KR20060123613A - Modafinil compositions - Google Patents

Abstract

Polymorphs and solvates of racemic, enantiomerically pure, and enantiomerically mixed modafinil are formed and discussed. In addition, said forms are described as useful for the treatment of many conditions including, but not limited to, narcolepsy.

Description

Modafinil Compositions

The present invention relates to modafinil-containing compositions, pharmaceutical compositions comprising modafinil, and methods of making the same.

Active Pharmaceutical Ingredients (APIs or APIs) in pharmaceutical compositions can be prepared in a variety of different forms. Such APIs can be prepared to have a variety of different chemical forms, including chemical derivatives, solvates, hydrates, co-crystals or salts, and the like. In addition, such APIs may be manufactured to have various physical forms. For example, the API may be amorphous, may have various crystalline polymorphs, or may exist in various solvated or hydrated states. By varying the form of the API, it is possible to change its physical properties. For example, crystalline polymorphs typically have different solubilities, and thermodynamically more stable polymorphs are less soluble than thermodynamically less stable polymorphs. Pharmaceutical polymorphs may differ in characteristics such as shelf life, bioavailability, morphology, vapor pressure, density, color and compressibility. Thus, varying the crystalline state of an API is one of a number of ways to adjust its physical properties.

It would be advantageous for these APIs to have new forms, in particular with improved properties as oral formulations. Specifically, it is desirable to identify improved forms of API that exhibit significantly improved properties, including increased water solubility and increased stability. In addition, it is desirable to improve the processability or manufacture of pharmaceutical formulations. For example, acicular crystal form or appearance of an API can cause aggregation even in a composition in which the API is mixed with other materials, resulting in an inhomogeneous mixture. The needle-like morphology may also cause filtration problems (see Mirmehrabi et al. J. Pharm. Sci. Vol. 93, No. 7, pp. 1692-1700, 2004). It is also desirable to increase the rate of dissolution in water of API-containing pharmaceutical compositions, to increase the bioavailability of orally administered compositions, and to initiate a therapeutic effect more quickly. In addition, when administered to a subject, an API in the form of reaching the peak plasma level more rapidly, sustaining the therapeutic plasma concentration for longer periods of time, and more overall exposure, as compared to the equivalent amounts of API in the form currently known is desirable. Do.

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

Modafinil is a chiral molecule due to the chiral S═O group. Thus, modafinil exists as two isomers, R-(-)-modafinil and S-(+)-modafinil. In particular, new forms of modafinil with improved properties as oral preparations would be advantageous. Specifically, it is desirable to identify improved forms of modafinil that have a significant increase in water solubility and a significant increase in both chemical and morphological stability. It is also desirable to increase the rate of dissolution in water of API-containing pharmaceutical compositions, to increase the bioavailability of orally administered compositions, and to initiate therapeutic effects more quickly. In addition, when administered to a subject, it is possible to reach peak plasma levels more quickly and / or to sustain plasma concentrations for longer periods of time as compared to equivalent amounts of API in the form currently known and to increase overall exposure at higher doses. A form of API is preferred.

Summary of the Invention

It has now been found that polymorphs and solvates of modafinil can be obtained. Some of these may have different properties compared to APIs in free form.

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

In another embodiment, the present invention provides the modafinil solvate of: chloroform, chlorobenzene, ethyl acetate and acetic acid.

Each method according to the present invention may comprise additional step (s) of incorporating the modafinil polymorph or solvate produced thereby into the pharmaceutical composition.

In a further embodiment, the present invention provides novel polymorphs of R-(-)-modafinil. In a specific embodiment, the present invention provides Form III, Form IV and Form V of R-(-)-modafinil. The invention also provides a process for the preparation of polymorphs of R-(-)-modafinil.

In a further embodiment, the present invention

(a) providing R-(-)-modafinil, and

(b) crystallizing the polymorph of R-(-)-modafinil from a suitable solvent

It provides a method for producing a polymorph of R-(-)-modafinil comprising a.

In further embodiments, the polymorph of R-(-)-modafinil is crystallized from an organic solvent. In a particular embodiment, the organic solvent is acetonitrile, dimethyl formamide (DMF), methanol, methyl ethyl ketone, N-methyl pyrrolidone, ethanol, isopropanol, isobutanol, formamide, isobutyl acetate, 1,4- Dioxane, tetrahydrofuran (THF), ethyl acetate, o-xylene, isopropyl acetate, dichloromethane, propylene glycol, acetic acid, water, acetone, nitromethane, toluene and benzyl alcohol. Both pure and mixed solvents are considered organic solvents according to the invention. In a particular embodiment, the organic solvent is ethanol. In another embodiment, a mixed solvent system is used for the crystallization of polymorphs of R-(-)-modafinil. The mixed solvent system may be, for example, ethanol and isopropyl alcohol, or may be ethyl acetate and ethanol. In a further embodiment, the crystallization in step (b) is completed via thermal crystallization. In a further embodiment, the crystallization in step (b) is completed via solvent evaporation.

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

The present invention further provides a medicament comprising a polymorph or solvate of modafinil and a process for preparing the same. Typically, the medicament further comprises one or more pharmaceutically acceptable carriers, diluents or excipients. The medicament according to the invention is described in more detail below.

Each method according to the invention may comprise additional step (s) of incorporating the modafinil polymorph or solvate produced thereby into the medicament.

In a further aspect of the invention, paroxysmal sleep-related excessive daytime sleepiness, multiple sclerosis-related fatigue, infertility, eating disorders, attention deficit hyperactivity disorder (ADHD), Parkinson's disease, Provided are methods of treating a subject suffering from incontinence, sleep apnea or myopathy, preferably a human subject. The method comprises administering to the subject a therapeutically effective amount of modafinil polymorph or modafinil solvate.

In another embodiment, a therapeutically effective amount of R-(-)-modafinil form III, R- in a subject suffering from one or more of the conditions or disorders mentioned above, including but not limited to sleep disorders such as paroxysmal sleep, and the like. A method of treating said subject, comprising administering (-)-modafinil Form IV or R-(-)-modafinil Form V.

PXRD diffractograms of the 2: 1 R-(-)-modafinil: S-(+)-modafinil polymorph.

Figure 2-DSC thermogram of the 2: 1 R-(-)-modafinil: S-(+)-modafinil polymorph.

3-PXRD diffractogram of the R-(-)-modafinil polymorph (form III).

4-DSC thermogram of R-(-)-modafinil polymorph (form III).

5-PXRD diffractogram of the R-(-)-modafinil polymorph (form III).

6-PXRD diffractogram of the R-(-)-modafinil polymorph (form IV).

FIG. 7-DSC thermogram of R-(-)-modafinil polymorph (Form IV).

8-PXRD diffractogram of the R-(-)-modafinil polymorph (form IV).

9-PXRD diffractogram of the R-(-)-modafinil polymorph (form V).

10-PXRD diffractogram of the R-(-)-modafinil polymorph (form V).

PXRD diffractogram of 2: 1 R-(-)-modafinil: S-(+)-modafinil.

12-2 DSC thermogram of R-(-)-modafinil: S-(+)-modafinil.

FIG. 13-PXRD diffractogram of R-(-)-modafinil Form IV.

FIG. 14-PXRD diffractogram of R-(-)-modafinil Form V.

FIG. 15-DSC thermogram of R-(-)-modafinil Form V.

FIG. 16-PXRD diffractogram of R-(-)-modafinil chloroform solvate.

Figure 17-TGA thermogram of R-(-)-modafinil chloroform solvate.

Figure 18-PXRD diffractogram of R-(-)-modafinil chlorobenzene solvate.

19-PXRD diffractogram of racemate modafinil ethyl acetate channel solvate.

20-TGA thermogram of racemate modafinil ethyl acetate channel solvate.

Figure 21-PXRD diffractogram of R-(-)-modafinil acetic acid solvate.

Figure 22-TGA thermogram of R-(-)-modafinil acetic acid solvate.

FIG. 23-DSC thermogram of R-(-)-modafinil acetic acid solvate.

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

As used herein and unless otherwise defined, the term “enantiomerically pure” includes compositions that are substantially enantiomerically pure, examples of which are about 90, 91, 92, 93, 94, 95, 96. Compositions containing at least 97, 98 or 99% enantiomeric excess. Enantiomeric excess is defined as Enantiomer A (%)-Enantiomer B (%), or the formula ee (%) = 100 × ([R]-[S] / ([R] + [S]) [where , R is a mole of R-(-)-modafinil and S is a mole of S-(+)-modafinil.

As used herein, the term “modafinil” includes racemates, other mixtures of R-isomers with S-isomers, single enantiomers, and the like, but specifically racemates, R-isomers, S-isomers, Or as any mixture of both R- and S-isomers.

