceutical composition or medicament comprising an altered release profile of R-(-)-modafinil therein is used in an oral formulation. This composition minimizes the first pass metabolism of modafinil to the sulfone. In another embodiment, the pharmaceutical composition or medicament comprising an altered release profile of racemic modafinil therein is used in an oral formulation. In another embodiment, the pharmaceutical composition or medicament comprising an altered release profile of S-(+)-modafinil therein is used in an oral formulation. In another embodiment, the pharmaceutical composition or medicament comprising an altered release profile of racemic modafinil and R-(-)-modafinil therein is used in an oral formulation. In another embodiment, the pharmaceutical composition or medicament comprising an altered release profile of racemic modafinil and S-(+)-modafinil therein is used in an oral formulation. In another embodiment, the pharmaceutical composition or medicament comprising an altered release profile of S-(+)-modafinil and R-(-)-modafinil therein is used in an oral formulation. In another embodiment, a pharmaceutical composition or medicament comprising an altered release profile of racemic modafinil, S-(+)-modafinil, and R-(-)-modafinil wherein For oral preparations.

In another embodiment, a pharmaceutical composition or medicament comprising an altered release profile of modafinil is for transdermal administration. This transdermal (TD) delivery avoids first-pass metabolism. Alternatively, a "pill-and-patch" strategy could be employed, in which only a fraction of the daily dose is delivered transdermally to form a base systemic level, on top of which oral therapy is added to ensure arousal.

Excipients used in the pharmaceutical compositions and medicaments of the present invention can be solid, semi-solid, fluid or combinations thereof. Preferably, the excipient is a solid. Compositions and medicaments of the invention comprising excipients can be prepared by known pharmaceutical techniques involving mixing the excipients with the API or therapeutic agent. Each dosage unit of the pharmaceutical composition or medicament of the present invention contains the desired amount of API, and if intended for oral administration, it may be, for example, a tablet, caplet, pill, hard or soft capsule, lozenge, cachet, Dispensable powders, granules, suspensions, elixirs, dispersions, fluids or any other form reasonably suitable for such administration. If used for parenteral administration, it may be in the form of, for example, a suspension or a transdermal patch. If for rectal administration, it may be in the form of, for example, a suppository. Presently preferred are oral dosage forms of discrete dosage units, such as tablets or capsules, each containing a predetermined amount of the API.

Non-limiting examples of excipients that can be used in the preparation of the pharmaceutical compositions or medicaments of the present invention are as follows.

The pharmaceutical compositions and medicaments of the present invention optionally include one or more pharmaceutically acceptable carriers or diluents as excipients. Suitable carriers or diluents illustratively include, but are not limited to, alone or in combination, lactose, including anhydrous lactose and lactose monohydrate; starches, including directly compressible starches and hydrolyzed starches (e.g., Celutab ^™ and Emdex ^TM ); mannitol; sorbitol; xylitol; glucose (e.g., Cerelose ^TM 2000) and glucose monohydrate; dibasic calcium phosphate dihydrate; sucrose-based diluents; sugar for confectionery; Alkaline calcium sulfate monohydrate, calcium sulfate dihydrate, granular calcium lactate trihydrate; dextrates; inositol; cereal hydrolyzed solids; amylose; cellulose, including microcrystalline cellulose, of food-grade origin and alpha- and amorphous cellulose (e.g., RexcelJ), powdered cellulose, hydroxypropylcellulose (HPC) and hydroxypropylmethylcellulose (HPMC); calcium carbonate; glycine; bentonite; block copolymers; Polyvinylpyrrolidone; etc. If present, such carriers or diluents constitute in total from about 5% to about 99%, preferably from about 10% to about 85%, more preferably from about 20% to about 80%, by weight of the total composition. The carrier, carriers, diluent or diluents are preferably selected to exhibit suitable flow characteristics and, where required for tablets, suitable compressibility.

Lactose, mannitol, disodium phosphate and microcrystalline cellulose (especially Avicel PH microcrystalline cellulose such as Avicel PH 101), alone or in combination, are preferred diluents. These diluents are chemically compatible with the API. The use of extragranular microcrystalline cellulose (ie microcrystalline cellulose added to granular compositions) can be used to improve hardness (for tablets) and/or disintegration time. Particular preference is given to lactose, especially lactose monohydrate. Lactose typically provides compositions with appropriate API release rates, stability, pre-compression flow, and/or drying properties at relatively low diluent costs. It provides a high density substrate that facilitates compaction during granulation (where wet granulation is used) and thus improves blend flow characteristics and tablet properties.

The pharmaceutical compositions and medicaments of the present invention optionally include one or more pharmaceutically acceptable disintegrants as excipients, especially for tablet formulations. Suitable disintegrants include, but are not limited to, starches, including sodium starch glycolate (e.g., Explotab ^™ from PenWest), and pregelatinized cornstarch (e.g., National ^™ 1551 from National Starch and Chemical Company), alone or in combination. , National ^TM 1550 and Colocorn ^TM 1500), clays (eg Veegum ^TM HV from RTVanderbilt), celluloses such as purified cellulose, microcrystalline cellulose, methyl cellulose, carmellose and sodium carboxymethyl cellulose, Croscarmellose sodium (eg, Ac-Di-Sol ^™ from FMC), alginates, crospovidone, and gums such as agar, guar, locust bean, karaya, pectin, and Tragacanth gum.

The disintegrant may be added at any suitable step during the preparation of the composition, in particular during the lubrication step prior to granulation or prior to compression. If present, such disintegrants amount to about 0.2% to about 30%, preferably about 0.2% to about 10%, more preferably about 0.2% to about 5%, by weight of the total composition.

Croscarmellose sodium is a preferred disintegrant for tablet or capsule disintegration, and if present, preferably comprises from about 0.2% to about 10%, more preferably from about 0.2% to about 7%, by weight of the total composition. %, more preferably from about 0.2% to about 5%. Croscarmellose sodium endows the granulated pharmaceutical composition and drug of the present invention with higher intragranular disintegration ability.

The pharmaceutical compositions and medicaments of the present invention optionally include one or more pharmaceutically acceptable binders or binders as excipients, especially for tablet formulations. Preferably such binders and binders impart sufficient cohesion to the tableted powder to allow conventional processing operations such as sizing, lubrication, compression and packaging, but still allow disintegration and assembly of the tablet upon ingestion substance is absorbed. Such binders may also prevent or inhibit crystallization or recrystallization of the API of the invention when the salt has been dissolved in solution. Suitable binders and binding agents ^include , but are not limited to, gum arabic; tragacanth; sucrose; gelatin; glucose ^; 1500); cellulose such as, but not limited to, methylcellulose and sodium carboxymethylcellulose (e.g., Tylose ^™ ); alginic acid and alginate salts; magnesium aluminum silicate; PEG; Povidones, such as povidone K-15, K-30, and K-29/32; polymethacrylates; HPMC; hydroxypropylcellulose (eg, Klucel™ from Aqualon); and ethylcellulose (eg, Klucel ^™ from Aqualon); , Ethocel ^(TM ) of the Dow Chemical Company). If present, such binders and/or binders constitute in total from about 0.5% to about 25%, preferably from about 0.75% to about 15%, more preferably from about 1% to about 10%, of the total weight of the pharmaceutical composition or medicament. %.

Many binders are polymers including amide, ester, ether, alcohol or ketone groups and are therefore preferred for inclusion in the pharmaceutical compositions and medicaments of the present invention. Particular preference is given to polyvinylpyrrolidones such as povidone K-30. Polymeric binders are available in different molecular weights, degrees of crosslinking and polymer grades. The polymeric binder may also be a copolymer, such as a block copolymer comprising a mixture of ethylene oxide and propylene oxide units. Variations in the proportions of these units in polymers are known to affect properties and performance. Examples of block copolymers with different block unit compositions are Poloxamer 188 and Poloxamer 237 (BASF Corporation).

The pharmaceutical compositions and medicaments of the present invention optionally include one or more pharmaceutically acceptable wetting agents as excipients. Such wetting agents are preferably selected to maintain the intimate association of the API with water, which is believed to improve the bioavailability of the composition.

Non-limiting examples of surfactants that can be used as wetting agents in the pharmaceutical compositions and medicaments of the present invention include quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride; Dioctyl sodium sulfosuccinate; polyoxyethylene alkylphenyl ethers such as nonoxynol (nonoxynol) 9, nonoxynol 10 and octoxynol 9, poloxamers (polyoxyethylene and polyoxynol propylene block copolymer), polyoxyethylene fatty acid glycerides and oils such as polyoxyethylene (8) caprylic/capric mono- and diglycerides (e.g. Labrasol ^™ from Gattefosse), polyoxyethylene (35) castor Sesame oil and polyoxyethylene(40) hydrogenated castor oil; polyoxyethylene alkyl ethers such as polyoxyethylene(20) cetostearyl ether; polyoxyethylene fatty acid esters such as polyoxyethylene(40) stearate , polyoxyethylene sorbitan such as Tween 20 and Tween 80 (e.g., Tween ^™ 80 from ICI); propylene glycol fatty acid esters such as propylene glycol laurate (e.g., Lauroglycol ^™ from Gattefosse); sodium lauryl sulfate ; their fatty acids and salts such as oleic acid, sodium oleate and triethanolamine oleate, glyceryl fatty acid esters such as glyceryl monostearate; sorbitan anhydrides such as sorbitan laurate, sorbitan Alcohol monooleate, sorbitan monopalmitate and sorbitan monostearate, tyloxapol, and mixtures thereof. If present, such wetting agents constitute 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%, of the total weight of the pharmaceutical composition or medicament.

Wetting agents that are anionic surfactants are preferred. Sodium lauryl sulfate is a particularly preferred wetting agent. If present, sodium lauryl sulfate constitutes in total from about 0.25% to about 7%, preferably from about 0.4% to about 4%, more preferably from about 0.5% to about 2%, of the total weight of the pharmaceutical composition or medicament.

The pharmaceutical compositions and medicaments of the present invention optionally include one or more pharmaceutically acceptable lubricants (including antiadherents and/or glidants) as excipients. Suitable lubricants include, but are not limited to, alone or in combination, glyceryl behenate (eg, Compritol ^™ 888 from Gattefosse); stearic acid and its salts, including magnesium, calcium, and sodium stearate; hydrogenated vegetable oils ( For example, Sterotex ^™ from Abitec); colloidal silica; talc; wax; boric acid; sodium benzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine; ^TM 4000 and Carbowax ^TM 6000); sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate. If present, such lubricants constitute 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%, of the total weight of the pharmaceutical composition or medicament.

Magnesium stearate is a preferred lubricant used eg to reduce friction between the equipment and the granulation mix during compression of the tablet formulation.

Suitable detackifying agents include, but are not limited to, talc, corn starch, DL-leucine, sodium lauryl sulfate, and metal stearates. Talc is a preferred anti-adhesive or glidant used, for example, to reduce adhesion to equipment surfaces and to reduce static electricity in the mixture. If present, talc constitutes from about 0.1% to about 10%, preferably from about 0.25% to about 5%, more preferably from about 0.5% to about 2%, of the total weight of the pharmaceutical composition or medicament.

Glidants can be used to facilitate powder flow in solid dosage forms. Suitable glidants include, but are not limited to, colloidal silicon dioxide, starch, talc, tribasic calcium phosphate, powdered cellulose, and magnesium trisilicate. Colloidal silicon dioxide is particularly preferred.

Other excipients such as coloring, flavoring and sweetening agents are known in the pharmaceutical art and can be used in the pharmaceutical compositions and medicaments of the present invention. Tablets may be enteric coated or uncoated. The compositions of the invention may additionally comprise, for example, buffering agents.

Optionally, one or more effervescent agents may be used as disintegrants and/or to enhance the sensory properties of the pharmaceutical compositions and medicaments of the present invention. When present in the pharmaceutical compositions and medicaments of the present invention to facilitate disintegration of the dosage form, preferably the total amount of one or more effervescent agents is from about 30% to about 75% by weight of the pharmaceutical composition or medicament, preferably about It is present in an amount of 45% to about 70% by weight, for example about 60% by weight.

According to a particularly preferred embodiment of the invention, the effervescent agent present in the solid dosage form in an amount less than effective to promote disintegration of the dosage form provides improved dispersion of the API in the aqueous medium. Without being bound by theory, it is believed that the effervescent agent effectively accelerates the dispersion of the API from the dosage form in the gastrointestinal tract, thereby further enhancing absorption and rapid onset of therapeutic action. When present in the pharmaceutical composition or medicament of the present invention to facilitate gastrointestinal tract dispersion but not to enhance disintegration, the effervescent agent is preferably present at about 1% by weight to about 20% by weight of the pharmaceutical composition or medicament, more preferably about 2.5% by weight. % to about 15% by weight, more preferably from about 5% to about 10% by weight.

"Effervescent" means herein an agent comprising one or more compounds that evolve a gas on contact with water, either together or separately. The gas evolved is usually oxygen or most usually carbon dioxide. Preferred effervescent agents include acids and bases which react in the presence of water to form 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 suitable bases as effervescent components useful in the present invention include carbonates (e.g., calcium carbonate), bicarbonates (e.g., sodium bicarbonate), sesquicarbonates, and its mixture. Calcium carbonate is the preferred base.

