CN1980888B - Modafinil compositions - Google Patents

Abstract

Polymorphs and solvates of modafinil in racemic, enantiomerically pure, and enantiomerically mixed forms are formed and discussed. In addition, the forms are described as being useful for treating a number of conditions including, but not limited to, narcolepsy.

Description

Composition of modafinil

technical field

The present invention relates to a composition comprising modafinil, a pharmaceutical composition comprising modafinil, and a preparation method thereof.

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 to have different physical forms. 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, resulting in an inhomogeneous mixture. 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 in water of API-containing pharmaceutical compositions, 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, as 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 water solubility as well as chemical and form stability. It would also be desirable to increase the dissolution rate in water of API-containing pharmaceutical compositions, to increase the bioavailability of orally administered compositions, and to 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 and/or has a longer therapeutic plasma concentration and Higher full contact.

Contents of the invention

It has now been found that polymorphs and solvates of modafinil are available, some of which have different properties compared to the free form of the API.

Embodiments of the invention including but not limited to 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, solvent molecules (eg, in solvates) may also be present in embodiments of the invention as racemic, enantiomerically pure or enriched forms.

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

The methods of the invention may each comprise one or more additional steps in which the modafinil polymorph or solvate thus produced is incorporated into a pharmaceutical composition.

In additional embodiments, the present invention provides novel R-(-)-modafinil polymorphs. In specific embodiments, the present invention provides Forms III, IV, and V of R-(-)-modafinil. The present invention also provides methods for producing R-(-)-modafinil polymorphs.

In additional embodiments, the present invention provides a method of producing a polymorphic form of R-(-)-modafinil, the method comprising:

(a) providing R-(-)-m modafinil;

(b) R-(-)-modafinil polymorph crystallized from a suitable solvent.

In additional embodiments, the R-(-)-modafinil polymorph is crystallized from an organic solvent. In specific embodiments, the organic solvent can be acetonitrile, dimethylformamide (DMF), methanol, methyl ethyl ketone, N-methylpyrrolidone, ethanol, isopropanol, isobutanol, formamide, acetic acid Isobutyl ester, 1,4-dioxane, tetrahydrofuran (THF), ethyl acetate, o-xylene, isopropyl acetate, methylene chloride, propylene glycol, acetic acid, water, acetone, nitromethane, toluene , and benzyl alcohol. According to the invention, both pure solvents and solvent mixtures are considered organic solvents. In a specific embodiment, the organic solvent is ethanol. In another embodiment, the polymorphic form of R-(-)-modafinil is crystallized using a mixed solvent system. A mixed solvent system may be, for example, ethanol and isopropanol, or ethyl acetate and ethanol. In other embodiments, the crystallization in step (b) is accomplished by thermal crystallization. In other embodiments, the crystallization in step (b) is accomplished by evaporating the solvent.

In another embodiment, the pharmaceutical composition comprises an altered one or more of racemic modafinil, R-(-)-modafinil, and S-(+)-modafinil release 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 medicaments comprising polymorphs or solvates of modafinil and methods for their 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 invention may each comprise one or more additional steps in which the modafinil polymorph or solvate thus produced is incorporated into a medicament.

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

In another embodiment, there is provided a method of treating a subject suffering from one or more of the aforementioned conditions or disorders, including but not limited to sleep disorders such as narcolepsy, comprising administering to the subject a therapeutically effective amount of Form III R-( -)-modafinil, R-(-)-modafinil form IV, or R-(-)-modafinil form V.

Description of drawings

Figures 1-2: PXRD diffraction patterns of polymorphic forms of R-(-)-modafinil:S-(+)-modafinil of 1.

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

Figure 3 - PXRD diffraction pattern of the polymorphic form (Form III) of R-(-)-modafinil.

Figure 4 - DSC thermogram of the polymorphic form (Form III) of R-(-)-modafinil.

Figure 5 - PXRD diffractogram of the polymorphic form (Form III) of R-(-)-modafinil.

Figure 6 - PXRD diffractogram of polymorphic form (Form IV) of R-(-)-modafinil.

Figure 7 - DSC thermogram of the polymorphic form (Form IV) of R-(-)-modafinil.

Figure 8 - PXRD diffractogram of polymorphic form (Form IV) of R-(-)-modafinil.

Figure 9 - PXRD diffractogram of polymorphic form (V-shape) of R-(-)-modafinil.