As used herein and unless otherwise defined, the term “racemate” refers to a material (eg polymorph or solvate) consisting of modafinil enantiomers of equimolar mixtures, solvents of equimolar mixtures, or both. Refer. For example, solvates comprising modafinil and non-stereomeric solvent molecules are "racemate solvates" only when modafinil enantiomers are present in equimolar mixtures. Similarly, solvates comprising modafinil and stereoisomeric solvent molecules are "racemate solvates" only if modafinil enantiomers are present in an equimolar mixture and solvent molecular enantiomers are also present in an equimolar mixture.

As used herein and unless otherwise defined, the term “enantiomerically pure” refers to a material consisting of modafinil and optionally a stereoisomer solvent molecule or a non-stereoisomer solvent molecule, wherein Enantiomeric excess is at least about 90% ee (enantiomeric excess).

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

Modafinil and some solvent molecules of the invention may exist in various stereoisomeric configurations because they have one or more chiral centers. Due to these chiral centers, modafinil and some solvates of the present invention exist not only as racemates, mixtures of enantiomers and individual enantiomers, but also as mixtures of diastereomers and diastereomers. All such racemates, enantiomers and diastereomers, including, for example, cis- and trans-isomers, R-enantiomers and S-enantiomers, and (D) -isomers and (L) -isomers, etc. Falls within the scope of. Solvates of the invention may include isomeric forms of modafinil or solvent molecules, or both. Isomer forms of modafinil and solvent molecules include, but are not limited to, stereoisomers such as enantiomers and diastereomers. In one embodiment, the solvate may comprise racemate modafinil and solvent molecules. In another embodiment, the solvate may comprise enantiomerically pure R-modafinil or S-modafinil and solvent molecules. In another embodiment, solvates of the present invention have enantiomeric excess of about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99% Modafinil and / or solvent molecules that are greater than or all intermediate values there between. In another embodiment, the polymorph or solvate of the present invention has an enantiomeric excess of about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% , Modafinil, which is greater than 99%, or all intermediate values therebetween.

"Enhanced" modafinil according to the present invention is capable of reducing both the R-(-)-and S-(+)-isomers of modafinil from at least about 5, 6, 7, 8, 9 or 10% by weight to about 90 , 91, 92, 93, 94 or 95% by weight or less. For example, a composition comprising 67% by weight of R-(-)-modafinil and 33% by weight of S-(+)-modafinil is a reinforced modafinil composition. In this example, the composition is neither racemate nor enantiomerically pure. The term "reinforced R-(-)-modafinil" describes modafinil compositions containing more than 50% R-(-)-modafinil and less than 50% S-(+)-modafinil. Can be used. Likewise, the term "reinforced S-(+)-modafinil" refers to modafinil compositions containing more than 50% S-(+)-modafinil and less than 50% R-(-)-modafinil. It can be used to describe.

The terms "R-(-)-modafinil" and "S-(+)-modafinil" are used to describe enhanced modafinil, enantiomerically pure modafinil, or substantially enantiomerically pure modafinil. Specifically, it may also exclude enhanced modafinil, enantiomerically pure modafinil and / or substantially enantiomerically pure modafinil.

Solvates and polymorphs comprising enantiomerically pure and / or enantiomerically enriched components (eg modafinil or solvent molecules) are chemically modified from those of the corresponding forms comprising racemic components. And / or physical properties.

Polymorphs and solvates of modafinil can be prepared according to the invention with racemate modafinil, enantiomerically pure modafinil, or any mixture of R-(-)-modafinil and S-(+)-modafinil For example fortified modafinil).

In another embodiment, a composition or medicament comprising solvates and polymorphs of the present invention is compared to free form modafinil, such as present in PROVIGIL® (Cephalon, Inc.). (See patent number RE37,516, issued again in the United States).

In another embodiment, the present invention provides the modafinil solvate of: chloroform, chlorobenzene, ethyl acetate and acetic acid.

Pharmaceutically acceptable forms can be administered by controlled or delayed release means. Controlled release pharmaceutical products have a common goal of improving drug therapy over that achieved by non-controlled release counterparts. Ideally, the use of a controlled release formulation that is optimally designed for medical treatment is characterized by minimizing the drug substance used to cure or control the condition in the shortest time. Advantages of controlled release formulations include 1) prolonging drug activity, 2) decreasing frequency of administration, 3) increasing patient compliance with treatment, 4) decreasing total drug use, 5) reducing local or systemic side effects, 6) Minimization, 7) decreased blood levels, 8) improved therapeutic efficacy, 9) increased or decreased drug activity, 10) improved control of disease or condition [Kim, Cherng-ju, Controlled Release Dosage Form Design, 2 Technomic Publishing, Lancaster, Pa .: 2000].

In general, conventional dosage forms provide rapid or immediate drug release from the agent. Depending on the pharmacology and pharmacodynamics of the drug, use of conventional dosage forms can cause wide variation in drug concentration in the patient's blood and other tissues. Such variations can affect a number of parameters such as frequency of administration, 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 drug initiation, duration of action, drug plasma levels and peak blood levels at appropriate concentrations. In particular, using controlled or extended release dosage forms or formulations, potentials may arise from both during the administration of a particular drug (ie, progressing below the minimum therapeutic level), as well as when the level of toxicity for this drug is exceeded. The maximum effect of the drug can be achieved while minimizing adverse effects and safety concerns.

Most controlled release formulations release an initial amount of a drug (active ingredient) that quickly produces the desired therapeutic effect, and gradually and sustain a different amount of drug to maintain this therapeutic or prophylactic level over a longer period of time. It is designed to release. In order to maintain a constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug that is metabolized and released from the body. Controlled release of the active ingredient may be stimulated by a variety of conditions including, but not limited to, pH, ionic strength, osmotic pressure, temperature, enzymes, water, and other physiological conditions or compounds, and the like.

A variety of known controlled or extended release dosage forms, formulations, and devices can be adapted to be suitable for use in the solvates, polymorphs, and compositions of the present invention. Examples thereof include U.S. Patents 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, 5,120,548, 5,073,543, 5,639,476, 5,354,556, 5,733,566, and 6,365,185 B1, each of which is incorporated herein by reference. Using these dosage forms, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems [eg OROS® (Alza Corporation, Mountain View, CA, USA) Material)], multi-layer coatings, particulates, liposomes or microspheres, or combinations thereof, may be used to sustain or release the one or more active ingredients to provide the desired release profile in various ratios. In addition, the preparation of immobilized and adsorbed polymorphs using ion exchange materials enables controlled delivery of the drug. Specific examples of anion exchangers include, but are not limited to, Duolite® A568 and Duolide® AP143 (Rohm & Haas, Spring House, Pa.).

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

One particular well known osmotic drug delivery system is what is referred to as Oros® (Alza Corporation, Mountain View, CA, USA). This technique can be readily adapted to deliver the compounds and compositions of the present invention. Various aspects of the technology are described in U.S. Patents 6,375,978 Bl, 6,368,626 B1, 6,342,249 B1, 6,333,050 B2, 6,287,295 B1, 6,283,953 B1, 6,270,787 B1, 6,245,357 B1 and 6,132,420, each of which is incorporated herein by reference. Specific adaptations of Oros® that can be used to administer the compounds and compositions of the present invention include Oros® Push-Pull ™, Delayed Push-Pull ™, Multilayer Push-Pull ™ and Push-Sticks. (Push-Stick) ™ systems, all of which are well known, and the like. See, for example, http://www.alza.com. Additional Oros® systems that can be used for controlled oral delivery of the compounds and compositions of the present invention include Oros®-CT and L-Oros® (see above and also Delivery Times, vol. II, issue II] (Alza Corporation).

Conventional Oros® oral dosage forms are prepared by compressing a drug powder into a hard tablet, coating the tablet with a cellulose derivative to form a semi-permeable membrane, and then drilling an orifice (e.g. using a laser) within the coating ( See Kim, Cherng-ju, Controlled Release Dosage Form Design, 231-238 (Technomic Publishing, Lancaster, Pa .: 2000). The advantage of this dosage form is that the rate of drug delivery is not affected by physiological or experimental conditions. Even drugs that exhibit pH-dependent solubility can be delivered at a constant rate regardless of the pH of the delivery medium. However, because these benefits are also provided by increased osmotic pressure in the dosage form after administration, conventional Oros® drug delivery systems do not effectively deliver drugs with low water solubility (see page 234 above). ).