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

In preferred embodiments of the invention wherein the effervescent agent comprises an acid and a base, the weight ratio of acid to base is from about 1:100 to about 100:1, more preferably from about 1:50 to about 50:1, more preferably From about 1:10 to about 10:1. In a further preferred embodiment of the invention wherein the effervescent agent comprises an acid and a base, the ratio of acid to base is about stoichiometric.

Excipients that dissolve metal salts of API typically have both hydrophilic and hydrophobic regions, or preferably are or have amphiphilic regions. One type of amphiphilic or partially amphiphilic excipient includes or is an amphiphilic polymer. Particular amphiphilic polymers are polyalkylene glycols, which generally consist of ethylene glycol and/or propylene glycol subunits. Such polyglycols may be esterified at their ends with carboxylic acids, esters, anhydrides or other suitable groups. Examples of such excipients include poloxamers (symmetrical block copolymers of ethylene glycol and propylene glycol such as Poloxamer 237), polyalkylene glycolates of vitamin E (including esters of carboxylic acids; e.g., d-alpha-tocopheryl polyethylene glycol-1000 succinate), and macrogolglyceride (by alcoholysis of oil and esterification of polyglycol Formed to yield mono-, di-, and tri-glycerides and mixtures of mono- and diglycerides; eg, stearoyl macrogol-32 glyceride). Such pharmaceutical compositions and medicaments are advantageously administered orally.

The pharmaceutical compositions and medicaments of the present invention may comprise about 10% to about 50% by weight, about 25% to about 50% by weight, about 30% to about 45% by weight or about 30% to about 35% by weight of API; about 10 wt %, about 50 wt %, about 25 wt % to about 50 wt %, about 30 wt % to about 45 wt %, or about 30 wt % to about 35 wt % of a crystallization inhibiting excipient; and about 5 % to about 50%, about 10% to about 40%, about 15% to about 35%, or about 30% to about 35% by weight binder. In one example, the weight ratio of API to crystallization inhibiting excipient to binder is about 1:1:1.

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

The illustrative process comprises the steps of (a) mixing a salt of the invention with one or more excipients to form a mixture, and (b) tableting or encapsulating the mixture separately to form a tablet or capsule .

In a preferred method, the solid dosage form is prepared by a process comprising: (a) the step of mixing the API salt of the invention with one or more excipients to form a mixture, (b) granulating the mixture to form a step of granulating, and (c) a step of tableting or encapsulating the mixture separately to form tablets or capsules. Step (b) can be accomplished by any dry or wet granulation technique known in the art, but a dry granulation step is preferred. The salts of the present invention are advantageously granulated to form particles of from about 1 micron to about 100 microns, from about 5 microns to about 50 microns, or from about 10 microns to about 25 microns. Preferably one or more diluents, one or more disintegrants and one or more binders are added, for example in a mixing step, optionally a wetting agent can be added, for example in a granulation step, and preferably in One or more disintegrants are added after granulation but before tableting or encapsulation. Lubricants are preferably added prior to tabletting. Mixing and granulation can be performed independently under low or high shear. The preferred method of choice forms granules that are uniform in API content, easily disintegrated, sufficiently free-flowing to permit reliable control of weight variations during capsule filling or tablet compression, and sufficiently dense in bulk to permit processing of the batch in the selected equipment and the specific The dose is filled into the designated capsule or tablet mold.

In an alternative embodiment, the solid dosage form is prepared by a process comprising a spray drying step, wherein the API is suspended with one or more excipients in one or more sprayable fluids, preferably aprotic (such as , non-aqueous or non-alcoholic) sprayable fluid, which is then rapidly spray-dried on a stream of hot air.

The granulated spray-dry powder produced by the above illustrative methods can be compressed or molded to make tablets or filled into capsules to make capsules. Conventional tableting and packaging techniques known in the art can be used. Where coated tablets are desired, conventional coating techniques are suitable.

Excipients for use in tablet compositions of the present invention are preferably selected to provide a maximum disintegration assay of less than about 30 minutes, preferably a maximum of about 25 minutes, more preferably a maximum of about 20 minutes, more preferably a maximum The disintegration time is about 15.

In another embodiment of the invention, a pharmaceutical composition or medicament comprising modafinil and an additional one may be prepared. Modafinil and the additional API may be in co-crystalline form, or may be included as a mixture or combination of active pharmaceutical ingredients. For example, a composition may include modafinil and caffeine as a combination. Compositions comprising modafinil and caffeine can be used as therapeutic agents to treat the same conditions as modafinil. In such a composition comprising modafinil and caffeine, caffeine may contribute to the dissolution profile with a fast release profile (relative to modafinil's small Tmax), while modafinil causes a rapid release after administration. The therapeutic effect exists for several hours. For example, the Tmax of caffeine can be 0.001, 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, or 0.8 times that of modafinil. Combination therapy involves administering two or more APIs in the same formulation, or in two or more co-administered formulations. The APIs can be administered together at the same time, or separately at specified intervals.

The uses of Modafinil are well known and include narcolepsy, fatigue associated with multiple sclerosis, infertility, eating disorders, attention deficit hyperactivity disorder (ADHD), Parkinson's disease, incontinence, sleep apnea or myopathy Treatment. In another embodiment, any one or more of the modafinil compositions of the present invention may be used to treat one or more of the above conditions. Dosage and administration of the modafinil compositions of the present invention can be determined using routine methods in the art, but are generally about 50 to about 700 mg/day.

In another embodiment, the compositions of the present invention may be administered to mammals by 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.

Example

General method for preparing its crystals

a) High-throughput crystallization using the CrystalMax_ platform

CrystalMax_ includes a sequence of automated, integrated high-throughput automation stations that enable rapid generation, identification and characterization of API and AP polymorphs, salts and co-crystals. Use the dedicated design software Architect ^TM for worksheet generation and combined mixture design. Typically, the API or API candidate is dispensed from the organic solvent into test tubes and dried under nitrogen flow. Salts and/or co-crystal formers can also be dispensed and dried in the same manner. Dispense the water and organic solvent combination into test tubes using a multi-channel dispenser. Each tube in the 96-tube array was then sealed within 15 seconds of combined dispensing to avoid solvent evaporation. The mixture was then supersaturated by heating to 70°C for 2 hours followed by a cooling ramp of 1°C/min to 5°C. Optical inspection is then performed to detect crystals and/or solid material. Once the solid has been identified in the tube, it is isolated by aspiration and dried. Raman spectra were then obtained from the solid and cluster classification of the spectral characteristic curves was performed using a dedicated software (Inquire ^™ ).

b) crystallization from solution

Co-crystals can be obtained by dissolving the individual components in a solvent and adding one to the other. The co-crystals can then be precipitated or crystallized as the solvent mixture is slowly evaporated. Co-crystals can also be obtained by dissolving both components in the same solvent or solvent mixture. Co-crystals can also be obtained by seeding saturated solutions of the two components and seeding with the ground co-crystal mixture.

c) Crystallization from the melt (co-melt)

Co-crystals can be obtained by melting the two components together (ie, co-melting) and allowing recrystallization to occur. In some cases, an antisolvent may be added to facilitate crystallization.

d) Thermal microscopy (Thermal microscopy)

Co-crystals can be obtained by melting the higher melting component on a glass slide and allowing it to recrystallize. The second component is then melted and allowed to recrystallize as well. Co-crystals may form as separate phases/bands between eutectic bands of the two original components.

e) kneading and/or grinding

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

In another embodiment, the co-crystals are prepared by adding solvent, without adding solvent, or both. Solvents used in this co-crystallization process can be, for example but not limited to, acetone, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, nitromethane, dichloromethane, chloroform, toluene, propylene glycol, dimethyl Sulfoxide (DMSO), dimethylformamide (DMF), diethyl ether, ethyl formate, hexane, acetonitrile, benzyl alcohol, water, or another organic solvent including alcohol.

f) Co-sublimation

Co-crystals can be obtained from co-sublimation of a mixture of the API and the co-crystal former as an intimate mixture in the same sample tube by heating, mixing, or placing the mixture under vacuum. Co-crystals can be obtained by co-sublimation using a Kneudsen apparatus, where the API and co-crystal former are contained in separate sample tubes attached to a single cold finger, each tube maintained at the same or a different temperature under a vacuum atmosphere To co-sublimate the two components onto the cold finger to form the desired co-crystal.

Analytical method

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

For DSC analysis, the purge gas used was dry nitrogen, the reference material was an empty crimped aluminum pan, and the sample purge was 50 mL/min.

DSC analysis of samples was performed by placing modafinil samples in aluminum pans with crimped pan lids. The starting temperature is typically 20°C, the heating rate is 10°C/min and the ending temperature is 200°C. Unless otherwise stated, all reported DSC transitions represent the temperature at the endothermic or exothermic transition of their respective peaks with an error of +/- 2°C.

Thermogravimetric analysis (TGA) analysis of samples was performed using Q500Differential Scanning Calorimeter (TA Instruments, New Castle, DE, U.S.A.) using Advantage for QW-Series, version 1.0.0.78, Thermal Advantage Release 2.0 (2001 TA Instruments-Water LLC ). In addition, the analysis software used was Universal Analysis 2000 for Windows 95/98/2000/NT, Version 3.1E; Build 3.1.0.40 (2001 TA Instruments-Water LLC).

For TGA experiments, the purge gas used was dry nitrogen, the equilibrium purge was 40 mL/min _N2 , and the sample purge was 60 mL/min _N2 .

Samples were subjected to TGA by placing modafinil samples in platinum pans. The starting temperature is typically 20°C, the heating rate is 10°C/min and the ending temperature is 300°C.

The powder X-ray diffraction (PXRD) pattern of the sample was obtained using D/Max Rapid, Contact (Rigaku/MSC, The Woodlands, TX, U.S.A.) using RINTRapid Control Software, Rigaku Rapid/XRD, version 1.0.0 (1999 Rigaku Co .) as its control software. In addition, the analysis 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.).

For PXRD analysis, the acquisition parameters are as follows: the ray source is Cu at 1.5406 mm at the K line; the x-y stage is manual; the collimator size is 0.3mm; the capillary (Charles SupperCompany, Natick, MA, U.S.A.) is 0.3mm ID ; use reflection mode; power to X-ray tube is 46kV; current to X-ray tube is 40mA; ω-axis vibrates in the range of 0-5 degrees at 1 deg/min; phi-axis at 2 deg/s Rotation at an angle of 360 degrees; 0.3 mm collimation tube; acquisition time of 60 minutes; temperature at room temperature; and no heater used. The sample is presented to the X-ray source in a boron-enriched glass capillary.

In addition, the analysis parameters are as follows: the range of integral 2θ is 2-60 degrees; the range of integral χ is 0-360 degrees; the number of χ parts is 1; the step size used is 0.02; integration utility is cylint; normalization is used; dark count is 8; the Ω offset is 180; and the χ and φ offsets are 0.

PXRD diffraction patterns were also obtained by Bruker AXS D8 Discover X-ray Diffractometer. This instrument is equipped with GADDS ^™ (General Area Diffraction Detection System), a Bruker AXS HI-STAR AreaDetector calibrated at a distance of 15.05 cm according to the system, a copper source (Cu/Kα 1.54056 Angstroms), an automated xyz stage and a 0.5 mm calibration standard. Straight. The sample is compressed into pellet form and mounted on an xyz stage. Diffraction patterns were obtained in reflectance mode at power settings of 40 kV and 40 mA while keeping the sample fixed at ambient conditions (25°C). Exposure times varied for each sample and were specified for each sample. The resulting diffractograms were subjected to a spatial retransformation process to account for the geometric pincushion distortion of the area detector, and then integrated in steps of 0.02 degrees along χ from −118.8 to −61.8 degrees and 2θ 2.1–37 degrees, with the normalization set Normalized to binary.

The relative intensity of the peaks in the diffractogram is not necessarily a limitation of the PXRD pattern, as different samples may have different peak intensities, for example due to crystalline impurities. Additionally, the angles of the individual peaks may vary by about +/- 0.1 degrees, preferably +/- 0.05 degrees. There may also be a shift of about +/- 0.1 degrees to about +/- 0.2 degrees for the entire pattern or most of the peaks of the pattern due to calibration, setup and other variations between different instruments and different operators. All reported PXRD peaks in the Figures, Examples, and elsewhere herein are reported with an error of approximately ±0.1 degrees 2Θ.

For the PXRD data herein, including Tables and Figures, each composition of the invention may be composed of any one, any two, any three, any four, any five, any six, any seven or any eight or More 2θ angular peak characterization. Compositions of the invention may also be characterized using any one, two, three, four, five or six DSC transitions. Compositions can also be characterized using different combinations of PXRD peaks and DSC transitions.

Thermal (hotstage) microscopy was performed on a Zeiss Axioplan 2 microscope equipped with a Mettler Toledo FP90 controller. The heat stage used was a Mettler Toledo FP82HT. All melting point determinations were performed by placing samples on glass slides and covering with coverslips. The initial temperature was set at 30 °C and the temperature was increased at a rate of 10 °C/. Melting was observed through a 5x microscope objective.