Figure 10 - PXRD diffraction pattern of polymorphic form (V-shape) of R-(-)-modafinil.

Figure 11-2: PXRD diffraction pattern of R-(-)-modafinil:S-(+)-modafinil of 1.

Figure 12-2: DSC differential thermogram of R-(-)-modafinil:S-(+)-modafinil of 1.

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

Figure 14 - PXRD diffraction pattern of V-form R-(-)-modafinil.

Figure 15 - DSC differential thermogram of V-shaped R-(-)-modafinil.

Figure 16 - PXRD diffraction pattern of R-(-)-modafinil chloroform solvate.

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

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

Figure 19 - PXRD diffractogram of racemic modafinil ethyl acetate channel solvate.

Figure 20 - TGA thermogram of racemic modafinil ethyl acetate channel solvate.

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

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

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

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, 95, 96 , 97, 98 or 99% enantiomeric excess compositions. 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 described as racemic compounds, R-isomers, S-isomers, or any mixture of R-isomers and S-isomers.

As used herein and unless otherwise specified, the term "racemic" refers to a substance consisting of an equimolar mixture of enantiomers of modafinil, a solvate, or both (such as a polymorph or solvates). For example, a solvate comprising modafinil and a nonstereomeric solvent molecule is a "racemic solvate" only when an equimolar mixture of the modafinil enantiomers is present. Similarly, solvates involving modafinil and stereoisomeric solvent molecules are "racemic" only when there is an equimolar mixture of modafinil enantiomers and an equimolar mixture of enantiomers of the solvent molecule Solvates".

As used herein and unless otherwise stated, the term "enantiomerically pure" refers to a substance consisting of modafinil and an optional stereoisomeric or non-stereomeric soluble molecule, wherein the stereoisomer The enantiomeric excess of the material is at least about 90% ee (enantiomeric excess).

For the purposes of the present invention, the chemical and physical properties of modafinil in the solvated or polymorphic form can be compared to a reference compound which is a different form 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. 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.

Modafinil and some solvent molecules of the present invention have one or more chiral centers and can exist in various stereoisomeric configurations. Because of these chiral centers, modafinil and several solvates of the present invention can be used as racemates, mixtures of enantiomers, 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 solvates of the present invention may include isomeric forms of modafinil or the solvent molecule or both. Isomeric forms of modafinil and solvent molecules include, but are not limited to, stereoisomers such as enantiomers and diastereomers. In one embodiment, the solvate comprises racemic modafinil and a solvent molecule. In another embodiment, the solvate comprises enantiomerically pure R- or S-modafinil and a solvent molecule. In another embodiment, the solvates of the present invention include those 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%, 99%, greater than 99% , or any intermediate enantiomeric excess of modafinil and/or solvent molecules. 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%, 99%, greater than 99%, or any intermediate enantiomeric excess of modafinil.

"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" may be used to describe enriched modafinil, enantiomerically pure modafinil, or substantially is enantiomerically pure modafinil, but also specifically excludes enriched modafinil, enantiomerically pure modafinil, and/or substantially enantiomerically pure modafinil .

Solvates and polymorphs comprising enantiomerically pure and/or enantiomerically enriched components (e.g., modafinil or co-crystal formers) may result relative to those comprising racemic components. Correspondingly those co-crystallized obtain adjusted chemical and/or physical properties.

It is also possible to use racemic modafinil, enantiomerically pure modafinil, or any mixture of R-(-)- and S-(+)-modafinil of the invention (e.g., rich Polymorphs and solvates of modafinil were prepared.

In another embodiment, compositions or medicaments comprising solvates and polymorphs of the present invention may be combined with PROVIGIL (Cephalon, Inc.) compared to the free form of modafinil obtained. (See US Reexamined Patent No. RE37,516).

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

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.

A568和Duolite

AP143(Rohm&Haas，Spring House，PA.USA)。There are a variety of known controlled-release or extended-release dosage forms, formulations, and devices that are suitable for use with the solvates and compositions of the 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，其每个都被并Included here as a reference. These dosage forms may be used to provide slow or controlled release of one or more active ingredients using, for example, hypromellose, other polymeric matrices, gels, permeable 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 solvate, hydrate, anhydrate, anhydrate, amorphous form, and one or more pharmaceutically acceptable excipients or diluents , wherein the pharmaceutical composition, medicament or dosage form is formulated for controlled release. Particular dosage forms employ osmotic drug delivery systems.