Specific dosage forms of the invention include a wall defining a cavity, the wall having a discharge orifice formed or formable therein and at least a portion of the wall being semi-permeable; An expandable layer located in a cavity remote from the exit orifice and capable of fluid communication with the semi-permeable portion of the wall; A dry or substantially dry drug layer in a cavity adjacent to the exit orifice and in direct or indirect contact with the expandable layer; And a fluidity-enhancing layer interposed between the inner surface of the wall and at least the outer surface of the drug layer located within the cavity, wherein the drug layer is a polymorph or solvate, hydrate, dehydrate, anhydrous or amorphous thereof. Include form. See US Pat. No. 6,368,626, which is incorporated by reference in its entirety.

Another specific dosage form of the invention includes a wall defining a cavity, the wall having a discharge orifice formed or formable therein and at least a portion of the wall being semi-permeable; An expandable layer located in a cavity remote from the exit orifice and capable of fluid communication with the semi-permeable portion of the wall; And a drug layer located in a cavity adjacent to the exit orifice and in direct or indirect contact with the expandable layer, wherein the drug layer comprises a liquid activator formulation absorbed within the porous particles, the porous particles being It is adapted to withstand sufficient densification force to form a densified drug layer without significantly exuding the active agent formulation, the dosage form optionally having a placebo layer between the discharge orifice and the drug layer, wherein the active agent formulation is a polymorph, or Solvates, hydrates, dehydrates, anhydrous or amorphous forms thereof. See US Pat. No. 6,342,249, the entirety of which is incorporated herein by reference.

In another embodiment, the pharmaceutical composition or medicament comprises a mixture of modafinil (eg polymorph or solvate) and racemate modafinil in a novel form of the invention. Such embodiments can be used, for example, as controlled, sustained or extended release dosage forms. In another embodiment, the extended release dosage form comprises racemic modafinil and the polymorphs or solvates of the present invention.

In another embodiment, the pharmaceutical composition or medicament comprises a modified release profile of one or more of racemic modafinil, R-(-)-modafinil and S-(+)-modafinil. Such modified release profiles may include, for example, two or more maximum plasma concentrations, eg, dual-release profiles. Such a modified release profile assists in treating a patient with a composition or a medicament of the present invention, for example in the afternoon, who will lose their alertness. 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 may be employed that comprises a predetermined amount of dropwise dosage that is released immediately after administration and subsequently exhibits an approximately zero order release profile over 2, 3, 4, 5, or 6 hours. . In such compositions, peak plasma levels can be reached at approximately noon.

In another embodiment, a pharmaceutical composition or medicament comprising a modified release profile of modafinil may comprise R-(-)-modafinil and S-(+)-modafinil, wherein R-(- ) -Modafinil gives an initial increase in plasma concentration (initial C _max due to R-(-)-modafinil, and S-(+)-modafinil gives a delayed increase in plasma concentration (S- Subsequent C _max ) due to (+)-modafinil. The delayed increase in C _max due to S-(+)-modafinil is 2, 3, 4, 5, 6 hours or more after reaching the initial C _max due to R-(-)-modafinil This may be after. In another embodiment, delayed C _max is approximately equivalent to initial C _max . In another embodiment, delayed C _max is greater than the initial C _max . In another embodiment, delayed C _max is smaller than the initial C _max . In another embodiment, the delay C _max is due to racemate modafinil, not S-(+)-modafinil. In another embodiment, the delay C _max is due to R-(-)-modafinil rather than S-(+)-modafinil. In another embodiment, the initial C _max is due to racemic modafinil, not R-(-)-modafinil. In another embodiment, the initial C _max is due to S-(+)-modafinil rather than R-(-)-modafinil. In another embodiment, the modified release profile has three, four, five, or more "collective releases" in plasma concentration.

In another embodiment, the pharmaceutical composition or medicament comprises at least one of racemic modafinil, R-(-)-modafinil or S-(+)-modafinil in its solvate or polymorphic form. And modified release profiles of modafinil.

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

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

Excipients used in the pharmaceutical compositions and medicaments of the present invention may be solids, semi-solids, liquids or combinations thereof. The excipient is preferably a solid. Compositions and medicaments of the present invention containing excipients may be prepared by techniques known in the art of pharmaceutics, including mixing excipients with APIs or therapeutic agents. The pharmaceutical compositions or medicaments of the present invention contain the desired amount of API per dosage unit, and are intended to be used for oral administration, for example tablets, caplets, pills, hard or soft capsules, lozenges, cachets , Dispersible powders, granules, suspensions, elixirs, dispersions, liquids, or any other form rationally adapted for such administration. If it is intended for parenteral administration, it may be in the form of a suspension or a transdermal patch, for example. If it is intended for rectal administration, it may be in the form of suppositories, for example. At present, preference is given to oral dosage forms, for example tablets or capsules, which are separate dosage units each containing a predetermined amount of API.

Examples of excipients that may be used to prepare the pharmaceutical compositions or medicaments of the invention include, but are not limited to:

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

Preferred diluents are lactose, mannitol, dibasic sodium phosphate and microcrystalline cellulose (especially Avicel PH microcrystalline cellulose, for example Avicel PH 101), or a combination thereof. These diluents are chemically compatible with the API. Extragranular microcrystalline cellulose (ie microcrystalline cellulose added to the granular composition) can be used to improve hardness (hardness to tablets) and / or disintegration time. Especially preferred are lactose, in particular lactose monohydrate. Typically, lactose provides a composition having a suitable release rate, stability, pre-press flowability, and / or drying properties in a relatively low cost diluent of the API. This aids densification during granulation (when wet granulation is used) and thus provides a high density substrate that improves blend flow and tablet properties.

Pharmaceutical compositions and medicaments of the invention optionally comprise one or more pharmaceutically acceptable disintegrants, in particular as excipients for tablet formulations. Suitable disintegrants include sodium starch glycolate (e.g. Explotab ™ from Pen West) and pregelatinized corn starch (e.g. from the National Starch and Chemical Company). National ™ 1551, National ™ 1550 and Colocorn ™ 1500), clay (e.g. Vegum ™ HV from RT Vanderbilt), cellulose, e.g. Purified cellulose, microcrystalline cellulose, methylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose, croscarmellose sodium (eg Ac-Di-Sol ™ from FMC), alginates, crospovidone, and rubbers, for example Agar, guar, locust bean, karaya, pectin and tragacanth gums and the like are included individually or in combination, but are not limited thereto.

Disintegrants can be added at any suitable stage during the preparation of the compositions of the present invention, in particular prior to granulation or during the lubrication stage prior to compression. If such disintegrants are present, they comprise a total of about 0.2% to about 30%, preferably about 0.2% to about 10%, more preferably about 0.2% to about 5%, based on the total weight of the composition. do.

Croscarmellose sodium is a preferred disintegrant for disintegrating tablets or capsules, and when present it is preferably from about 0.2% to about 10%, more preferably from about 0.2% to about based on the total weight of the composition 7%, even more preferably about 0.2% to about 5%. Croscarmellose sodium confers excellent intragranular disintegration ability to the granular pharmaceutical compositions and medicaments of the present invention.

Pharmaceutical compositions and medicaments of the invention optionally comprise one or more pharmaceutically acceptable binders or adhesives, in particular as excipients for tablet formulation. Such binders and adhesives are sufficient to allow conventional processing operations, such as sizing, lubrication, compaction and packaging, to the powder to be purified, but sufficient to allow the tablets to disintegrate and the composition to be absorbed upon ingestion. It is preferable to give cohesiveness. The binder may also prevent or inhibit crystallization or recrystallization of the API of the present invention once the salt is dissolved in solution. Suitable binders and adhesives include acacia; Tragacanth; Sucrose; gelatin; Glucose; Starches such as pre-gelled starch (eg, National ™ 1511 and National ™ 1500), and the like; Celluloses such as methylcellulose and carmellose sodium (eg Tylose ™) and the like; Alginic acid and salts of alginic acid; Magnesium aluminum silicate; PEG; Guar rubber; Polysaccharide acid; Bentonite; Povidones such as povidone K-15, K-30 and K-29 / 32; Polymethacrylates; HPMC; Hydroxypropylcellulose (eg Klucel ™ from Aqualon); And ethylcellulose (eg, Ethocel ™ from The Dow Chemical Company), or in combination thereof. If such binders and / or adhesives are present, they are based on the total weight of the pharmaceutical composition or medicament in total from about 0.5% to about 25%, preferably from about 0.75% to about 15%, more preferably about 1 to about 10%.