HPLC method: (adapted from Donovan et al., Therapeutic Drug Monitoring 25:197-202.

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

Mobile phase A: 20mM sodium phosphate, pH 3.0

B: 70:30 mobile phase A: acetonitrile

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

Flow Program: Gradient

Run time: 35 minutes

Detection: UV@225nm

Injection volume: 10 microliters

Column temperature: 30+/-1°C

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

Needle Wash: Acetonitrile

Cleaning solvent & blocking wash: 90:10 (v/v) water: acetonitrile

Mobile phase preparation:

1. Prepare 1M sodium dihydrogen phosphate: Dissolve 120 g of sodium dihydrogen phosphate in water and make it 1000 mL; filter.

2. Prepare mobile phase A (20mM sodium phosphate, pH 3.0): For one liter, dilute 20mL of 1M sodium phosphate with water to 1000mL; adjust the pH to 3.0 with phosphoric acid.

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

Sample Preparation:

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

Raman collection

Leave the sample in the glass vial in which it was processed or transfer an aliquot of the sample to a glass slide. Place glass vials or slides in the combustion chamber. Measurements were performed using an Almega ^™ Dispersive Raman (Almega ^™ Dispersive Raman, Thermo-Nicolet, 5225 Verona Road, Madison, WI 53711-4495) system equipped with a 785 nm laser source. Laser light was directed onto the sample surface by manually bringing the sample into focus using the microscope portion of the setup with a 10x objective (unless otherwise noted). Spectra were obtained using the parameters described in Table A. (Exposure time and number of exposures may vary; parameter changes noted for each acquisition)

Table A. Raman Spectroscopy Acquisition Parameters parameter settings used Contact time (s) 2.0 Number of contacts 10 Laser source wavelength(nm) 785 Laser power (%) 100 aperture shape pinhole Aperture size (um) 100 Spectral range 104-3428 Grating position single Temperature when collecting (°C) 24.0

IR acquisition

IR spectra were obtained using NexusTM 470 FT-IR, Thermo-Nicolet, 5225 Verona Road, Madison, WI 53711-4495 and analyzed using Control and Analysissoftware: OMNIC, Version 6.0a, (C) Thermo-Nicolet, 1995-2004. The data for the co-crystallization are presented in Table IV and in the accompanying figures.

Example 1

Racemic modafinil: malonic acid cocrystal

To a solution containing racemic modafinil (150 mg, 0.549 mmol) in acetic acid (600 microliters) was added malonic acid (114.9 mg, 1.104 mmol). The mixture was then heated on a hot plate at 67°C until all material dissolved. The solution was then dried under a stream of nitrogen to yield a 1:1 modafinil:malonic acid cocrystal as a colorless solid. The solid material was characterized using PXRD. The material was then dried overnight under a stream of nitrogen to yield the same material with a slight excess of malonate. The colorless solid was characterized by PXRD (Bruker), DSC, TGA, IR and Raman spectroscopy. PXRD data for modafinil:malonic acid (1:1) cocrystals are listed in Table IV, and the diffractogram is shown in Figure 1 (data as is). DSC indicates an endothermic transition at about 106° C., and the thermogram is shown in FIG. 2 . The TGA differential thermogram is shown in FIG. 3 . Figures 4A and 4B represent the Raman spectrum of modafinil: malonate co-crystal, and three Raman spectra of modafinil, malonate and co-crystal, respectively. Figures 5A and 5B represent the IR spectrum of modafinil: malonate cocrystal and the three IR spectra of modafinil, malonate and cocrystal, respectively. Modafinil:malonic acid cocrystals may be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 1, including but not limited to 5.00, 9.17, 10.08, 16.81, 18.26, 19.43, 21.36, 21.94, 22.77, 24.49, 25.63, 26.37, and 28.45 degrees 2θ.

Modafinil:malonic acid co-crystals were also prepared by triturating the API with the co-crystal former. Racemic modafinil (2.50 g, 0.009 mol) and malonic acid (1.01 g, 0.0097 mmol) were mixed in a large mortar and ground over a period of seven days (within 7 days relative to the first day Malonate was added in increments of a ratio of approximately 1:1.05, and malonate was added over the next seven days in increments yielding a modafinil:malonate ratio of 1:2). The mixture was milled for 45 minutes initially and 20 minutes after each addition of more malonic acid. On the seventh day, the mixture of co-crystals and starting components was heated in a sealed 20 mL vial at 80° C. for about 35 minutes in order to complete the co-crystal formation. The resulting material was subjected to PXRD analysis (Bruker) and is represented in Figure 6A (data as is). Modafinil:malonic acid cocrystals can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 6A, including but not limited to 5.08, 9.28, 16.81, 18.27, 19.45, 21.39, 21.99, 22.83, 23.50, 24.58, 25.12, and 28.49 degrees 2θ. The DSC thermogram of the co-crystal in Figure 6B shows an endothermic transition at about 116°C. Single crystal data for the modafinil:malonic acid cocrystal were obtained and reported below. Figure 7 shows a packing diagram of modafinil:malonate.

Crystal data: C ₁₈ H ₁₉ NO ₆ S, M=377.40, monoclinic C2/c; a=18.728(8) Å, b=5.480(2) Å, c=33.894(13) Å, α=90° , β=91.864(9) degree, γ=90 degree, T=100(2)K, Z=8, Dc=1.442Mg/m ³ , V=3477(2) cubic angstrom, λ=0.71073 angstrom, measure 6475 reflections, 3307 unique diffraction points (R _int =0.1567). The final residuals are R ₁ =0.1598, wR ₂ =0.3301 for I>2σ(I) and R ₁ =0.2544, wR ₂ =0.3740 for all 3307 data.

Other methods have also been used to prepare modafinil:malonic acid cocrystals. A third preparation was performed by placing modafinil (30 mg, 0.0001 mol) and excess malonic acid in a stainless steel vial. Add 20 µl of acetone to the vial. The vial was then placed in a mill (wig-l-bug, Bratt Technologies, 115V/60Hz) and the solid mixture was milled for 5 minutes. The resulting powders were then collected and characterized by PXRD and DSC. In another preparation of modafinil:malonic acid cocrystals, the third preparation above was carried out without addition of solvent. All of the above methods using malonic acid appeared to produce co-crystals that were identical by PXRD and DSC analysis.

Example 2

Racemic Modafinil: Glycolic Acid Cocrystal

Racemic modafinil (1 mg, 0.0037 mmol) and glycolic acid (0.30 mg, 0.0037 mmol) were dissolved in acetone (400 microliters). The solution was evaporated to dryness and the resulting solid was characterized by PXRD (Rigaku). PXRD data for modafinil:glycolic acid cocrystals are listed in Table IV. See Figures 8A and 8B. Figure 8A shows the PXRD diffraction pattern after subtraction of background noise. Figure 8B shows the raw PXRD data as-is.

An alternative method of preparing modafinil: glycolic acid co-crystals was also performed. To a solution of modafinil (1 mg, 0.0037 mmol) dissolved in a mixture of acetone and methanol (3:1, 100 μl) was added glycolic acid (0.28 mg, 0.0037 mmol) dissolved in methanol (50 μl) ). The solvent was then evaporated to dryness under a stream of nitrogen to obtain a mixture of the two starting components. Acetone (200 microliters) was then added to the mixture, which was heated to 70°C and maintained at 70°C for 2 hours. The samples were then cooled to 5°C and maintained at this temperature for 1 day. After 1 day, the cap was removed from the vial and the solvent was evaporated to dryness to yield modafinil:glycolic acid cocrystals as a colorless solid. Modafinil:glycolic acid co-crystals were characterized by PXRD. Modafinil:glycolic acid cocrystals can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 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 degrees 2θ. Likewise, modafinil:glycolic acid cocrystals can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 8B, which include but Not limited to 2Θ of 9.53, 14.93, 15.99, 19.05, 20.05, 21.61, 22.77 and 25.05 degrees.

Example 3

Racemic modafinil:maleic acid cocrystal

To a solution of modafinil (150 mg, 0.549 mmol) in acetic acid (600 microliters) was added maleic acid (30.7 mg, 0.264 mmol). The mixture was then heated on a hot plate at 67°C until all material dissolved. The solution was then dried under a stream of nitrogen to yield a colorless amorphous material. Store the amorphous material in a sealed vial at room temperature. After 2 days, a solid material started to form which was collected and characterized using PXRD (Rigaku) as modafinil:maleic acid co-crystals as shown in Figures 9A and 9B. Figure 9A shows the PXRD diffraction pattern after subtraction of background noise. Figure 9B shows raw PXRD data. PXRD data for modafinil:maleic acid cocrystals are listed in Table IV. Modafinil:maleic acid cocrystals can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 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 degrees 2θ. Likewise, modafinil:maleic acid cocrystals can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 9B, which include 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 degrees 2Θ.

Example 4

Racemic Modafinil:L-Tartrate Cocrystal

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). The solution was then evaporated at room temperature to give a colorless viscous mass. The material was further dried under nitrogen flow for 2 days, then placed in a vial and capped. After 6 days, a small amount of colorless solid formed. About 60% of the amount of amorphous that remained clear had become solid one day after the solid was first observed. A sample of this material was analyzed by PXRD (Bruker) as shown in FIG. 10 . Modafinil:L-tartaric acid cocrystals can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 10, including but not limited to 6.10, 7.36, 9.38, 14.33, 16.93, 17.98, 18.81, 20.15, 20.71, 22.49, and 25.04 degrees 2θ.

Example 5

Racemic Modafinil:Citrate Cocrystal

Racemic modafinil (25.3 mg, 93 mmol) and citric acid monohydrate (26.8 mg, 128 mmol) were triturated together for 3 minutes. Then 1 mg of the resulting mixture was dissolved in acetone (100 μl) and heated to 70° C. and maintained at this temperature for 2 hours. The solution was then cooled to 5°C and maintained at this temperature for 2 days. After 2 days, the cap was removed from the vial and a drop of water was added. The solvent was then evaporated to afford modafinil: citric acid monohydrate co-crystals as a colorless solid. Modafinil: citric acid monohydrate co-crystals were characterized by PXRD (Rigaku) as shown in Figure 11A (background subtracted). Modafinil:citric acid cocrystals can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 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 degrees 2θ.

Other methods have also been used to prepare modafinil:citric acid monohydrate cocrystals. A second preparation was performed by placing modafinil (30 mg, 0.0001 mol) and excess citric acid monohydrate in a stainless steel vial. Add 20 µl of acetone to the vial. The vial was then placed in a mill (wig-l-bug, Bratt Technologies, 115V/60Hz) and the solid mixture was milled for 5 minutes. The resulting powders were then collected and characterized by PXRD and DSC. The DSC thermogram is shown in FIG. 11B . In another preparation of modafinil: citric acid monohydrate co-crystals, the second preparation above was carried out without adding solvent. All of the above methods using citric acid monohydrate appeared to produce co-crystals that were identical by PXRD and DSC analysis.

Example 6

Racemic modafinil:succinic acid cocrystal

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

An alternative method for the preparation of modafinil:succinic acid cocrystals was also performed. 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). The mixture was then dissolved on a hot plate at 65 °C. The flask was then seeded with modafinil:succinic acid cocrystals prepared above. Methanol was then evaporated using a rotary evaporator and a 65°C hot water bath to yield modafinil:succinic acid cocrystals as a colorless solid. Synthesis of modafinil:succinic acid co-crystals was confirmed by PXRD (Rigaku) of the collected solids. Modafinil:succinic acid cocrystals can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 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 degrees 2θ. Likewise, modafinil:succinic acid cocrystals can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 12B, which include but Not limited to 2Θ of 5.45, 9.93, 15.87, 17.99, 18.75, 19.95, 21.95, 23.03, and 25.07 degrees. Single crystal data for the modafinil:succinic acid cocrystal were obtained and reported below. Figure 14 shows the packing diagram of modafinil:succinic acid cocrystals.

Crystal data: C ₁₇ H ₁₈ NO ₄ S, triclinic P-1; a=5.672(4) Å, b=8.719(6) Å, c=16.191(11) Å, α=93.807(14) degrees, β =96.471(17) degree, γ=92.513(13) degree, T=100(2)K, Z=2, Dc=1.392Mg/m ³ , V=792.8(9) cubic angstrom, λ=0.71073 angstrom, measured 2448 reflections, 1961 independent diffraction points (Rint = 0.0740). The final bias factors were R ₁ =0.1008, wR ₂ =0.2283 for I>2σ(I), and R ₁ =0.1593, wR ₂ =0.2614 for all 1961 data.

A third method was also used to prepare modafinil:succinic acid cocrystals. These methods were performed by placing modafinil (30 mg, 0.0001 mol) and excess succinic acid in stainless steel vials. Add 20 µl of acetone to the vial. The vial was placed in a mill (wig-l-bug, Bratt Technologies, 115V/60Hz) and the solid mixture was milled for 5 minutes. The resulting powders were then collected and characterized by PXRD and DSC. All of the above methods using succinic acid appeared to produce co-crystals that were identical by PXRD and DSC analysis.