(AlzaCorporation，Mountain View，Calif.USA)。这种技术可以容易地适合于递送本发明的化合物和组合物。该技术的多个方面在美国专利6,375,978B1、6,368,626B1、6,342,249B1、6,333,050B2、6,287,295B1、6,283,953B1、6,270,787B1、6,245,357B1和6,132,420中公开，其每个被并入本文作为参考。可用于给药本发明的化合物和组合物的具体的OROS改型包括但不限于OROS

Push-Pull^TM、Delayed Push-Pull^TM、Multi-Layer Push-Pull^TM和Push-Stick^TM Systems，其都是众所周知的。参见例如，            http://www.alza.com。可用于本发明的化合物和组合物的受控制的口服递送的另外的OROS

系统包括OROS

-CT和L-OROS

.Id.，还参见Delivery Times，vol.II，issue II(Alza Corporation)。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 that can be used to administer the compounds and compositions of the invention Modifications include but are not limited to OROS

Push-Pull ^™ , Delayed Push-Pull ^™ , Multi-Layer Push-Pull ^™ and Push-Stick ^™ Systems are all well known. See, eg, http://www.alza.com . Additional OROS Useful for Controlled Oral Delivery of Compounds and Compositions of the Invention

System including OROS

-CT and L-OROS

.Id., see also Delivery Times, vol. II, issue II (Alza Corporation).

药物递送系统不能用于有效地递送具有低水溶性的药物。Id.at 234。Conventional OROS Oral dosage forms are produced by compressing drug powder into hard tablets, coating the tablet with a cellulose derivative to form a semipermeable membrane, and then drilling holes in the coating (eg, 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 efficiently deliver drugs with low water solubility. Id. at 234.

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 includes its polymorph, or 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 The compressive force of the layer without significant exudation of the fluid, active agent formulation, the dosage form optionally has a placebo layer between the outlet and the drug layer, wherein the active agent formulation includes its polymorphs, or solvates, hydrates , Dehydrated matter, anhydrous matter or amorphous matter. See US Patent 6,342,249, which is hereby incorporated by reference in its entirety.

In another embodiment, a pharmaceutical composition or medicament comprises a mixture of the novel forms (eg, polymorphs or solvates) of modafinil of the invention and racemic 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 racemic modafinil and a polymorph or solvate of the invention.

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 such compositions, peak plasma levels can be reached around noon.

In another embodiment, the pharmaceutical composition or medicament comprising an altered 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 Subsequent Cmax of S-(+)-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 solvates 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 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 pharmaceutical composition comprising an altered release profile of racemic modafinil, S-(+)-modafinil and R-(-)-modafinil wherein in oral formulations.

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, especially 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 binders include, but are not limited to, gum arabic; tragacanth; sucrose; gelatin; glucose; starches such as, but not limited to, pregelatinized starch (e.g., National ^™ 1511 and National ^TM 1500); celluloses such as, but not limited to, methylcellulose and sodium carmellose (eg, Tylose ^™ ); alginic acid and alginates; magnesium aluminum silicate; PEG; guar gum; polysaccharide acids; bentonite; povidone, such as povidone K-15, K-30, and K-29/32; polymethacrylates; HPMC; hydroxypropylcellulose (eg, Klucel ^™ from Aqualon); and ethylcellulose ( For example, Ethocel ^(TM ) from 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 amounts to about 0.25% to about 7%, preferably about 0.4% to about 4%, more preferably about 0.5% to about 2%, by weight of the total 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 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.

In additional embodiments, the present invention provides novel polymorphic forms of R-(-)-modafinil. In specific embodiments, the invention provides R-(-)-modafinil in forms III, IV and V. The present invention also provides methods for producing R-(-)-modafinil polymorphs.

In another embodiment, the present invention provides a method of producing a polymorphic form of R-modafinil, the method comprising:

(a) providing R-(-)-m modafinil; and

(b) Crystallization of the polymorphic form of R-modafinil from a suitable solvent.

In additional embodiments, the R-(-)-modafinil polymorph is crystallized from an organic solvent. In a specific embodiment, the organic solvent is ethanol. In another embodiment, the polymorphic form of R-(-)-modafinil is crystallized using a mixed solvent system. Mixed solvent systems may be, for example, ethanol and isopropanol, and ethyl acetate and ethanol. In other embodiments, the crystallization in step (b) is accomplished by thermodynamic recrystallization. In other embodiments, the crystallization in step (b) is accomplished by evaporating the solvent.