Since many binders are polymers comprising amide groups, ester groups, ether groups, alcohol groups or ketone groups, they are preferably included in the pharmaceutical compositions and medicaments of the present invention. Particular preference is given to polyvinylpyrrolidone, for example povidone K-30. Polymeric binders can vary in molecular weight, degree of crosslinking and polymer grade. The polymeric binder may be a copolymer, for example a block copolymer containing a mixture of ethylene oxide units and propylene oxide units. The variation in the ratio of these units in a given polymer affects properties and performance. Examples of block copolymers having block units of various compositions include Poloxamer 188 and Poloxamer 237 (BASF Corporation).

The pharmaceutical compositions and medicaments of the invention optionally comprise one or more pharmaceutically acceptable wetting agents as excipients. Such humectants are preferably selected such that the API is closely associated with water to maintain conditions that are believed to improve the bioavailability of the composition.

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, poly Oxyethylene alkylphenyl ethers such as nonoxynol 9, nonoxynol 10 and octoxynol 9, poloxamers (polyoxyethylene and polyoxypropylene block copolymers), polyoxyethylene fatty acid glycerides and oils such as Polyoxyethylene (8) caprylic / capric monoglycerides and diglycerides (eg Labrasol ™ from Gattefosse), polyoxyethylene (35) castor 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 esters such as polysorb Bait 20 and polysorbate 80 (eg Tween ™ 80 of ICI), propylene glycol fatty acid esters such as propylene glycol laurate (eg Lauroglycol ™ of Gatefoss), sodium Lauryl sulfate, fatty acids and salts thereof such as oleic acid, sodium oleate and triethanolamine oleate, glyceryl fatty acid esters such as glyceryl monostearate, sorbitan esters such as sorbitan monolaurate Sorbitan monooleate, sorbitan monopalmitate and sorbitan monostearate, tiloxapol and Although the mixtures of the present invention is not limited thereto. If such a humectant is present, it is based on the total weight of the pharmaceutical composition or medicament 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 Account for%.

The wetting agent is preferably an anionic surfactant. Sodium lauryl sulfate is a particularly preferred wetting agent. If sodium lauryl sulphate is present it is based on the total weight of the pharmaceutical composition or medicament in total from about 0.25% to about 7%, more preferably from about 0.4% to about 4%, even more preferably about From 0.5% to about 2%.

Pharmaceutical compositions and medicaments of the invention optionally comprise one or more pharmaceutically acceptable lubricants (including anti-sticking agents and / or glidants) as excipients. Suitable lubricants include glyceryl behaphate (eg Compritol ™ 888 from Gatefoss); Stearic acid and its salts (including magnesium, calcium and sodium stearate); Hydrogenated vegetable oils (eg, Sterotex ™ from Abitec); Colloidal silica; talc; Wax; Boric acid; Sodium benzoate; Sodium acetate; Sodium fumarate; Sodium chloride; DL-leucine; PEG (eg, Carbowax ™ 4000 and Carbowax ™ 6000 from The Dow Chemical Company); Sodium oleate; Sodium lauryl sulfate; And magnesium lauryl sulfate each or in combination thereof. If such lubricants are present, they are based on the total weight of the pharmaceutical composition or medicament 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 Account for%.

A preferred lubricant, for example, for use in reducing the friction between the equipment and the granular mixture during compaction of tablet formulations is magnesium stearate.

Suitable antiadhesives include, but are not limited to, talc, corn starch, DL-leucine, sodium lauryl sulfate and metallic stearate. Talc is a preferred antiadhesive or glidant for use, for example, to reduce formulation adhesion to the equipment surface and to reduce static charge in the blend. If talc is present, it is based on the total weight of the pharmaceutical composition or medicament, based on the total weight of about 0.1% to about 10%, more preferably about 0.25% to about 5%, even more preferably about 0.5% to Account for about 2%.

Glidants can be used to enhance powder flowability of the solid formulation. Suitable fluidizing agents 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 colorants, flavors and sweeteners are known in the pharmaceutical art and can be used in the pharmaceutical compositions and medicaments of the present invention. Tablets may or may not be coated, for example with enteric skin. The composition of the present invention may further comprise a buffer, for example.

Optionally, one or more blowing agents can be used as disintegrants and / or to enhance the organoleptic properties of the pharmaceutical compositions and medicaments of the present invention. If one or more blowing agents are present in the pharmaceutical compositions and medicaments of the present invention to enhance disintegration of the dosage form, this is preferably from about 30% to about a total of the total weight of the pharmaceutical compositions or medicaments of the present invention. 75%, preferably from about 45% to about 70%, for example about 60%.

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

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

Examples of suitable bases as components of the blowing agent useful in the present invention include, but are not limited to, carbonates (eg calcium carbonate), bicarbonates (eg sodium bicarbonate), sesquicarbonates and mixtures thereof. Calcium carbonate is the preferred base.

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

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

Typically, excipients that solubilize the metal salts of the API have both hydrophilic and hydrophobic regions, or preferably amphiphilic or amphiphilic regions. One type of amphipathic or partially amphiphilic excipient comprises an amphipathic polymer or is an amphipathic polymer. Specific amphiphilic polymers are polyalkylene glycols which generally consist of ethylene glycol and / or propylene glycol subunits. Such polyalkylene glycols can be esterified at their ends by carboxylic acids, esters, acid anhydrides or other suitable moieties. Examples of such excipients include poloxamers (symmetric block copolymers of ethylene glycol and propylene glycol, eg poloxamer 237), polyalkylene glycolated esters of tocopherols (including esters formed from di- or polyfunctional carboxylic acids, eg For example d-alpha-tocopherol polyethylene glycol-1000 succinate) and macrogol glycerides (gacolyzing the oil and esterifying polyalkylene glycols to produce a mixture of monoglycerides, diglycerides and triglycerides with monoesters and diesters Formed by, for example, stearoyl macrogol-32 glycerides). Such pharmaceutical compositions and medicaments are advantageously administered orally.

Pharmaceutical compositions and medicaments of the present invention may comprise about 10 to about 50 weight percent, about 25 to about 50 weight percent, about 30 to about 45 weight percent, or about 30 to 35 weight percent API; About 10 to about 50 weight percent, about 25 to about 50 weight percent, about 30 to about 45 weight percent, or about 30 to about 35 weight percent of an excipient that inhibits crystallization; And about 5 to about 50 weight percent, about 10 to about 40 weight percent, about 15 to about 35 weight percent, or about 30 to about 35 weight percent binder. In one example, the weight ratio of excipient: binder to inhibit API: crystallization is about 1: 1: 1.

Solid dosage forms of the present invention may be prepared by any suitable method that is not limited to the methods described herein.

For example, the process may comprise (a) blending a salt of the invention with one or more excipients to form a blend; And (b) tableting or encapsulating the blend to form tablets or capsules, respectively.

In a preferred method, (a) blending an API salt of the invention with one or more excipients to form a blend; (b) granulating the blend to form granules; And (c) tableting or encapsulating the blend to form tablets or capsules, respectively. Step (b) may be carried out by any dry or wet granulation technique known in the art, but is preferably carried out by a dry granulation step. Advantageously, the salts of the present invention are granulated to form particles of about 1 μm to about 100 μm, about 5 μm to about 50 μm, or about 10 μm to about 25 μm. For example, it is preferable to add at least one diluent, at least one disintegrant and at least one binder in the blending step; For example, wetting agents may optionally be added in the granulation step; It is preferred to add one or more disintegrants after granulation but prior to tableting or encapsulation. The lubricant is preferably added before tableting. The blending and granulation steps can be performed independently under low shear or under high shear. The API content is uniformly and easily disintegrated, flows easily enough so that the weight fluctuations can be controlled to a reliable level during capsule filling or tableting, and processes specific batches at selected doses and individual dosages for special capsules or tablet dies. It is desirable to select a method in which the granules are sufficiently dense in bulk so that they can be formed.

In another embodiment, the solid dosage form comprises one or more sprayable liquids, preferably non-protic (eg non-aqueous or non-alcoholic) sprayable liquids, with the API in combination with one or more excipients. Prepared by a process comprising a spray drying step of suspending in water followed by rapid spray drying under warm air.

Capsules may be prepared by compressing or molding the granules or spray dried powders resulting from any of the above exemplary methods to produce or encapsulate tablets. Conventional tableting and encapsulation techniques known in the art can be used. Conventional coating techniques are suitable when preparing coated tablets.

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

In another embodiment of the invention, a pharmaceutical composition or medicament may be prepared comprising modafinil and additional API. Modafinil and additional APIs can be included as a mixture or combination of active pharmaceutical ingredients. For example, the composition may comprise modafinil and caffeine in combination. Compositions comprising modafinil and caffeine can be used as therapeutic agents to treat the same conditions as in the case of modafinil. As such, in compositions comprising modafinil and caffeine, caffeine can yield a rapid release characteristic (lower T _max compared to modafinil) for solubility profiles, whereas modafinil has a therapeutic effect that lasts for several hours after administration Be sure to For example, the T _max of caffeine can be 0.001, 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, or 0.8 times that of modafinil. Combination therapy includes administration of two or more APIs in the same formulation or in two or more co-administered formulations. The API may be administered together at the same time, or may be administered separately at specified intervals.