Example 7

Racemic Modafinil:DL-Tartrate Cocrystal

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 at reflux for 1 min. The suspension was filtered while hot through 0.2 micron PTFE filter paper to remove insoluble DL-tartaric acid. The remaining solution was allowed to cool to room temperature, then to 0 °C for 1 hour. After 1 hour, large colorless crystals were observed. The mother liquor was decanted off and the solid was air dried and characterized by PXRD (Rigaku) as shown in FIG. 15 . Modafinil:DL tartrate cocrystals can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 15, including but not limited to 4.75 , 9.53, 10.07, 15.83, 17.61, 19.37, 20.25, 21.53, 22.55, and 23.75 degrees 2θ (as collected).

Example 8

Racemic Modafinil: Fumaric Acid Cocrystal (Form I)

Modafinil (30 mg, 0.0001 mol) and fumaric acid (2.3 mg, 0.0002 mol) were placed in a stainless steel vial. Add 20 µl of acetone to the vial. The vial was placed in a mill (wig-l-bug, Bratt Technologies, 115V/60Hz) and the solid mixture was milled for 5 minutes. The resulting powder was then collected and characterized using PXRD (Rigaku) as modafinil:fumaric acid co-crystals (Form I), as shown in FIG. 16 . The co-crystal was a 2:1 co-crystal comprising two moles of modafinil per mole of fumaric acid. Modafinil:fumaric acid cocrystals (Form I) can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 16, which Including but not limited to 5.45, 9.95, 10.91, 15.93, 18.03, 18.81, 19.93, 20.25, 21.37, 21.95, 23.09 and 25.01 degrees 2Θ (as collected). Single crystal data for the modafinil:fumaric acid cocrystal (Form I) were obtained and reported below. Figure 17 shows the packing diagram of modafinil: fumaric acid cocrystal (Form I).

Crystal data: C ₁₇ H ₁₇ NO ₄ S, M=331.38, triclinic P-1; a=5.7000(15) Å, b=8.735(2) Å, c=16.204(4) Å, α=93.972( 6) degree, β=97.024(6) degree, γ=93.119(7) degree, T=100(2)K, Z=2, Dc=1.381Mg/m ₃ , V=797.2(4) cubic Angstrom, λ = 0.71073 Angstroms, 4047 reflections measured, 2615 independent diffraction points (Rint = 0.0475). _The final bias factors were R ₁ =0.0784, wR ₂ =0.1584 for I>2σ(I) and R 1 =0.1154, wR ₂ =0.1821 for all 2615 data.

Example 9

Racemic modafinil:fumaric acid cocrystal (Form II)

Modafinil (30 mg, 0.0001 mol) and fumaric acid (1.2 mg, 0.0001 mol) were placed in a stainless steel vial. Add 20 µl of acetone to the vial. The vial was placed in a mill (wig-l-bug, Bratt Technologies, 115V/60Hz) and the solid mixture was milled for 5 minutes. The resulting powder was then collected and characterized using PXRD (Rigaku) as modafinil:fumaric acid co-crystals (Form II), as shown in FIG. 18 . Modafinil:fumaric acid cocrystals (Form II) can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 18, which Including but not limited to 6.47, 8.57, 9.99, 13.89, 14.53, 16.45, 17.13, 17.51, 18.39, 20.05, 20.79, 25.93, and 27.95 degrees 2Θ (as collected).

Example 10

Racemic modafinil: 2,5-dihydroxybenzoic acid co-crystal

Modafinil (30 mg, 0.0001 mol) and 2,5-dihydroxybenzoic acid (1.5 mg, 0.0001 mol) were placed in a stainless steel vial. Add 20 µl of acetone to the vial. The vial was placed in a mill (wig-l-bug, Bratt Technologies, 115V/60Hz) and the solid mixture was milled for 5 minutes. The resulting powder was then collected and characterized by PXRD (Bruker), as shown in FIG. 19 . Modafinil:2,5-dihydroxybenzoic acid cocrystals can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 19, These 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 degrees 2Θ (as collected).

Example 11

Racemic modafinil: oxalic acid cocrystal

Modafinil:oxalic acid co-crystals were prepared by placing racemic modafinil (30 mg, 0.0001 mol) and oxalic acid (1-2 mg, 0.0001-0.0002 mol) in a stainless steel vial. Add 20 µl of acetone to the vial. The vial was placed in a mill (wig-l-bug, Bratt Technologies, 115V/60Hz) and the solid mixture was milled for 5 minutes. The resulting powder was then collected and characterized by PXRD (Bruker), as shown in FIG. 20 . In another preparation of modafinil: oxalic acid cocrystals, the above preparation was carried out without addition of solvent. Both methods produced the same co-crystals by PXRD analysis. Modafinil:oxalic acid cocrystals can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 20, including but not limited to 5.98, 13.68, 14.80, 17.54, 19.68, 21.12, 21.86, and 28.90 degrees 2Θ (as collected).

Example 12

Racemic Modafinil: 1-Hydroxy-2-Naphthoic Acid Co-Crystals

Racemic modafinil (30 mg, 0.0001 mol) and 1-hydroxy-2-naphthoic acid (21 mg, 0.0001 mol) were placed in a stainless steel vial. Add 20 µl of acetone to the vial. The vial was placed in a mill (wig-l-bug, Bratt Technologies, 115V/60Hz) and the solid mixture was milled for 5 minutes. The resulting powder was then collected and characterized by PXRD (Bruker), as shown in FIG. 21 . Modafinil: 1-hydroxy-2-naphthoic acid cocrystals can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 21, These include, but are not limited to, 5.72, 7.10, 11.48, 14.16, 15.66, 17.92, 19.18, 20.26, 21.28, 21.94, 24.38, and 26.86 degrees 2Θ (as collected). The PXRD peaks at 10.05 and 26.36 degrees 2Θ may result from excess co-crystal formers.

Example 13

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

R-(-)-modafinil was prepared by trituration of R-(-)-modafinil (29.7 mg, 0.109 mmol, 82.2% R-isomer) with malonic acid (11.9 mg, 0.114 mmol) : Co-crystal of malonic acid. The milled mixture was then heated to 80°C for 10 minutes. The powder was analyzed by PXRD (Bruker) and DSC as shown in Figures 22 and 23, respectively. The PXRD pattern confirmed the formation of a co-crystal and exhibited many similarities to the PXRD pattern of the racemic modafinil:malonic acid co-crystal. R-(-)-modafinil:malonic acid cocrystals can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 22 , which 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 degrees 2Θ (data collected as is). 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 was prepared by trituration of R-(-)-modafinil (30.9 mg, 0.113 mmol, 82.2% R-isomer) with succinic acid (14.8 mg, 0.125 mmol): Succinic acid co-crystallization. The milled mixture was then heated to 145°C for 5 minutes. The powder was analyzed by PXRD (Bruker) and DSC as shown in Figures 24 and 25, respectively. The PXRD pattern confirmed the formation of a co-crystal and exhibited many similarities to the PXRD pattern of the racemic modafinil:succinic acid co-crystal made from solution. R-(-)-modafinil:succinic acid cocrystals can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 24, These 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 degrees 2Θ (data collected as is). DSC indicated a melting 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

Prepare R-(-)-modafinil by triturating R-(-)-modafinil (30.0 mg, 0.110 mmol, 82.2% R-isomer) with citric acid monohydrate (27.1 mg, 0.129 mmol) Finney: citric acid cocrystals. The powder was analyzed by PXRD (Bruker) and DSC as shown in Figures 26 and 27, respectively. The PXRD pattern confirmed the formation of a co-crystal and exhibited many similarities to the PXRD pattern of the racemic modafinil:citric acid co-crystal. R-(-)-modafinil:citric acid cocrystals can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 26, This includes, but is 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 degrees 2Θ (data collected as is). DSC indicated a melting 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 obtained from high-throughput crystallization experiments using dichloromethane. 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. The solid material was collected and characterized by PXRD (Bruker) and DSC, as shown in Figures 28 and 29, respectively. R-(-)-modafinil:DL-tartaric acid cocrystals can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 28 , which include but are not limited to 4.67, 15.41, 17.97, 19.46, 20.50, 22.91 and 24.63 degrees 2Θ (as collected). There are endothermic transitions at about 107, 152 and 187°C.

Example 17

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

To 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 o-di Toluene (4.5 mL). The mixture was heated to reflux for less than a minute at which time both solids had dissolved. The solution was then allowed to cool slowly to room temperature, at which time a solid crystallized. The solid was collected by filtration and air dried. The powder was characterized by PXRD (Bruker) as shown in Figure 30. The same was prepared from benzene, toluene, and acetone using the methods described above. R-(-)-modafinil: 1-hydroxyl-2-naphthoic acid co-crystal can pass through any one, any two, any three, any four, any five or any six or More peaks characterized including but not limited to 5.27, 8.85, 10.60, 12.11, 14.47, 17.80, 18.80, 21.20, 23.03 and 25.61 degrees 2Θ (as collected).

Also from high-throughput crystallization experiments using vials containing a 1:1 mixture of R-(-)-modafinil (over 98% R-isomer) and 1-hydroxy-2-naphthoic acid in nitromethane R-(-)-modafinil: 1-hydroxy-2-naphthoic acid co-crystals were obtained. The solid material was collected and characterized by PXRD (Bruker) and DSC, as shown in Figures 31 and 32, respectively. R-(-)-modafinil: 1-hydroxyl-2-naphthoic acid co-crystal can be obtained by any one, any two, any three, any four, any five or any six or More peaks characterized including but not limited to 5.34, 8.99, 10.68, 12.15, 14.51, 21.28, 23.14 and 24.50 degrees 2Θ (as collected). DSC indicated endothermic transitions at about 118 and 179°C.

Example 18

R-(-)-modafinil: orotic acid co-crystallization

R-(-)-modafinil (1 mg, 0.0036 mmol, over 98% R-isomer) and orotic acid (1.14 mg, 0.0073 mmol) in acetone (100 microliters) from Qualcomm Quantitative crystallization experiment obtained R-(-)-modafinil: orotic acid co-crystallization. The solid material was collected and characterized by PXRD (Bruker) and DSC, as shown in Figures 33 and 34, respectively. R-(-)-modafinil:orotic acid cocrystals can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 33 , which include but are not limited to 9.77, 17.85, 20.52, 20.95, 24.03, and 26.80 degrees 2Θ (as collected). The PXRD peaks at 14.61 and 28.60 may correspond to excess co-crystal former. There are endothermic transitions at about 116, 130 and 169°C.

Table IV: Co-crystallization of Modafinil co-crystal former Representative PXRD peaks (degrees, 2θ) Malonate 5.00, 9.17, 10.08, 16.81, 18.26, 19.43, 21.36, 21.94, 22.77, 24.49, 25.63, 26.37, 28.45 glycolic acid 9.53, 14.93, 15.99, 19.05, 20.05, 21.61, 22.77, 25.05 maleic acid 4.69, 6.17, 9.63, 10.25, 15.67, 16.53, 17.21, 18.05, 19.99, 21.85, 22.47 L-Tartrate 6.10, 7.36, 9.38, 14.33, 16.93, 17.98, 18.81, 20.15, 20.71, 22.49, 25.04 citric acid 5.29, 7.29, 9.31, 12.41, 13.29, 17.29, 17.97, 18.79, 21.37, 23.01 Succinic acid 5.45, 9.93, 15.87, 17.99, 18.75, 19.95, 21.95, 23.03, 25.07 DL-Tartrate 4.75, 9.53, 10.07, 15.83, 17.61, 19.37, 20.25, 21.53, 22.55, 23.75 Fumaric Acid (Type I) 5.45, 9.95, 10.91, 15.93, 18.03, 18.81, 19.93, 20.25, 21.37, 21.95, 23.09, 25.01 Fumaric Acid (Type II) 6.47, 8.57, 9.99, 13.89, 14.53, 16.45, 17.13, 17.51, 18.39, 20.05, 20.79, 25.93, 27.95 2,5-Dihydroxybenzoic acid 6.96, 12.92, 14.76, 17.40, 18.26, 20.10, 20.94, 23.46, 24.36 oxalic acid 5.98, 13.68, 14.80, 17.54, 19.68, 21.12, 21.86, 28.90 1-Hydroxy-2-naphthoic acid 5.72, 7.10, 11.48, 14.16, 15.66, 17.92, 19.18, 20.26, 21.28, 21.94, 24.38, 26.86 ^* malonate 5.04, 9.26, 16.73, 18.23, 19.37, 21.90, 22.74, 24.44, 25.67 ^* Succinic acid 5.36, 9.83, 15.80, 17.88, 18.70, 19.87, 21.21, 21.85, 25.96 ^* citric acid 5.18, 7.23, 9.23, 12.32, 13.23, 17.25, 17.92, 18.76, 20.25, 21.30, 23.71 ^** DL-Tartrate 4.67, 15.41, 17.97, 19.46, 20.50, 22.91, 24.63 ^** 1-Hydroxy-2-naphthoic acid 5.27, 8.88, 10.60, 12.11, 14.47, 17.80, 18.80, 21.20, 23.03, 25.61 ^** Orotic acid 9.77, 17.85, 20.52, 20.95, 24.03, 26.80 ^** 2,5-Dihydroxybenzoic acid 7.07, 7.51, 9.07, 12.31, 16.03, 17.63, 18.39, 19.83, 21.27, 23.57, 26.93, 28.85

^* = API is R-(-)-modafinil with 82.2% (purity) R-(-)-modafinil (17.8% S-(+)-modafinil)

^** = API is R-(-)-modafinil with more than 98% (purity) R-(-)-modafinil (less than 2% S-(+)-modafinil

All other co-crystals included racemic modafinil.