In a further embodiment, the present invention provides novel polymorphs of R-(-)-modafinil. In a specific embodiment, the present invention provides Form III, Form IV and Form V of R-(-)-modafinil. The present invention also provides a method for producing a polymorph of R-(-)-modafinil.

In a further embodiment, the present invention

(a) providing R-(-)-modafinil, and

(b) crystallizing the polymorph of R-(-)-modafinil from a suitable solvent

It provides a method for producing a polymorph of R-(-)-modafinil comprising a.

In further embodiments, the polymorph of R-(-)-modafinil is crystallized from an organic solvent. In a particular embodiment, the organic solvent is ethanol. In another embodiment, a mixed solvent system is used for the crystallization of polymorphs of R-(-)-modafinil. The mixed solvent system may be, for example, ethanol and isopropyl alcohol, or may be ethyl acetate and ethanol. In a further embodiment, the crystallization in step (b) is completed through thermal recrystallization. In a further embodiment, the crystallization in step (b) is completed via solvent evaporation.

The use of modafinil is well known in the art and includes the treatment of paroxysmal sleep, multiple sclerosis-related fatigue, infertility, eating disorders, attention deficit hyperactivity disorder (ADHD), Parkinson's disease, incontinence, sleep apnea or myopathy . 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. Dosages and administrations for the modafinil compositions of the invention may be determined using routine methods in the art, but will generally fall within about 50 to about 700 mg per day.

In another embodiment, a therapeutically effective amount of R-(-)-modafinil form III, R- in a subject suffering from one or more of the conditions or disorders mentioned above, including but not limited to sleep disorders such as paroxysmal sleep, and the like. Provided is a method of treating said subject comprising administering (-)-modafinil Form IV or R-(-)-modafinil Form V.

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

Analytical Method

Differential Scanning Calorimetry (DSC) analysis of samples was performed on the Advanced (Version 1.0.0.78, Thermal Advantage Release 2.0 (2001 TA Instruments-Water LLC) for the QW-Series. ) Was performed using a Q1000 differential scanning calorimeter (TA Instruments, New Castle, Delaware, USA.) In addition, the analysis software used was Universal Analytics for Windows 95/98/2000 / NT. Universal Analysis 2000 (version 3.1E; Build 3.1.0.40 (2001 TA Instruments-Water LLC)).

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

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

Thermogravimetric analysis (TGA) of samples was carried out using the Q500 Thermogravimetric Analyzer (TA Instruments, Delaware, USA) using Advantages for the QW-Series [Version 1.0.0.78, Thermal Advantage Release 2.0 (2001 TA Instruments-Water LLC)] New Castle). The analytical software used was also Universal Analytics 2000 (version 3.1E; Build 3.1.0.40 (2001 TA Instruments-Water LLC) for Windows 95/98/2000 / NT).

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

TGA was performed on the sample by placing the modafinil sample in a platinum pan. The starting temperature was typically 20 ° C. and the termination temperature was 300 ° C. with a heating rate of 10 ° C. per minute.

D / Max Rapid, Contact (D /) using RINT Rapid Control software, control software, Rigaku Rapid / XRD, version 1.0.0 (1999 Rigaku Co.) Max Rapid, Contact) (Rigaku / MSC, The Woodlands, TX) was used to obtain a Powder X-Ray Diffraction (PXRD) pattern for the sample. 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, Materialal Data, Inc.). Data, Inc.).

Acquisition parameters for PXRD analysis were as follows: the source was Cu with K-ray at 1.5406 Hz, the xy stage was manual, the collimator size was 0.3 mm, the capillary (Charles Supper) Company), Natick, Mass., USA, had a 0.3 mm ID, used reflection mode, had a power of 46 kV for the X-ray tube, a 40 mA current for the X-ray tube, and an Omega axis of 1 The oscillation was in the range of 0-5 ° at a rate of 1 ° per minute, the pie-axis spun at a 360 ° angle at a rate of 2 ° per second, a 0.3 mm collimator was used, the collection time was 60 minutes, and the temperature was It was at room temperature and no heater was used. Samples were provided to an X-ray source in a boron rich glass capillary.

In addition, the analytical parameters were as follows: the integrated 2-theta range was 2 to 60 °, the integrated chi range was 0 to 360 °, the number of chi sections was 1, the step size used was 0.02, and the integrated utility was It was a cylint, standardization was used, the dark count was 8, the omega offset was 180, and the chi and pi offsets were zero.

PXRD diffractograms were also obtained via a Bruker AXS D8 Discover X-ray diffractometer. The instrument includes GADDS ™ (General Area Diffraction Detection System), Bruker AXS HI-STAR area detector with 15.05 cm spacing according to system calibration, copper source (Cu / K _α 1.54056 Å ), Automated xyz stage, and 0.5 mm collimator. The sample was densified to pellet form and placed on the xyz stage. The diffractogram was obtained under ambient conditions (25 ° C.) with the output setting at 40 kV and 40 mA in reflection mode while keeping the sample stationary. The exposure time for each sample was varied. The spatial diffraction process is performed to reveal the reason for the geometric pincushion deformation of the area detector on the obtained diffractogram, and then -118.8 ° at a step size of 0.02 ° using a normalization setpoint with bin regulation. At 2-theta from 2.1 to 37 ° with a chi of -61.8 °.

The relative intensity of the peak in the diffractogram does not necessarily limit the PXRD pattern because the peak intensity may vary from sample to sample, for example due to crystalline impurities. In addition, the angle of each peak may vary by about ± 0.1 °, preferably by ± 0.05 °. The entire pattern or most pattern peaks may shift by about ± 0.1 ° to about ± 0.2 ° due to calibration differences, setpoint differences, and per-device and per-operator variables. All PXRD peaks presented in the figures, examples, and any other portion herein are reported to have an error of about ± 0.1 ° 2-theta.

In the PXRD data herein, including the tables and figures, each composition of the invention comprises any one, two, three, four, five, six, seven of any two-theta angle peaks. , Eight or more. Any one, two, three, four, five or six DSC transitions may be used to characterize the compositions of the present invention. Various combinations of PXRD peaks and DSC transitions may be used to characterize the compositions of the present invention.

Thermal microscopy was completed on a Zeiss Axioplan 2 microscope equipped with a Mettler Toledo FP90 controller. The hot end used was METTLER TOLEDO FP82HT. Samples were placed on microscope slides and covered with coverslips to complete all melting point measurements. The initial temperature was set at 30 ° C. and this temperature was raised at a rate of 10 ° C. per minute. Melting was observed through a 5 × microscope objective.

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

Column: Astec Cyclobond I 2000 RSP 250 × 4.6 mm (Part No. 411121)

Mobile Phase A: 20 mM Sodium Phosphate, pH 3.0

        B: mobile phase A: acetonitrile at 70:30

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

Flow program: gradient

Travel time: 35 minutes

Detection: 225 nm UV

Injection volume: 10 μl

Column temperature: 30 ± 1 ℃

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

Needle Wash Solution: Acetonitrile

Purging solvent and seal wash: 90:10 (v / v) of water: acetonitrile

Mobile  Produce:

1. Preparation of 1 M monobasic sodium phosphate: 120 g of monobasic sodium phosphate was dissolved in water, brought to 1000 mL and filtered.

2. Preparation of Mobile Phase A (20 mM Sodium Phosphate, pH 3.0): Using water, dilute 20 mL of 1 M sodium phosphate per liter to 1000 mL and adjust the pH to 3.0 with phosphoric acid.

3. Preparation of Mobile Phase B (70:30 (v / v) 20 mM sodium phosphate, pH 3.0: acetonitrile): 700 mL of mobile phase A and 300 mL of acetonitrile were mixed per liter.

Sample manufacture:

1. Samples were dissolved in 90:10 (v / v) 20 mM sodium phosphate, pH 3.0: acetonitrile to a concentration of approximately 20 μg / mL.

Raman Acquisition:

Samples were left in glass vials and processed therein, or aliquots of samples were transferred to glass slides. The glass vial or slide was placed in the sample chamber. Almega ™ Dispersive Raman with 785 nm laser source (Almega ™ Dispersive Raman, Thermo-Nicolet, USA 53711-4495 Madison Verona Road, Wisconsin, USA 5225 Material) system. The microscope portion of the device equipped with a 10 × magnification objective lens (unless otherwise specified) was used to manually focus the sample so that the laser was directed toward the sample surface. Spectra were acquired using the parameters summarized in Table A below (exposure time and number of exposures may vary and changes to the parameters will be described for each acquisition):

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

IR  Obtain:

Acquire IR spectra using a Nexus ^TM 470 FT-IR (Thermo-Nicolet, Madison Verona Rd. 5225, 53711-4495, USA), and use the software for contrast and analysis [OMNIC, version 6.0a , (C) Thermo-Nicolet, 1995-2004].

Example  One

2: 1 R-(-)-modafinil: S-(+)-modafinil

Anhydrous ammonia gas was bubbled into a solution containing R-benzhydrylsulfinyl methyl ester (8.62 g, 0.0299 mol, about 80:20 (weight ratios) R-isomer: S-isomer in methanol (125 mL) for 10 minutes. The pressure in the reaction was increased to allow sodium bicarbonate to flow back from the trap into the reaction mixture, the reaction was stopped and the precipitate was collected The precipitate was concentrated under reduced pressure to give a yellow solid residue (2.8 g). Was passed through a column (silica gel, grade 9385, 230-400, mesh 60 cc, eluent: 3: 1 (v / v) ethyl acetate: hexanes), then the filtrates were combined and concentrated under reduced pressure to give a pale yellow solid. (Most of the yellow color remaining in the column) The mixture was then heated to boiling to recrystallize the solid from ethanol and then cooled to room temperature to give 2: 1 R-(-)-modafinil: S-(+) Modafinil (580 mg) ) Was obtained as a colorless solid, and PXRD and DSC analysis of the obtained solid showed that the solid was approximately 2: 1 weight ratio of pure R-(-)-modafinil and S-(+)-modafinil. It was determined to be in the form.

The 2: 1 R-(-)-modafinil: S-(+)-modafinil solids thus obtained were 8.97 °, 10.15 °, 12.87 °, 14.15 °, 15.13 °, 15.77 °, 18.19 ° and 20.39 ° 2 Can be characterized by any one, two, three, four, five, six or more of the peaks in FIG. 1 including but not limited to theta (data collected).

DSC of the solid described above showed an endothermic transition at about 167 ° C. (see FIG. 2).

Example  2

Of R-(-)-modafinil Polymorph

Several polymorphs of R-(-)-modafinil were observed and each of them was characterized by PXRD. 3, 6, and 9 show PXRD diffractograms (collected data) of Polymorph Form III, Form IV, and Form V. FIG.

Recrystallization has proven to be an effective technique for forming and obtaining polymorphs of R-(-)-modafinil. Suitable solvents for recrystallization of one or more polymorphs of R-(-)-modafinil include acetonitrile, dimethyl formamide (DMF), methanol, methyl ethyl ketone, N-methyl pyrrolidone, ethanol, isopropanol, iso Butanol, formamide, isobutyl acetate, 1,4-dioxane, tetrahydrofuran (THF), ethyl acetate, o-xylene, isopropyl acetate, dichloromethane, propylene glycol, acetic acid, water, acetone, nitromethane, toluene And benzyl alcohol and the like. Pure solvents and solvent mixtures can be used to crystallize one or more polymorphs of R-(-)-modafinil.

R-(-)-modafinil Form III

Anhydrous ammonia gas was bubbled into a solution containing R-benzhydrylsulfinyl methyl ester (8.3 g, 0.0288 mol) in methanol (75 mL) for 10 minutes. The reaction was then stirred in a 5 ° C. ice bath for 1 hour and bubbled ammonia gas for 10 minutes. Stirring continued for another 2 hours and bubbling ammonia gas for another 10 minutes. After a further hour of stirring a precipitate (575 mg) was formed and collected. Then, the filtrate was neutralized with concentrated HCl to form another precipitate which was collected. The mixture is then heated to boiling to recrystallize the solid residue from a 1: 1 (v / v) mixture of ethanol and isopropyl alcohol and then cooled to room temperature to give R-(-)-modafinil Form III (1.01 g ) Was obtained as a colorless solid.

R-(-)-modafinil Form III includes, but is not limited to, 7.21 °, 10.37 °, 17.73 °, 19.23 °, 21.17 °, 21.77 ° and 23.21 ° 2-theta (rigaga PXRD, data collected) Any one, two, three, four, five, six or more of the peaks in FIG. 3 may be characterized.

DSC of R-(-)-modafinil Form III characterized in FIG. 4 showed an endothermic transition at about 161 ° C.

A second batch of R-(-)-modafinil Form III was prepared and further analyzed via thermal microscopy and PXRD. In addition, solubility data was also obtained. These data are discussed below.

The solubility of R-(-)-modafinil Form III was about 6.1-7.0 mg / mL. The solubility was measured from an isopropyl acetate slurry stirred at 25 ° C. Solubility measurements were performed via HPLC. The solids of the solubility samples were dried under nitrogen and characterized by PXRD and thermal microscopy. No morphological changes were observed during this procedure.

The melting point of R-(-)-modafinil Form III was measured using a thermal (thermal end) microscope at 10 ° C./min heating rate, and measured to be about 156 to 158 ° C.

R-(-)-modafinil Form III is 7.19 °, 10.37 °, 12.11 °, 14.41 °, 17.73 °, 19.17 °, 21.71 °, 23.17 °, 24.39 °, 25.17 °, 26.07 ° and 27.91 ° 2-theta ( Ligaku PXRD, background removed data) can be characterized by any one, two, three, four, five, six or more of the peaks in FIG. have.

R-(-)-modafinil form IV

Anhydrous ammonia gas was bubbled into a solution containing R-benzhydrylsulfinyl methyl ester (8.3 g, 0.0288 mol) in methanol (75 mL) for 10 minutes. The reaction was then stirred in a 5 ° C. ice bath for 1 hour and bubbled ammonia gas for 10 minutes. Stirring was continued for another 1 hour. After a further hour of stirring a precipitate (422 mg) was formed which was collected. Then, the filtrate was neutralized with concentrated HCl to form another precipitate which was collected. Solid material (3 g) was passed through a column (silica gel, grade 9385, 230-400, mesh 60 cc, eluent: 3: 1 (v / v) ethyl acetate and hexane). The column was then washed with ethyl acetate (250 mL). The filtrates were combined and concentrated under reduced pressure to afford R-(-)-modafinil Form IV (590 mg) as a colorless solid.

R-(-)-modafinil Form IV includes, but is not limited to, 7.79 °, 10.31 °, 11.77 °, 16.49 °, 17.33 °, 19.47 ° and 23. 51 ° 2-theta (rigaga PXRD, data collected) Any one, two, three, four, five, six or more of the peaks in FIG.

DSC of R-(-)-modafinil Form IV characterized in FIG. 7 showed an endothermic transition at about 147 ° C.

A second batch of R-(-)-modafinil Form IV was prepared and further analyzed via thermal microscopy and PXRD. In addition, solubility data was also obtained. These data are discussed below.

The solubility of R-(-)-modafinil Form IV was about 3.5-4.0 mg / mL. The solubility was measured from an isopropyl acetate slurry stirred at 25 ° C. Solubility measurements were performed via HPLC. The solids of the solubility samples were dried under nitrogen and characterized by PXRD and thermal microscopy. No morphological changes were observed during this procedure.

The melting point of R-(-)-modafinil Form IV was measured using a thermal (thermal end) microscope at 10 ° C./min heating rate, and measured to be about 147 to 158 ° C.

R-(-)-modafinil Form IV is 7.77 °, 10.33 °, 11.75 °, 16.53 °, 19.43 °, 19.89 °, 21.87 °, 23.49 ° and 26.69 ° 2-Theta (Rigaku PXRD, background removed data) Any, one, two, three, four, five, six or more of the peaks in FIG. 8 including but not limited to.

R-(-)-modafinil Form V

R-(-)-modafinil Form IV (prepared in the above procedure) was heated in ethanol solution until the mixture boiled and then cooled to room temperature. The solid material was then collected and characterized as R-(-)-modafinil Form V.

R-(-)-modafinil form V is 6.61 °, 10.39 °, 13.99 °, 16.49 °, 17.73 °, 19.03 °, 20.87 °, 22.31 ° and 25.99 ° 2-theta (ligaga PXRD, data collected) Any one, two, three, four, five, six or more of the peaks in FIG. 9, including but not limited to these, may be characterized.

A second batch of R-(-)-modafinil Form V was prepared and further analyzed via thermal microscopy and PXRD. In addition, solubility data was also obtained. These data are discussed below.