Example 19

Acetic acid solvate of racemic modafinil

Acetic acid (40 microliters) was added to racemic modafinil (12.9 mg, 0.047 mmol). The mixture was heated at 50°C to completely dissolve the solids. The solution was allowed to cool to room temperature and stand overnight without precipitation. The solution was then evaporated under nitrogen flow until a precipitate was observed. The resulting solid was further dried under nitrogen flow. The product was characterized by PXRD (Rigaku), TGA, DSC and Raman spectroscopy, as shown in Figures 35-38, respectively. An alternative process for the preparation of the acetic acid solvate of modafinil was also performed. Modafinil acetic acid solvate was prepared by dissolving racemic modafinil (12.9 mg, 0.047 mmol) in acetic acid (40 μl) and incubating at 65°C for 30 minutes to dissolve, then cooling to 25°C and incubating overnight. samples of objects. The sample was then evaporated to about 1/3 volume. After the samples were centrifuged, rapid nucleation and crystal growth were observed. An additional 20 μl of acetic acid was then added. The sample was heated at 50°C until partial dissolution of the crystals was observed. The samples were then cooled to room temperature over a period of 1 hour and then to 5°C over a period of 3 hours to induce crystal growth. The samples were then dried under nitrogen. Rapid crystallization was observed. Modafinil acetic acid solvate can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 35, including but not limited to 6.17, 9.63, 15.69, 17.97, 19.99 and 21.83 degrees 2Θ (data collected as is).

Example 20

Tetraoxyfuran solvate of racemic modafinil

The tetrahydrofuran (THF) solvate of modafinil was prepared by dissolving racemic modafinil (10.4 mg, 0.038 mmol) in tetrahydrofuran (1 mL). The powder was incompletely dissolved in THF and transformed into long, fine, needle-like crystals after overnight, which were collected and analyzed by PXRD (Rigaku), as shown in FIG. 39 . Modafinil THF solvate can be characterized by any one, any two, any three, any four, any five or any six or more peaks in Figure 39, including but not limited to 6.97, 9.79, 10.97, 16.19, 19.03, 19.71, 20.59, 22.25, and 25.13 degrees 2Θ (data collected as is).

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, which transformed into long, thin, needle-like crystals, which were collected and subjected to PXRD (Rigaku) analysis, as shown in FIG. 40 . Modafinil 1,4-dioxane solvate can be characterized by any one, any two, any three, any four, any five or any six or more peaks in Figure 40, which Including but not limited to 6.93, 9.85, 10.97, 16.19, 18.97, 19.61, 20.33, 20.65 and 22.07 degrees 2Θ (data collected as is). The PXRD pattern also contained several spikes which were the result of instrumental error and could not be removed.

Example 22

Methanol solvate of racemic modafinil

The methanol solvate of modafinil was obtained by evaporating 2 mL of a 30 mg/mL solution of racemic modafinil in methanol overnight under a stream of nitrogen. The methanol solvate was characterized by PXRD (Rigaku), TGA and DSC, as shown in Figures 41, 42 and 43, respectively. Modafinil methanol solvate can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 41, including but not limited to 6.15, 9.89, 12.25, 15.69, 17.97, 20.07, 21.85, and 22.73 degrees 2Θ (data collected as is).

Example 23

Nitromethane solvate of racemic modafinil

To racemic modafinil (12.9 mg, 0.047 mmol) was added nitromethane (1 mL). The incompletely dissolved mixture was left to stand overnight, which transformed into large rectangular crystals. The solid was collected and analyzed by PXRD (Rigaku) as shown in FIG. 44 . Modafinil nitromethane solvate may be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 44, including but not limited to 6.17, 9.77, 15.89, 18.11, 20.07, 22.17, 22.91, 25.31, and 25.83 degrees 2θ (data collected as is).

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 boiling to dissolve all solid material. Once the solids had dissolved, the solution was placed on an aluminum block at 5 °C. After 15 minutes at 5°C, crystals started to form at the bottom of the vial. The solution was then decanted and individual crystals were collected and analyzed by PXRD (Rigaku), as shown in FIG. 45 . The crystals were determined to be the acetone solvate of modafinil. The acetone solvate of modafinil may be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 45, including but not limited to 6.11 , 9.53, 15.81, 18.11, 20.03, 21.63, 22.45, 25.23, 25.65, 28.85, 30.23, and 32.93 degrees 2θ (as collected). Several other co-crystal formers, including adipic, lactobionic, maleic, and glycolic acids, can also be used to obtain acetone solvates according to the methods described above.

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 solid was characterized by PXRD (Rigaku), as shown in FIG. 46 . The solid obtained was a mixture of acetone solvate and another modafinil product. This composition can be characterized by any one, any two, any three, any four, any five or any six or more peaks in Figure 46, including but not limited to 6.11, 9.53, 15.77, 18.03, 20.01 and 21.61 degrees 2Θ (background removed). 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 solid was characterized by PXRD (Rigaku), as shown in FIG. 47 . The resulting solid is likely a solvate of modafinil. This composition can be characterized by any one, any two, any three, any four, any five or any six or more peaks in Figure 47, including but not limited to 5.87, 8.95, 12.49, 13.99, 18.19, 19.99, 21.57 and 25.01 degrees 2Θ (removal of background).

Example 27

A new form of racemic modafinil

Racemic modafinil was dispensed from a stock solution containing 50 mg modafinil in 20 mL of a 15:5 acetone/methanol mixture. The solution was then evaporated to dryness under nitrogen flow. Benzoic acid was partitioned from acetone solution and the mixture was evaporated to dryness again. Then 200 microliters of isopropanol or methanol was added and the vial was capped. After standing at room temperature for one day, the cap was removed and the solvent was evaporated. The samples were subjected to PXRD (Rigaku) as shown in FIG. 48 . A new form of racemic modafinil that may be a polymorph or a co-crystal is indicated as Form VII. Form VII can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 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 degrees 2Θ (data collected as is).

Example 28

Pharmacokinetics of racemic modafinil:malonate cocrystals in dogs

In a pharmacokinetic study, racemic modafinil:malonate cocrystals (from Example 1) were administered to dogs. Modafinil:malonate co-crystal particles with a median particle size of approximately 16 microns were administered in the study. For reference, micronized modafinil with a median particle size of approximately 2 microns was also administered in the study. The AUC of modafinil:malonic acid cocrystals was determined to be 40 to 60% higher than that of pure modafinil. This higher bioavailability demonstrates the modulation of important pharmacokinetic parameters by embodiments of the present invention. A compilation of important pharmacokinetic parameters measured in animal studies is included in Table V.

Table V - Pharmacokinetic parameters of modafinil:malonate cocrystals and pure modafinil in dogs parameter Pure Modafinil Modafinil: malonic acid cocrystal Median particle size 2 microns 16 microns C_max(ng/mL) 11.0±5.9 10.3±3.4 T_max(hour) 1.3±0.6 1.7±0.6 AUC (relative) 1.0 1.4-1.6 Half-life (hours) 2.1±0.7 5.1±2.4

Example 29

Solid state stability of racemic modafinil:malonic acid cocrystals

The stability of the racemic modafinil:malonic acid cocrystals was measured over a period of four weeks at different temperatures and relative humidity. No degradation was found at 20 or 40°C. At 60°C, about 0.14% degradation per day was determined according to a simple exponential model. At 80°C, about 8% degradation per day was determined.

The stability of the modafinil:malonic acid cocrystals was also measured over a period of 26 weeks at different temperatures and relative humidity. Figures 49 and 50 represent plots of area % impurity versus time (weeks) measured by HPLC for samples stored under different conditions, including 25°C, 60% RH; 40°C, 75% RH; 40°C, ambient RH ; 60°C, ambient RH; 80°C, ambient RH; and -20°C. These data indicate that the compounds are stable when stored at or below 40°C for at least 26 weeks. Figure 51 compares the PXRD patterns of modafinil:malonic acid cocrystal samples initially and after subjecting the samples to several temperatures and RH levels for 26 weeks.

Example 30

Formulation of racemic modafinil:malonic acid cocrystals

The formulation of racemic modafinil:malonate cocrystals was accomplished using lactose. Two mixtures, one modafinil and lactose and the second modafinil: malonate cocrystals and lactose, were ground together in a mortar and pestle separately. The mixture targets a 1:1 weight ratio of modafinil to lactose. In the modafinil and lactose mixture, grind together 901.2 mg of modafinil and 901.6 mg of lactose. In the modafinil:malonic acid co-crystals and lactose mixture, 1221.6 mg of the co-crystals and 871.4 mg of lactose were ground together. The obtained powder was analyzed by PXRD and DSC. The PXRD pattern and DSC thermogram of the mixture showed no change from their respective components. The DSC of the co-crystal mixture only showed the melting peak of the co-crystal at 113.6°C, and the heat of fusion was 75.9 J/g. The heat of fusion is 59.5% of the value (127.5 J/g) found using the co-crystal alone. This result is consistent with a 58.4% weight ratio of co-crystallization in the mixture. The DSC of a mixture of modafinil and lactose has a melting point of 165.7°C. This is slightly lower than the measured melting point of modafinil (168.7°C). The heat of fusion of the mixture (59.3 J/g) was 46.9% of that of modafinil alone (126.6 J/g), which fits the estimate of 50%.

In vitro dissolution of both modafinil: malonate cocrystals and pure modafinil was tested in capsules. Both gelatin and hydroxypropylmethylcellulose (HPMC) capsules were used in the dissolution studies. Capsules were formulated with and without the presence of lactose. All formulations were ground in a mortar and pestle prior to transfer into capsules. Capsules were tested for dissolution in 0.01M HCl (see Figure 52).

In 0.01N HCl, use the sifted and ground material in capsules:

Modafinil and modafinil: malonate cocrystals were passed through a 38 micron sieve. With 200.0 mg of sieved modafinil, 280.4 mg of sieved modafinil:malonic acid cocrystal, 200.2 mg of ground modafinil, or 280.3 mg of ground modafinil:malonate Co-crystal-filled gelatin capsules (Size 0, B&B Pharmaceuticals, Lot #15-01202). Dissolution studies were performed in a Vankel VK 7000 Benchsaver Dissolution Testing Apparatus with a VK750D heater/circulator set at 37°C. At 0 minutes, the capsules were dropped into a container containing 900 mL of 0.01M HCl and stirred by a paddle.

Absorbance readings were taken using a Cary 50 spectrophotometer (wavelength set to 260 nm) at the following time points: 0, 5, 10, 15, 20, 25, 30, 40, 50, and 60 minutes. Compare the absorbance value to the standard and calculate the modafinil concentration of the solution.

The milled material was used in gelatin or HPMC capsules with and without lactose in 0.01N HCl:

Modafinil and modafinil: malonate co-crystals were mixed with an equivalent amount of lactose (Spectrum, Lot QV0460) for about 5 minutes. Gelatin capsules (size 0, B&B) were filled with 400.2 mg of modafinil and lactose (approx. Pharmaceuticals, Lot #15-01202), with 399.9 mg of modafinil and lactose, 560.9 mg of modafinil:malonic acid cocrystals and lactose, 199.9 mg of modafinil or 280.5 mg of modafinil: Malonic acid co-crystals filled HPMC capsules (size 0, Shionogi, Lot #A312A6). Dissolution studies were performed as described above.

Example 31

in vitro dissolution

Figure 53 presents in vitro dissolution data for micronized racemic modafinil:malonate cocrystals and micronized modafinil in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). Both samples were mixed with lactose and filled into HPMC capsules. Co-crystals released modafinil into solution more rapidly than the free form of modafinil in both SGF and SIF. Figure 54 compares the dissolution of HPMC capsules filled with co-crystals of modafinil: malonate mixed with lactose and the dissolution of PROVIGIL tablets. Figure 55 shows a dynamic vapor sorption (DVS) isotherm plot for modafinil: malonic acid cocrystals. This graph shows no appreciable water adsorption up to 40% RH at 26°C.

Example 32

in vivo test

A pharmacokinetic study was performed in dogs using racemic modafinil:malonate and PROVIGIL tablets (200 mg) formulated with lactose. Seven capsules were filled with modafinil: malonic acid co-crystals and lactose, 476.24 +/- 2 mg, each containing 200 mg of modafinil. Figure 56 shows co-crystal formulations with increased Cmax and increased bioavailability. Several important pharmacokinetic parameters are described in Table VI. In Table VI, "Cmax" is the maximum plasma concentration, "AUC(inf)" is the extrapolated area under the curve, "t1 _/2 " is the time from the start of dosing when the plasma level drops to half the Cmax level, "Tmax" is the time from dosing to reach the maximum plasma concentration, "CL" is the clearance of modafinil, and "F%" is the % bioavailability.