The solubility of R-(-)-modafinil Form V was about 2.1 to 2.6 mg / mL. The solubility was measured from an isopropyl acetate slurry stirred at 25 ° C. Solubility measurements were performed via HPLC. The solids of the solubility samples were dried under nitrogen and characterized by PXRD and thermal microscopy. No morphological changes were observed during this procedure.

The melting point of R-(-)-modafinil Form V was measured using a thermal (thermal end) microscope at 10 ° C / min heating rate, which was determined to be about 159 ° C.

R-(-)-modafinil Form V is 6.53 °, 10.19 °, 13.90 °, 16.56 °, 17.35 °, 17.62 °, 18.99 °, 20.93 °, 22.08 °, 23.36 ° and 25.91 ° 2-Theta (Bruker PXRD , Collected data) can be characterized by any one, two, three, four, five, six or more of the peaks in FIG. 10.

The R-(-)-modafinil polymorph with the PXRD diffractogram for the corresponding racemate modafinil Form III, Form IV and Form V of US Patent Application No. 20020043207 (published April 18, 2002) Based on similarity, we named Form III, Form IV and Form V.

Example  3

2: 1 R-(-)-modafinil: S-(+)-modafinil

A solution containing R-(-)-modafinil (80.16 mg, 0.293 mmol) and racemate modafinil (20.04 mg, 0.0366 mmol) in ethanol (2 mL) was prepared. The mixture was heated to boiling to dissolve all solids and then cooled to room temperature (25 ° C.). The solution was kept at room temperature for 15 minutes and then left at 5 ° C. overnight. The solution was then decanted to dry the remaining crystals under a flow of nitrogen gas and characterized using HPLC, PXRD, DSC and thermal microscopy.

The obtained crystals contained about 63 to about 67% of R-(-) modafinil and the remaining crystals were S-(+)-modafinil. HPLC analysis shows that the crystal is a 2: 1 phase containing two R-(-)-modafinil molecules per S-(+)-modafinil molecule.

PXRD was completed for a single crystal sample of 2: 1 R-(-)-modafinil: S-(+)-modafinil. 2: 1 R-(-)-modafinil: S-(+)-modafinil is 8.95 °, 10.17 °, 11.87 °, 14.17 °, 15.11 °, 17.39 °, 18.31 °, 20.39 °, 21.09 °, 24.41 ° And any 1, 2, 3, 4, 5, 6 or any of the peaks in FIG. 11 including but not limited to 26.45 ° 2-Theta (Ligaku PXRD, collected data). The above can be characterized.

The 2: 1 R-(-)-modafinil: S-(+)-modafinil, characterized in FIG. 12, showed an endothermic transition at about 168 ° C.

Melting point of 2: 1 R-(-)-modafinil: S-(+)-modafinil using thermal (thermal end) microscopy at 5 ° C./min heating rate, measured at about 160-166 ° C. It became.

Example  4

R-(-)-modafinil Form IV

105.9 mg of R-(-)-modafinil were slurried in 1.5 mL of ethanol for 2 days. The liquid was filtered off and dried under flowing nitrogen gas. The resulting solid was analyzed via PXRD and determined to be R-(-)-modafinil Form IV (FIG. 13).

R-(-)-modafinil Form IV includes but is not limited to 7.64 °, 10.17 °, 11.61 °, 16.41 °, 19.34 °, 21.71 °, 22.77 °, and 23.36 ° 2-theta (Bruker PXRD, data collected) Any one, two, three, four, five, six or more of the peaks in FIG. 13, which are not limited, may be characterized.

In addition, R-(-)-modafinil Form IV was recovered by thermal recrystallization from ethanol and evaporation of the solvent from ethanol slowly.

Example  5

R-(-)-modafinil Form V

107.7 mg of R-(-)-modafinil were partitioned into 3 mL of ethyl acetate. The suspension was heated on a hot plate (60 ° C.) to dissolve the solids.

Approximately 1/3 to 1/2 of the heated solvent was removed by evaporation with flowing nitrogen gas. The mixture was then cooled to room temperature (25 ° C.). The solid was separated from the liquid using a centrifugal filter. The resulting solid was analyzed via PXRD and DSC and determined to be R-(-)-modafinil Form V (FIGS. 14 and 15).

R-(-)-modafinil Form V is 6.52 °, 10.23 °, 13.93 °, 16.37 °, 17.61 °, 18.97 °, 20.74 °, 22.21 °, 23.36 ° and 25.90 ° 2-Theta (Bruker PXRD, collected Data) can be characterized by any one, two, three, four, five, six or more of the peaks in FIG. 14 including, but not limited to.

DSC of R-(-)-modafinil Form V was completed. 15 shows an endothermic transition at about 161 to 162 (161.57) ° C.

Example  6

R-(-)-modafinil chloroform solvate

200 μl of chloroform was added to 30.5 mg of R-(-)-modafinil. The mixture was heated at 75 ° C. for 30 minutes before further 200 μl of chloroform was added. After 30 minutes more solid was completely dissolved. The sample was heated for 2 more hours. After heating, the sample was cooled to 5 ° C. at a rate of about 1 ° C./min. When reaching 5 ° C., the sample was still a homogeneous liquid solution. The sample was then left under nitrogen flow for 1 minute and crystals began to form. The sample was incubated again at 5 ° C., resulting in a greater amount of solids precipitated. The sample was then dried under nitrogen flow and characterized by PXRD and TGA.

PXRD for R-(-)-modafinil chloroform solvate was completed. R-(-) modafinil chloroform solvates are 8.97 °, 12.07 °, 14.20 °, 16.91 °, 17.49 °, 18.56 °, 20.87 °, 21.45 °, 23.11 ° and 25.24 ° 2-theta (Bruker PXRD, collected Data) can be characterized by any one, two, three, four, five, six or more of the peaks in FIG. 16, including but not limited to.

TGA of R-(-)-modafinil chloroform solvate was completed. 17 shows about 15% weight loss between about 25 ° C. and about 150 ° C. FIG.

Example  7

R-(-)-modafinil chlorobenzene solvate

R-(-)-modafinil (102.6 mg, 0.375 mmol) was suspended in chlorobenzene (5 mL) and heated on a 60 ° C. hotplate. The mixture was cooled to about 25 ° C. The slurry was then heated again and THF was added until the solids dissolved. The solution was then cooled while stored at room temperature for 4 days in a sealed vial. After storage the resulting solids were collected by vacuum filtration and characterized by PXRD.

PXRD for R-(-)-modafinil chlorobenzene solvate was completed. R-(-) modafinil chlorobenzene solvates are 4.51 °, 6.25 °, 7.77 °, 10.37 °, 11.43 °, 11.97 °, 16.61 °, 17.95 °, 20.19 °, 20.89 °, 23.41 ° and 30.43 ° 2-theta May be characterized by any one, two, three, four, five, six or more of the peaks in FIG. 18, including but not limited to Rigaku PXRD, data collected. have.

Example  8

Ethyl Acetate Channel Solvate Of Racemate Modafinil

Of racemate modafinil from a solution of racemate modafinil (53.7 mg, 0.196 mmol) and 1-hydroxy-2-naphthoic acid (75.5 mg, 0.401 mmol) in 2.4 mL of ethyl acetate, dissolved on a 60 ° C. hotplate. Ethyl acetate channel solvate was prepared. It was first cooled and the solution was seeded with milled co-crystals of R-(-)-modafinil: 1-hydroxy-2-naphthoic acid (see Example 17 of Application No. PCT / US2004 / 29013).

PXRD was completed for the ethyl acetate channel solvate of racemate modafinil. Ethyl acetate channel solvates of racemate modafinil include, but are not limited to, 8.88 °, 14.09 °, 19.83 °, 21.59 °, 23.04 ° and 25.94 ° 2-theta (Bruker PXRD, data collected) Any one, two, three, four, five, six or more of the peaks in E. may be characterized.

TGA of the ethyl acetate channel solvate of racemate modafinil was completed. 20 shows about 3.6% weight loss between about 25 ° C. and about 150 ° C. FIG.

Example  9

R-(-)-modafinil acetic acid solvate

R-(-)-modafinil acetic acid solvate was prepared by grinding R-(-)-modafinil (105.5 mg) in 0.066 mL of acetic acid in a stainless steel cylinder equipped with a Wig-L-Bug grinder / mixer for 10 minutes. Formed. The powder was then analyzed by DSC, TGA and PXRD.

PXRD for R-(-)-modafinil acetic acid solvate was completed. Solvates include any of the peaks in FIG. 21, including but not limited to 9.17 °, 10.20 °, 16.61 °, 17.59 °, 18.90 °, 21.11 ° and 24.11 ° 2-theta (Bruker PXRD, data collected) It can be characterized by one, two, three, four, five, six or more of the.

TGA of R-(-)-modafinil acetic acid solvate was completed. Figure 22 shows about 11% weight loss between about 25 ° C and about 125 ° C.

DSC of R-(-)-modafinil acetic acid solvate was completed. Figure 23 shows an endothermic transition at about 56 ° C.

Claims (26)

A composition comprising a 2: 1 R-(-)-modafinil: S-(+)-modafinil. The method of claim 1, (a) powder X-ray of (i) 2: 1 R-(-)-modafinil: S-(+)-modafinil and comprising 2-theta angle peaks at 8.97 °, 10.15 ° and 20.39 ° Characterized by a diffraction pattern, (ii) is characterized by a powder X-ray diffraction pattern of R-(-)-modafinil: S-(+)-modafinil of 2: 1 and comprising 2-theta angle peaks at 8.97 ° and 18.19 ° , (iii) is characterized by a powder X-ray diffraction pattern of R-(-)-modafinil: S-(+)-modafinil of 2: 1 and comprising 2-theta angle peaks at 10.15 ° and 20.39 ° , (iv) is characterized by a powder X-ray diffraction pattern of R-(-)-modafinil: S-(+)-modafinil of 2: 1 and comprising 2-theta angle peaks at 15.77 ° and 19.25 ° , or (v) characterized by a powder X-ray diffraction pattern of R-(-)-modafinil: S-(+)-modafinil of 2: 1 and comprising a 2-theta angular peak at 8.97 ° A composition; or (b) a 2: 1 R-(-)-modafinil: S-(+)-modafinil and differential scanning calorimetry (DSC) thermogram comprising an endothermic transition at about 167 ° C A composition, characterized in that. The composition of claim 1 which is a pharmaceutical composition. A composition comprising R-(-)-modafinil form III. The method of claim 4, wherein (a) is characterized by a powder X-ray diffraction pattern (i) modafinil polymorph and comprising 2-theta angular peaks at 7.21 °, 10.37 ° and 17.73 °, or (ii) is characterized by a powder X-ray diffraction pattern which is modafinil polymorph and comprises 2-theta angle peaks at 7.21 ° and 10.37 °, or (iii) is characterized by a powder X-ray diffraction pattern which is modafinil polymorph and comprises 2-theta angle peaks at 17.73 ° and 19.23 °, or (iv) characterized by a powder X-ray diffraction pattern which is modafinil polymorph and comprises 2-theta angle peaks at 10.37 ° and 21.77 °, or (v) a powder X-ray diffraction pattern characterized by a modafinil polymorph and comprising a 2-theta angular peak at 7.21 °. The composition is a polymorph; or (b) a modafinil polymorph and a DSC thermogram comprising an endothermic transition at about 161 ° C. The composition of claim 4 which is a pharmaceutical composition. A composition comprising R-(-)-modafinil Form V. The method of claim 7, wherein (a) is characterized by a powder X-ray diffraction pattern which is modafinil polymorph and comprises 2-theta angle peaks at 6.61 °, 10.39 °, and 16.49 °, or (b) is characterized by a powder X-ray diffraction pattern which is modafinil polymorph and comprises 2-theta angle peaks at 6.61 ° and 10.39 °, or (c) is characterized by a powder X-ray diffraction pattern which is a modafinil polymorph and comprises 2-theta angle peaks at 13.99 ° and 17.73 °, or (d) is characterized by a powder X-ray diffraction pattern which is modafinil polymorph and comprises 2-theta angle peaks at 20.87 ° and 22.31 °, or (e) a powder X-ray diffraction pattern characterized by a modafinil polymorph and comprising a 2-theta angular peak at 6.61 °. A composition that is polymorphic. 8. The composition of claim 7, which is a pharmaceutical composition. A composition comprising R-(-)-modafinil Form IV. The method of claim 10, (a) (i) is characterized by a powder X-ray diffraction pattern which is a modafinil polymorph and comprises 2-theta angle peaks at 7.79 °, 10.31 °, and 11.77 °, or (ii) is characterized by a powder X-ray diffraction pattern which is modafinil polymorph and comprises 2-theta angle peaks at 7.79 ° and 10.31 °, or (iii) characterized by a powder X-ray diffraction pattern which is modafinil polymorph and comprises 2-theta angle peaks at 16.49 ° and 17.33 °, or (iv) characterized by a powder X-ray diffraction pattern that is modafinil polymorph and includes 2-theta angle peaks at 19.47 ° and 23.51 °, or (v) a powder X-ray diffraction pattern characterized by a modafinil polymorph and comprising a 2-theta angular peak at 7.79 °. The composition is a polymorph; or (b) a modafinil polymorph and a DSC thermogram comprising an endothermic transition at about 147 ° C. The composition of claim 10 which is a pharmaceutical composition. (a) providing R-(-)-modafinil, and (b) crystallizing the polymorph of R-(-)-modafinil from a suitable solvent A method for producing a polymorph of R-(-)-modafinil comprising a. (a) providing R-(-)-modafinil and the S-isomeric form of modafinil, and (b) crystallizing 2: 1 R-(-)-modafinil: S-(+)-modafinil from the solvent or solvent mixture A method of producing a 2: 1 R-(-)-modafinil: S-(+)-modafinil comprising: (a) providing R-(-)-modafinil, and (b) crystallizing R-(-)-modafinil Form III from solvent or solvent mixture Comprising R-(-)-modafinil Form III. (a) providing R-(-)-modafinil, and (b) crystallizing R-(-)-modafinil Form IV from solvent or solvent mixture Comprising R-(-)-modafinil Form IV. (a) providing R-(-)-modafinil, and (b) crystallizing R-(-)-modafinil form V from a solvent or solvent mixture A method of making R-(-)-modafinil Form V, comprising: The composition of claim 2 further comprising a diluent, excipient or carrier. The composition of claim 18 which is a pharmaceutical composition. Therapeutically effective amounts of R- ( -) Administering Form III, Form IV, or Form V of modafinil. The method of claim 20, wherein the subject is a human subject. The method of claim 20, wherein R-(-)-modafinil Form III is administered. Solvate of R-(-)-modafinil, wherein the solvent molecule is selected from the group consisting of chloroform, chlorobenzene and acetic acid. The method of claim 23, wherein (a) is characterized by a powder X-ray diffraction pattern which is a chloroform solvate and comprises 2-theta angle peaks at 8.97 °, 12.07 ° and 14.20 °, or (b) is characterized by a powder X-ray diffraction pattern which is a chloroform solvate and comprises 2-theta angle peaks at 17.49 °, 18.56 ° and 20.87 °, or (c) is characterized by a powder X-ray diffraction pattern which is a chloroform solvate and comprises 2-theta angle peaks at 8.97 ° and 12.07 °, or (d) is characterized by a powder X-ray diffraction pattern which is a chloroform solvate and comprises 2-theta angle peaks at 20.87 ° and 23.11 °, or (e) characterized by a powder X-ray diffraction pattern which is a chloroform solvate and comprises a 2-theta angular peak at 8.97 °. Solvates. The method of claim 23, wherein (a) is characterized by a powder X-ray diffraction pattern which is a chlorobenzene solvate and comprises 2-theta angle peaks at 4.51 °, 6.25 ° and 7.77 °, or (b) is characterized by a powder X-ray diffraction pattern which is a chlorobenzene solvate and comprises 2-theta angle peaks at 10.37 °, 16.61 ° and 17.95 °, or (c) is characterized by a powder X-ray diffraction pattern which is a chlorobenzene solvate and comprises 2-theta angle peaks at 4.51 ° and 7.77 °, or (d) is characterized by a powder X-ray diffraction pattern which is a chlorobenzene solvate and comprises 2-theta angle peaks at 10.37 ° and 17.95 °, or (e) a powder X-ray diffraction pattern characterized by a chlorobenzene solvate and comprising a 2-theta angular peak at 4.51 °. Solvates. The method of claim 23, wherein (a) is characterized by a powder X-ray diffraction pattern which is an acetic acid solvate and comprises 2-theta angle peaks at 9.17 °, 10.20 ° and 16.61 °, or (b) is characterized by a powder X-ray diffraction pattern which is an acetic acid solvate and comprises 2-theta angle peaks at 6.53 °, 6.94 ° and 17.59 °, or (c) is characterized by a powder X-ray diffraction pattern which is an acetic acid solvate and comprises 2-theta angle peaks at 9.17 ° and 10.20 °, or (d) is characterized by a powder X-ray diffraction pattern which is an acetic acid solvate and comprises 2-theta angle peaks at 16.61 ° and 17.59 °, or (e) a powder X-ray diffraction pattern characterized by acetic acid solvate and comprising a 2-theta angular peak at 9.17 °. Solvates.

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