Table VI - PK Parameters of Modafinil: Malonate Co-Crystals and PROVIGIL in Vivo

Example 33

R-(-)-modafinil: 2,5-dihydroxybenzoic acid co-crystal

R-(-)-modafinil (50 mg, 0.183 mmol, over 98% R-isomer) and 2,5-dihydroxybenzoic acid (28.2 mg, 0.183 mmol) were placed in a stainless steel vial. Add 10 µl of acetone to the vial. The vial was placed in a mill (wig-l-bug, Bratt Technologies, 115V/60Hz) and the solid mixture was milled for 5 minutes. The resulting powder was then collected and characterized by PXRD (Rigaku), as shown in FIG. 57 . R-(-)-modafinil: 2,5-dihydroxybenzoic acid co-crystal can be obtained by any one, any two, any three, any four, any five or any six or More peaks characterized including but not limited to 7.07, 9.07, 12.31, 13.03, 14.09, 18.93, 19.83 and 21.27 degrees 2Θ (as collected). Other PXRD peaks at 7.51, 16.03, 17.63, 18.39, 23.57, 26, 93 and 28.85 degrees 2Θ corresponded to excess co-crystal former.

Example 34

Channel solvate of racemic modafinil

Unexpected discovery of a channel solvate of modafinil. The channel solvate was prepared 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 hot plate at 60°C . The solution was then evaporated while hot under a stream of nitrogen to a total volume of 1.6 mL. After cooling, the solution was seeded with triturated racemic modafinil: 1-hydroxy-2-naphthoic acid co-crystals. Individual crystals were obtained and characterized by single crystal 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, α=90 degrees, β=104.140(4) degrees, γ=90 degrees, V=1547.3(5) cubic angstroms, Z=2. Figures 58 and 59 show the packing diagrams of the acetone channel solvate of modafinil. The stacking diagram shows that acetone has a variable location within the channel structure. Ethyl acetate channel solvates were also prepared according to the method described above using ethyl acetate instead of acetone.

Example 35

o-xylene hemisolvate of racemic modafinil

Ortho-diphenoxy was formed 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). Toluene hemisolvate. The mixture was heated on a hot plate with vortexing until all solids were dissolved. The solution was then left to crystallize in a sealed vial. The resulting powder was collected in a centrifugal filter and analyzed by PXRD (Bruker), as shown in FIG. 60 . The hemisolvate was also analyzed and characterized using Raman spectroscopy (Figure 61), TGA (Figure 62) and DSC (Figure 63). Ortho-xylene solvates may be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 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 degrees 2θ. Ortho-xylene solvates may be characterized by any one, any two, any three, any four, any five, or any six or more peaks in the spectrum of Figure 61 (middle), including but not limited to 1641, 1407, 1379, 1211, 1024 and 721 cm ^-1 .

Example 36

Benzene hemisolvate of racemic modafinil

The o-xylene semi-halide 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). solvates. The mixture was heated on a hot plate with vortexing until all solids were dissolved. The solution was then left to crystallize in a sealed vial. The resulting powder was collected in a centrifugal filter and analyzed by PXRD (Bruker) as shown in FIG. 64 . The hemisolvates were also analyzed and characterized using Raman spectroscopy (Figure 65), TGA (Figure 66) and DSC (Figure 67). Benzene solvates may be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 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 degrees 2θ. Benzene solvates can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 65 (middle spectrum), which include but are not limited to 1637 , 1600, 1409, 1380, 1214, 1025, 998 and 721 cm ^-1 .

Example 37

Toluene hemisolvate of racemic modafinil

Toluene hemisolvate was formed by making up 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) . The mixture was heated on a hot plate with vortexing until all solids were dissolved. The solution was then left to crystallize in a sealed vial. The resulting powder was collected in a centrifugal filter and analyzed by PXRD (Bruker), as shown in FIG. 68 . The hemisolvate was also analyzed and characterized using Raman spectroscopy (Figure 69), TGA (Figure 70) and DSC (Figure 71). Toluene solvates can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 68, including but not limited to 5.30, 5.96, 10.65, 12.90, 14.51, 17.60 and 18.15 degrees 2Θ. Toluene solvates can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 69 (middle spectrum), including but not limited to 1640 , 1581, 1408, 1380, 1209, 1024, 1001 and 722 cm ^-1 .

Example 38

Pharmacokinetics of modafinil isomers

A dog pharmacokinetic study (N=6) of single intravenous doses of R-(-)-modafinil was performed. The purity of R-(-)-modafinil in the administered formulation was about 80%. This formulation was compared in a crossover design to a racemic modafinil formulation also administered to the same dogs by the intravenous route. Results are reported in Table VII. In Table VII, "Cmax" is the maximum plasma concentration, "AUC(inf)" is the extrapolated area under the curve, "t _1/2 " is the time from the start of dosing when the plasma level drops to half the Cmax level, " _Vd " is the volume of distribution, and "CL" is the clearance of modafinil.

Table VII - PK parameters of racemic modafinil and R-(-)-modafinil from in vivo tests

These results indicated that there was no significant difference between the pharmacokinetics of R-(-)-modafinil and racemic modafinil after intravenous administration.

These results are in contrast to the pharmacokinetics of the isomer administered by the oral route (see US Patent 4,927,855, which is incorporated herein by reference in its entirety). In the study, four dogs were given a 30 mg/kg oral dose of R-(-)-modafinil (40-982), S-(+)-modafinil (40-983) or Racemic Modafinil (40-476). AUC values were calculated from plasma concentrations of the forms (40-476) and sulfone metabolites measured 2 to 9 hours after dosing. Table VIII presents the pharmacokinetic data.

Table VIII - PK parameters of racemic modafinil, R-(-)-modafinil and S-(+)-modafinil from in vivo tests Compound administered (30mg/kg) Average AUC (racemate) (mg/L×hr) Average AUC(sulfone)(mg/L×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 suggest that there are significant differences in the metabolism of the two isomers of modafinil, resulting in differential formation of the inactive sulfone metabolite, which, when administered as R-(-)-modafinil Generates higher API exposure. The different profiles observed between the intravenous and oral routes can be explained by the formation of sulfone metabolites mainly catalyzed by cytochrome CYP3A4 present at intestinal and hepatic levels and the effect of CYP3A4 on S-(+)-modafinil The fact that the affinity for is higher than for R-(-)-modafinil (stereoselective metabolism). This results in faster metabolite formation of S-(+)-modafinil, which shortens API exposure.

Example 39

R-(-)-Modafinil Ethanol Solvate

A solution in ethanol (3 mL) was prepared containing R-(-)-modafinil (100 mg, 0.366 mmol, 85.4% R-isomer) and racemic modafinil (40 mg, 0.146 mmol). The mixture was heated to reflux to dissolve all solids, then cooled to room temperature (25°C). After 15 minutes at room temperature, 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 (Figures 72 and 73). The solid was determined to be the ethanol solvate of R-(-)-modafinil.

R-(-)-modafinil ethanol solvate can be characterized by any one, any two, any three, any four, any five or any six or more peaks in Figure 72, which Including but not limited to 6.13, 9.59, 15.69, 17.97, 20.05, 21.55, 22.35, 25.77 and 29.07 degrees 2Θ (Rigaku PXRD, data collected as is).

The TGA of R-(-)-modafinil ethanol solvate characterized in Figure 73 showed a weight loss of 5.4% at 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 ground powder was then analyzed by PXRD, DSC and TGA (Figures 74, 75 and 76). The powder was determined to be a benzyl alcohol solvate of R-(-)-modafinil.

R-(-)-modafinil benzyl alcohol solvate can be characterized by any one, any two, any three, any four, any five or any six or more peaks in Figure 74, These 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 degrees 2Θ (Bruker PXRD, data collected as is).

The DSC of R-(-)-modafinil benzyl alcohol solvate characterized in Figure 75 showed an endothermic transition at 83°C.

The TGA of R-(-)-modafinil benzyl alcohol solvate characterized in Figure 76 showed a weight loss of 28.5% at about 25°C and about 125°C.

Example 41

R-(-)-Modafinil Isopropanol Solvate

R-(-)-modafinil was slurried overnight in isopropanol. The fluid was filtered off in a centrifugal filter and then dried at 5°C under nitrogen flow. The resulting solid was analyzed by PXRD.

R-(-)-modafinil isopropanol solvate can be characterized by any one, any two, any three, any four, any five or any six or more peaks in Figure 77 , which include but are not limited to 5.76, 7.77, 10.49, 15.79, 18.58, 21.53, 25.76, and 27.74 degrees 2Θ (Bruker PXRD, data collected as is).

Example 42

R-(-)-Modafinil Acetonitrile Solvate

100 mg of R-(-)-modafinil was slurried in acetonitrile for 2 days. The solid was filtered from the suspension and analyzed by PXRD.

R-(-)-modafinil acetonitrile solvate can be characterized by any one, any two, any three, any four, any five or any six or more peaks in Figure 78, which Including but not limited to 5.29, 6.17, 8.16, 10.19, 11.19 and 21.86 degrees 2Θ (Bruker PXRD, data collected as is).

Example 43

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

R-(-)-modafinil (20 to 30 mg, over 98% R-isomer) and glutaric acid (15-20 mg) were triturated together in the presence of a drop of benzyl alcohol.

The resulting solid was characterized by PXRD (see Figure 79) and likely included co-crystals. R-(-)-modafinil: glutaric acid cocrystals can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 79 , which include but are not limited to 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 degrees 2Θ (Bruker PXRD, data collected as is).

Wet milling with acetone and with water was also performed, both resulting in the formation of co-crystals.

Example 44

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

R-(-)-modafinil (20 to 30 mg, over 98% R-isomer) and citric acid monohydrate (15-20 mg) were triturated together in the presence of a drop of benzyl alcohol.

The resulting solid was characterized by PXRD (see Figure 80) and likely included co-crystals. R-(-)-modafinil:citric acid cocrystals can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 80, These include, but are not limited to, 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 degrees 2Θ (Bruker PXRD, data collected as is).

Wet milling with acetone was also performed, which resulted in the formation of co-crystals.

Example 45

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

R-(-)-modafinil (20 to 30 mg, over 98% R-isomer) and L-tartaric acid (15-20 mg) were triturated together in the presence of a drop of benzyl alcohol.

The resulting solid was characterized by PXRD (see Figure 81) and likely included co-crystals. R-(-)-modafinil:L-tartaric acid cocrystals can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 81 , which include but are not limited to 4.56, 10.33, 14.45, 17.29, 19.91, 21.13, 23.10, 24.10, and 26.76 degrees 2Θ (Bruker PXRD, data collected as is).

Wet milling with acetone and with water was also performed, both resulting in the formation of co-crystals.

Example 46

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

R-(-)-modafinil (20 to 30 mg, over 98% R-isomer) and oxalic acid (15-20 mg) were triturated together in the presence of a drop of benzyl alcohol.

The resulting solid was characterized by PXRD (see Figures 82A and 82B) and may include one or more co-crystals. R-(-)-modafinil: oxalic acid (Form I) co-crystals can pass any one, any two, any three, any four, any five, or any six or more of Figure 82A Peak characterization including but not limited to 5.99, 14.73, 16.59, 17.38, 18.64, 25.66 and 28.85 degrees 2Θ (Bruker PXRD, data collected as is). R-(-)-modafinil: oxalic acid (Form II) co-crystals can pass any one, any two, any three, any four, any five, or any six or more of Figure 82B Peak characterization including but not limited to 5.66, 14.76, 17.20, 17.63, 19.60, 24.90 and 28.84 degrees 2Θ (Bruker PXRD, data collected as is).

Wet milling with acetone and with water was also performed, both resulting in the formation of co-crystals.

Example 47

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

R-(-)-modafinil (20 to 30 mg, over 98% R-isomer) and palmitic acid (15-20 mg) were triturated together in the presence of a drop of benzyl alcohol.

The resulting solid was characterized by PXRD (see Figure 83) and likely included co-crystals. R-(-)-modafinil:palmitic acid cocrystals can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 83, These include, but are not limited to, 20 at 3.80, 6.55, 7.66, 10.24, 11.49, 19.48, 21.09, 21.74, 22.20, 22.97, and 23.99 degrees (Bruker PXRD, collected data as is).

Example 48

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

R-(-)-modafinil (20 to 30 mg, over 98% R-isomer) and L-proline (15-20 mg) were triturated together in the presence of a drop of benzyl alcohol.

The resulting solid was characterized by PXRD (see Figure 84) and likely included co-crystals. R-(-)-modafinil:L-proline co-crystals can be obtained by any one, any two, any three, any four, any five or any six or more of Figure 84 Peak characterization including but not limited to 6.52, 8.53, 10.25, 14.69, 19.06, 19.71, 20.75, 22.29, 22.75, 25.08 and 26.27 degrees 2Θ (Bruker PXRD, data collected as is).

Wet milling with acetone and with methanol was also performed, both resulting in the formation of co-crystals.

Example 49

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

R-(-)-modafinil (20 to 30 mg, over 98% R-isomer) and salicylic acid (15-20 mg) were triturated together in the presence of a drop of benzyl alcohol.

The resulting solid was characterized by PXRD (see Figure 85) and likely included co-crystals. R-(-)-modafinil:salicylic acid cocrystals can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 85 , which include but are not limited to 8.92, 10.85, 12.18, 14.04, 17.07, 17.59, 18.81, 21.24, 23.32, 25.22, and 28.59 degrees 2Θ (Bruker PXRD, data collected as is).

Example 50

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

R-(-)-modafinil (20 to 30 mg, over 98% R-isomer) and lauric acid (15-20 mg) were triturated together in the presence of a drop of benzyl alcohol.

The resulting solid was characterized by PXRD (see Figure 86) and likely included co-crystals. R-(-)-modafinil:lauric acid cocrystals can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 86, These include, but are not limited to, 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 degrees 2Θ (Bruker PXRD, data collected as is).

Wet milling with acetone and with methanol was also performed, both resulting in the formation of co-crystals.

Example 51

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

R-(-)-modafinil (20 to 30 mg, over 98% R-isomer) and L-malic acid (15-20 mg) were triturated together in the presence of a drop of acetone.

The resulting solid was characterized by PXRD (see Figure 87) and likely included co-crystals. R-(-)-modafinil:L-malic acid co-crystals can pass any one, any two, any three, any four, any five, or any six or more peaks in Figure 87 Characterization, which includes, but is not limited to, 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 degrees 2Θ (Bruker PXRD, data collected as is).

Example 52

Preparation of Diphenylmethylthioacetic Acid from Diphenylmethanol

To a solution of diphenylmethanol (100 g, 0.542 mol) in trifluoroacetic acid (300 mL) was added thioglycolic acid (50 g, 0.542 mol) dropwise at room temperature (about 22°C) over 20 minutes. The progress of the reaction was monitored by thin layer chromatography (TLC). The reaction was complete within one hour, at which point water (1000 mL) was slowly added to the reaction mixture to precipitate the product. The resulting precipitate was filtered, washed with water and dried under high vacuum overnight to afford 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 method)

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, followed by the addition of 5N NaOH (200 mL). The reaction mixture was then heated to reflux (101-102°C) for 30 minutes and then cooled to 60°C. A solution of chloroacetic acid (53.4 g, 0.565 mol) and NaOH (22.2 g) in water (150 mL) was slowly added to the reaction mixture over 45 minutes. The reaction mixture was stirred for an additional 30 minutes. The reaction was then cooled to room temperature and washed with tert-butyl methyl ether (200ml) to remove any non-carboxylic acid impurities. The aqueous layer was acidified (pH 2.0) with concentrated HCl (50 mL). The resulting precipitate was filtered, washed with water (2 x 200 mL) and heptane (200 mL), and air dried to give benzhydrylthioacetic acid (116.8 g, 100%) as a colorless solid. See US Patent 4,066,686)

Example 54

Preparation of benzhydrylthioacetic acid from diphenylmethanol using trifluoroacetic acid in dichloromethane

To a solution of diphenylmethanol (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) dropwise over 20 minutes. ). The reaction was complete within 1 hour. The solvent was removed in vacuo to give a crude solid which was dried under high vacuum overnight. The solid was treated with 2N NaOH (1.0 L) and washed with tert-butyl methyl ether (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

Preparation of benzhydrylsulfinylacetic acid from benzhydrylthioacetic acid

To a suspension of benzhydrylthioacetic acid (63.7 g, 0.246 mol) in methanol (250 mL) was added concentrated _H2SO4 ( _1.6 mL) in isopropanol (65 mL) at room temperature (ca. 22 °C) solution. To the suspension was added dropwise 30% _H2O2 in water (65 mL) over ₂₅ minutes. The reaction was monitored by TLC and was complete within 2 hours. The solution was diluted with a solution of NaHSO ₃ (125 mg) in water (700 mL). The resulting precipitate was filtered, washed with water, then methanol:water (1:1) and dried to give benzhydrylsulfinylacetic acid (47.6 g). ¹ H-NMR indicated the desired product was obtained, along with 10% of 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. (See Prisinzano, T. et al., Tetrahedron Asymm., 2004, 15, 1053-1058)

Example 56

Oxidation of benzhydrylthioacetic acid

To a 50 L three necked round bottom flask equipped with a mechanical stirrer, 2 L dropping funnel, nitrogen inlet and internal temperature probe was added benzhydrylthioacetic acid (3.5 kg, 13.54 mol), methanol (14 L) and _H A solution of _SO4 (72g) in isopropanol (6.5L). To this mixture was added dropwise 30% _{aqueous H2O2} (3.75 L) over 80 min, keeping the temperature below 30 °C. The reaction mixture was stirred for a further 7 hours, causing the formation of a crystalline solid. The reaction was monitored by 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. The peroxide was quenched with NaHSO ₃ solution.

Example 57

Resolution of Diphenylmethylsulfinylacetic Acid Using S-(-)-α-Methylbenzylamine

To a solution of (±)-benzhydrylsulfinylacetic acid (62.4 g, 0.227 mol) in water (300 mL) at 80 °C was added S-(-)-α-methylbenzylamine (30 mL, 0.236 mol) and It was stirred at reflux (101-102° C.) for 10 minutes. The solution was gradually cooled to 40°C and the resulting precipitate was filtered, washed with water and dried to give a colorless solid (71.4 g). The salt was recrystallized in water (500ml) to give another colorless solid (53.5g). 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 by HPLC was >99.9% ee. (See US Patent 4,927,855)

Example 58

Amidation of R-(-)-benzhydrylsulfinylacetic acid using N,N-carbonyldiimidazole affords R-(-)- Modafinil

To a 50 L three necked round bottom flask equipped with a mechanical stirrer, nitrogen inlet and internal temperature probe was charged R-(-)-diphenylmethylsulfinylacetic acid (1.32 kg, 4.81 mol) and tetrahydrofuran (7.0 L) . To the slurry was added N,N-carbonyldiimidazole (1.215 kg, 7.49 mol) in tetrahydrofuran (7 L) to give a colorless solution. The solution was then stirred for 30 minutes and NH ₃ gas (191 g, 2.5 eq.) was bubbled through the reaction mixture for 3.5 hours. The volatiles were then removed in vacuo to give a crude solid which was triturated with 20% methanol in tert-butyl methyl ether (7.0 L) overnight. The solid material was then collected and further purified by refluxing the solid in a 1:1 mixture of ethanol and tert-butyl methyl ether (3 L). The reaction was then cooled to room temperature and the solid material was filtered and dried to afford R-(-)-modafinil (501 g, 99.6% chemical purity and 100% ee) as a colorless solid.

Example 59

Preparation of racemic modafinil by activation with N,N-carbonyldiimidazole (CDI)

To a suspension of (±)-benzhydrylsulfinylacetic acid (10.0 g, 0.036 mol) in tetrahydrofuran (100 mL) was added N,N-carbonyldiimidazole (7.1 g, 0.043 mol), resulting in a colorless solution . The solution was stirred for 10 min while _CO2 evolved while a precipitate formed. _NH gas was bubbled through the reaction mixture for 10 min to raise the reaction temperature 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, brine and dried over _Na2SO4 . The organic layer was then concentrated in vacuo to give crude modafinil (11.5 g). Recrystallization from 60% methanol in water gave pure modafinil (6.0 g) as a colorless solid.

Example 60

Synthesis of (±)-Modafinil from Diphenylmethanol

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

To a solution of NH ₄ Cl (0.29 mol, 2.0 eq) and NH ₄ OH (300 ml) in methanol (200 mL) was added a solution of benzhydrylthioacetic acid (38.2 g, 0.145 mol) in methanol (50 ml), keeping the temperature low at 20°C. The reaction was stirred for 1 hour and diluted with water (100), causing a precipitate to form. The precipitate was collected, washed with water and dried to give benzhydrylthioacetamide (31 g) as a colorless solid.

Oxidation of benzhydrylthioacetamide with _H2O2 gave racemic modafinil according to the same procedure used in the oxidation of _{benzhydrylthioacetic} acid to prepare R-(-)-modafinil.

Claims (51)

1. A co-crystal composition comprising: modafinil and a co-crystal former, wherein the co-crystal former is selected from the group consisting of malonic acid, glycolic acid, fumaric acid, tartaric acid, citric acid, succinic acid, 2,5- Dihydroxybenzoic 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 horse tonic acid, and wherein modafinil and the co-crystal former are hydrogen bonded to each other. 2. The co-crystallized composition of claim 1, (a) wherein the co-crystal composition is a pharmaceutical co-crystal composition; or (b) further comprising a pharmaceutically acceptable diluent, excipient or carrier. 3. The co-crystallized composition of claim 1, wherein: (a) The co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2Θ angles, wherein: the co-crystal is a modafinil:malonic acid co-crystal and the X-ray diffraction pattern is included at 5.08, 9.28 , peaks at 16.81, 18.27, 19.45 and 22.83 degrees; (b) the co-crystal is characterized by a DSC thermogram, wherein the co-crystal is a modafinil: malonate co-crystal and the DSC thermogram comprises an endothermic transition at 116°C; and (c) The co-crystal is characterized by a Raman spectrum comprising peaks expressed in ^cm , wherein: the co-crystal is a modafinil:malonic acid co-crystal and the Raman spectrum is comprised at 1601, 1183, 1032 , 1004, 767, 718, 633 and 265 peaks. 4. The co-crystal composition of claim 1, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein: The co-crystal was a modafinil: glycolic acid co-crystal and the X-ray diffraction pattern included peaks at 9.51, 14.91, 15.97, 19.01, 20.03, 22.75, 25.03, and 25.71 degrees. 5. The co-crystallized composition of claim 1, wherein: (a) The co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2θ angles, wherein the co-crystal is a modafinil:maleic acid co-crystal and the X-ray diffraction pattern is comprised at 4.69, 6.15, Peaks at 9.61, 10.23, 19.97, and 21.83 degrees; and (b) The co-crystal is characterized by a DSC thermogram, wherein the co-crystal is a modafinil:maleic acid co-crystal and the DSC thermogram includes an endothermic transition at 168°C. 6. The co-crystal composition of claim 1 , wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2θ angles, wherein the co-crystal is a modafinil:L-tartaric acid co-crystal and the X The ray diffraction pattern included peaks at 6.10, 7.36, 14.33, 16.93, 20.15, 20.71, 22.49, 25.04, and 29.72 degrees. 7. The co-crystal composition of claim 1, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein the co-crystal is a modafinil:citric acid co-crystal and the X-ray The diffractogram included peaks at 5.29, 7.29, 9.31, 12.41, 13.29, 14.61, 17.29, 17.97 and 21.37 degrees. 8. The co-crystallized composition of claim 1, wherein: (a) The co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2θ angles, wherein the co-crystal is a modafinil:succinic acid co-crystal and the X-ray diffraction pattern is comprised at 5.45, 9.93, 17.99 , 19.95, 21.95 and 25.07 degree peaks; and (b) The co-crystal is characterized by a DSC thermogram, wherein the co-crystal is a modafinil:succinic acid co-crystal and the DSC thermogram includes an endothermic transition at 149°C. 9. The co-crystal composition of claim 1 , wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2θ angles, wherein the co-crystal is a modafinil:DL-tartaric acid co-crystal and the X The ray diffraction pattern included peaks at 4.75, 9.53, 10.07, 15.83, 17.61, 20.25, 21.53 and 22.55 degrees. 10. The co-crystal composition of claim 1 , wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2θ angles, wherein the co-crystal is a modafinil:fumaric acid co-crystal and the X The ray diffraction pattern included peaks at 5.45, 9.95, 15.93, 18.03, 18.81, 19.93, 21.95 and 23.09 degrees. 11. The co-crystal composition of claim 1 , wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2θ angles, wherein the co-crystal is a modafinil:fumaric acid co-crystal and the X The ray diffraction pattern included peaks at 6.47, 8.57, 9.99, 13.89, 14.53, 16.45, 18.39, 20.05 and 20.79 degrees. 12. The co-crystal composition of claim 1, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein the co-crystal is modafinil:2,5-dihydroxybenzoic acid co- crystallized and the X-ray diffraction pattern included peaks at 6.96, 12.92, 14.76, 17.40, 18.26, 20.10 and 20.94 degrees. 13. The co-crystal composition of claim 1 , wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2θ angles, wherein said co-crystal is a modafinil:oxalic acid co-crystal and said X-ray diffraction The graph includes peaks at 5.98, 13.68, 14.80, 17.54, 19.68, 21.12 and 21.86 degrees. 14. The co-crystal composition of claim 1, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co- crystallized and the X-ray diffraction pattern included peaks at 5.72, 7.10, 11.48, 14.16, 15.66 and 20.26 degrees. 15. The co-crystallized composition of claim 1, wherein: (a) The co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2Θ angles, wherein the co-crystal is a modafinil:malonic acid co-crystal and the X-ray diffraction pattern is comprised at 5.04, 9.26, peaks at 16.73, 18.23, 19.37, and 22.74 degrees; and (b) The co-crystal is characterized by a DSC thermogram, wherein the co-crystal is a modafinil: malonate co-crystal and the DSC thermogram includes an endothermic transition at 115°C. 16. The co-crystallized composition of claim 15, wherein modafinil is R-(-)-modafinil. 17. The co-crystallized composition of claim 1, wherein: (a) The co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2θ angles, wherein the co-crystal is a modafinil:succinic acid co-crystal and the X-ray diffraction pattern is comprised at 5.36, 9.83, 15.80 , 17.88, 19.87 and 21.85 degree peaks; and (b) The co-crystal is characterized by a DSC thermogram, wherein the co-crystal is a modafinil:succinic acid co-crystal and the DSC thermogram includes an endothermic transition at 145°C. 18. The co-crystallized composition of claim 17, wherein modafinil is R-(-)-modafinil. 19. The co-crystallized composition of claim 1, wherein: (a) The co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2θ angles, wherein the co-crystal is a modafinil:citric acid co-crystal and the X-ray diffraction pattern is included at 5.18, 7.23, 9.23 , 12.32, 13.23, 17.25, 17.92 and 21.30 degree peaks; and (b) The co-crystal is characterized by a DSC thermogram, wherein the co-crystal is a modafinil:citric acid co-crystal and the DSC thermogram includes an endothermic transition at 89°C. 20. The co-crystallized composition of claim 19, wherein modafinil R-(-)-modafinil. 21. The co-crystal composition of claim 1, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co- crystallized and the X-ray diffraction pattern included peaks at 5.27, 8.85, 10.60, 14.47, 21.20 and 23.03 degrees. 22. The co-crystallized composition of claim 21, wherein modafinil R-(-)-modafinil. 23. The co-crystal composition of claim 1 , wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2θ angles, wherein the co-crystal is a modafinil:DL-tartaric acid co-crystal and the X The ray diffraction pattern included peaks at 4.67, 15.41, 17.97, 19.46, 22.91 and 24.63 degrees. 24. The co-crystallized composition of claim 23, wherein modafinil R-(-)-modafinil. 25. The co-crystal composition of claim 1, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein said co-crystal is a modafinil:orotic acid co-crystal and said X The ray diffraction pattern included peaks at 9.77, 17.85, 20.52, 24.03 and 26.80 degrees. 26. The co-crystallized composition of claim 25, wherein modafinil R-(-)-modafinil. 27. The co-crystallized composition of claim 1, wherein modafinil R-(-)-modafinil. 28. The co-crystallized composition of claim 1, wherein modafinil is S-(+)-modafinil. 29. A process for the preparation of a pharmaceutical co-crystal composition comprising modafinil and a co-crystal former of claim 1, comprising: (a) providing modafinil and a compound selected from the group consisting of malonic acid, glycolic acid, fumaric acid, tartaric acid, citric acid, succinic acid, 2,5-dihydroxybenzoic acid, oxalic acid, 1-hydroxy-2-naphthoic acid, Co-crystal formers of orotic acid, glutaric acid, L-tartaric acid, palmitic acid, L-proline, salicylic acid, lauric acid, L-malic acid and maleic acid; (b) grinding, heating, co-subliming, co-melting, or contacting modafinil and the co-crystal former under crystallization conditions such that a solid phase forms in which modafinil and the co-crystal former hydrogen bond to each other combine; (c) isolating the co-crystals so formed; and (d) Incorporating the co-crystal into a pharmaceutical composition. 30. The method of claim 29, further comprising: admixing a pharmaceutically acceptable diluent, excipient or carrier. 31. A process for preparing a co-crystal comprising modafinil and a co-crystal former selected from the group consisting of malonic acid, benzamide, mandelic acid, glycolic acid, fumaric acid and maleic acid, comprising: (a) providing modafinil and said co-crystal former; (b) grinding, heating, co-subliming, co-melting or contacting modafinil with the co-crystal former under crystallization conditions such that a solid phase is formed; and (c) Isolating the co-crystals thus formed. 32. A method of modulating the solubility of modafinil for use in a pharmaceutical composition, the method comprising: (a) Modafinil is mixed with malonic acid, glycolic acid, fumaric acid, tartaric acid, citric acid, succinic acid, 2,5-dihydroxybenzoic acid, oxalic acid, 1-hydroxy-2-naphthoic acid, Co-crystal-forming compounds of orotic acid, glutaric acid, L-tartaric acid, palmitic acid, L-proline, salicylic acid, lauric acid, L-malic acid, and maleic acid were ground under crystallization conditions, heated, and co-crystallized. sublimating, co-melting, or contacting in solution such that a co-crystal of modafinil and the co-crystal-forming compound is formed, wherein the modafinil and the co-crystal-forming compound are hydrogen-bonded to each other; (b) isolating the co-crystal, wherein the co-crystal has an adjusted solubility compared to modafinil; and (c) Incorporating the co-crystal with adjusted solubility into a pharmaceutical composition. 33. A method of adjusting the dose response of modafinil for use in a pharmaceutical composition, the method comprising: (a) Modafinil is mixed with malonic acid, glycolic acid, fumaric acid, tartaric acid, citric acid, succinic acid, 2,5-dihydroxybenzoic acid, oxalic acid, 1-hydroxy-2-naphthoic acid, Co-crystal-forming compounds of orotic acid, glutaric acid, L-tartaric acid, palmitic acid, L-proline, salicylic acid, lauric acid, L-malic acid, and maleic acid were ground under crystallization conditions, heated, and co-crystallized. sublimating, co-melting, or contacting in solution such that a co-crystal of modafinil and the co-crystal-forming compound is formed, wherein the modafinil and the co-crystal-forming compound are hydrogen-bonded to each other; (b) isolating the co-crystal, wherein the co-crystal has a modulated dose response compared to modafinil; and (c) Incorporating the co-crystal with modulated dose response into a pharmaceutical composition. 34. A method of modulating the dissolution of modafinil for use in a pharmaceutical composition, the method comprising: (a) Modafinil is mixed with malonic acid, glycolic acid, fumaric acid, tartaric acid, citric acid, succinic acid, 2,5-dihydroxybenzoic acid, oxalic acid, 1-hydroxy-2-naphthoic acid, Co-crystal-forming compounds of orotic acid, glutaric acid, L-tartaric acid, palmitic acid, L-proline, salicylic acid, lauric acid, L-malic acid, and maleic acid were ground under crystallization conditions, heated, and co-crystallized. sublimating, co-melting, or contacting in solution such that a co-crystal of modafinil and the co-crystal-forming compound is formed, wherein the modafinil and the co-crystal-forming compound are hydrogen-bonded to each other; (b) isolating the co-crystal, wherein the co-crystal has modulated dissolution compared to modafinil; and (c) Incorporating the co-crystal with modulated dissolution into a pharmaceutical composition. 35. A method of modulating the bioavailability of modafinil for use in a pharmaceutical composition, the method comprising: (a) Modafinil is mixed with malonic acid, glycolic acid, fumaric acid, tartaric acid, citric acid, succinic acid, 2,5-dihydroxybenzoic acid, oxalic acid, 1-hydroxy-2-naphthoic acid, Co-crystal-forming compounds of orotic acid, glutaric acid, L-tartaric acid, palmitic acid, L-proline, salicylic acid, lauric acid, L-malic acid, and maleic acid were ground under crystallization conditions, heated, and co-crystallized. sublimating, co-melting, or contacting in solution such that a co-crystal of modafinil and the co-crystal-forming compound is formed, wherein the modafinil and the co-crystal-forming compound are hydrogen-bonded to each other; (b) isolating the co-crystal, wherein the co-crystal has modulated bioavailability compared to modafinil; and (c) Incorporating the co-crystal with modulated bioavailability into a pharmaceutical composition. 36. A method of increasing the stability of modafinil for use in a pharmaceutical composition, the method comprising: (a) Modafinil is mixed with malonic acid, glycolic acid, fumaric acid, tartaric acid, citric acid, succinic acid, 2,5-dihydroxybenzoic acid, oxalic acid, 1-hydroxy-2-naphthoic acid, Co-crystal-forming compounds of orotic acid, glutaric acid, L-tartaric acid, palmitic acid, L-proline, salicylic acid, lauric acid, L-malic acid, and maleic acid were ground under crystallization conditions, heated, and co-crystallized. sublimating, co-melting, or contacting in solution such that a co-crystal of modafinil and the co-crystal-forming compound is formed, wherein the modafinil and the co-crystal-forming compound are hydrogen-bonded to each other; (b) isolating the co-crystal, wherein the co-crystal has increased stability compared to modafinil; and (c) Incorporating the co-crystal with increased stability into a pharmaceutical composition. 37. A method of modulating the morphology of modafinil for use in a pharmaceutical composition, the method comprising: (a) Modafinil is mixed with malonic acid, glycolic acid, fumaric acid, tartaric acid, citric acid, succinic acid, 2,5-dihydroxybenzoic acid, oxalic acid, 1-hydroxy-2-naphthoic acid, Co-crystal-forming compounds of orotic acid, glutaric acid, L-tartaric acid, palmitic acid, L-proline, salicylic acid, lauric acid, L-malic acid, and maleic acid were ground under crystallization conditions, heated, and co-crystallized. sublimating, co-melting, or contacting in solution such that a co-crystal of modafinil and the co-crystal-forming compound is formed, wherein the modafinil and the co-crystal-forming compound are hydrogen-bonded to each other; (b) isolating the co-crystal, wherein the co-crystal has a different morphology compared to modafinil; and (c) admixing the co-crystals with modulated morphology into a pharmaceutical composition. 38. The co-crystallized composition of claim 1, wherein said composition is a pharmaceutical composition. 39. The pharmaceutical composition of claim 38, further comprising a pharmaceutically acceptable diluent, excipient or carrier. 40. The co-crystal composition of claim 38 in the preparation for the treatment of patients with narcolepsy, fatigue associated with multiple sclerosis, infertility, eating disorders, attention deficit hyperactivity disorder, Parkinson's disease, incontinence, sleep apnea Use of the drug in subjects with excessive daytime sleepiness associated with or myopathy. 41. The use of claim 40, wherein the subject is a human subject. 42. The co-crystal composition of claim 1, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein the co-crystal is modafinil:2,5-dihydroxybenzoic acid co- crystallized and the X-ray diffraction pattern included peaks at 7.07, 7.51, 9.07, 12.31, 14.09, 16.03, 17.63, 18.39, 21.27, 23.57 and 26.93 degrees. 43. The co-crystal composition of claim 1, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein the co-crystal is a modafinil: glutaric acid co-crystal and the X The ray diffraction pattern included peaks at 8.67, 9.78, 18.92, 19.74, 20.50, 21.36, 22.25, 23.87 and 27.16 degrees. 44. The co-crystal composition of claim 1, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein said co-crystal is a modafinil:citric acid co-crystal and said X-ray The diffractogram included peaks at 5.23, 7.06, 9.10, 12.43, 13.18, 17.95, 20.85, 21.39 and 22.96 degrees. 45. The co-crystal composition of claim 1 , wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2θ angles, wherein the co-crystal is a modafinil:L-tartaric acid co-crystal and the X The ray diffraction pattern included peaks at 4.56, 10.33, 14.45, 17.29, 19.91 and 21.13 degrees. 46. The co-crystal composition of claim 1, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein said co-crystal is a modafinil:oxalic acid co-crystal and said X-ray diffraction The graph includes peaks at 5.99, 14.73, 17.38, 18.64, 25.66 and 28.85 degrees. 47. The co-crystal composition of claim 1, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein the co-crystal is a modafinil:palmitic acid co-crystal and the X-ray The diffractogram included peaks at 3.80, 6.55, 7.66, 10.24, 19.48, 21.09 and 23.99 degrees. 48. The co-crystal composition of claim 1 , wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein the co-crystal is a modafinil:L-proline co-crystal and the co-crystal is The X-ray diffraction pattern includes peaks at 6.52, 8.53, 10.25, 19.06, 22.29, 22.75 and 25.08 degrees. 49. The co-crystal composition of claim 1, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein said co-crystal is a modafinil:salicylic acid co-crystal and said X The ray diffraction pattern included peaks at 8.92, 10.85, 12.18, 14.04, 17.07, 18.81, 21.24, 23.32 and 25.22 degrees. 50. The co-crystal composition of claim 1, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein said co-crystal is a modafinil:lauric acid co-crystal and said X-ray The diffractogram included peaks at 3.12, 6.55, 10.24, 13.97, 16.40, 17.62, 19.02, 21.38 and 23.81 degrees. 51. The co-crystal composition of claim 1, wherein the co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks expressed in 2-theta angles, wherein said co-crystal is a modafinil:L-malic acid co-crystal and said The X-ray diffraction pattern included peaks at 4.62, 9.32, 10.32, 15.83, 17.38, 19.30, 21.48 and 24.26 degrees.

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