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, there is provided a method of treating a subject afflicted with one or more of the aforementioned conditions or disorders, including but not limited to sleep disorders such as narcolepsy, comprising administering to the subject a therapeutically effective amount of Form III R- (-)-modafinil, R-(-)-modafinil form IV, or R-(-)-modafinil form V.

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

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; uild3.1.0.40 (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 Q500 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; uild3.1.0.40 (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.).

的Cu；x-y载物台为手动的；准直管尺寸为0.3mm；毛细管(Charles SupperCompany，Natick，MA，U.S.A.)为0.3mm ID；使用反射模式；到X射线管的功率为46kV；到X射线管的电流为40mA；ω轴以1度/分钟的速度在0-5度的范围内振动；Φ轴以2度/秒的速度以360度的角度旋转；0.3mm准直管；采集时间为60分钟；温度为室温；以及不使用加热器。样品在富含硼的玻璃毛细管中呈递到X射线源。For PXRD analysis, the acquisition parameters are as follows: the ray source is the K line at 1.5406

Cu; xy stage is manual; collimation tube size is 0.3mm; capillary (Charles SupperCompany, Natick, MA, USA) is 0.3mm ID; use reflection mode; The current of the ray tube is 40mA; the ω axis vibrates within the range of 0-5 degrees at a speed of 1 degree/minute; the Φ axis rotates at an angle of 360 degrees at a speed of 2 degrees/second; a 0.3mm collimator tube; acquisition time was 60 minutes; the temperature was room temperature; and no heater was 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), Bruker AXS HI-STAR AreaDetector calibrated at a distance of 15.05 cm according to the system, copper source (Cu/K _α 1.54056 Angstroms), automated xyz stage and 0.5 mm calibration 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 from 2.1 to 37 degrees, the normalization set Normalized to binary.

The relative intensities of peaks in a diffractogram are 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. Most peaks throughout the plot or graph may also be shifted by about +/- 0.1 degrees to about +/- 0.2 degrees due to calibration, setup and other variations from different instruments and from 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 2000 RSP 250x4.6mm (Part No.411121)

Mobile phase A: 20 mM sodium phosphate, pH 3.0

B: 70:30 mobile phase A: acetonitrile

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

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 1 M 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) 20 mM 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

Parameters Settings used Contact time (s) 2.0 Contacts                               Laser source wavelength (nm) 785 Laser power (%) 100 Aperture shape Pinhole Aperture size (um) 100 Spectral Range ... Grating position Single The temperature at the time of collection (°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.

Example 1

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

Bubble anhydrous ammonia through methanol containing R-benzhydrylsulfinylmethyl ester (8.62 g, 0.0299 mol, about 80:20 R-isomer:S-isomer by weight) (125 mL) solution for 10 minutes. Pressure build-up from the reaction caused sodium bicarbonate to flow back from the retort into the reaction mixture. The reaction was stopped and the precipitate was collected. The filtrate was concentrated under reduced pressure to obtain a yellow solid residue (2.8 g). The yellow solid was columned (silica gel, grade 9385, 230-400 mesh, 60 Angstroms) with 3:1 v/v ethyl acetate:hexane as eluent. The filtrates were then combined and concentrated under reduced pressure to give a slightly yellowish solid (most of the yellow color remained on the column). The solid was then recrystallized from ethanol by heating the mixture until it boiled and then cooled to room temperature to give 2:1 R-(-)-modafinil:S-(+)-modafinil as a colorless solid (580mg). The resulting solid was subjected to PXRD and DSC analysis and was determined to be R-(-)-modafinil and S-(+)-modafinil present in approximately 2:1 weight ratio in pure form.

The 2:1 R-(-)-modafinil obtained above: S-(+)-modafinil solid passed through any one, any two, any three, any four, any Five, or any six or more peaks characterize including but not limited to 8.97, 10.15, 12.87, 14.15, 15.13, 15.77, 18.19, and 20.39 degrees 2Θ (for directly acquired data).

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

Example 2

Polymorphs of R-(-)-modafinil

Several polymorphs of R-(-)-modafinil were observed, each characterized by PXRD. Figures 3, 6, and 9 show these PXRD diffractograms (data obtained for direct collection) of the Form III, Form IV, and Form V polymorphs.

Recrystallization has proven to be an efficient technique for forming and obtaining polymorphs of R-(-)-modafinil. Suitable solvents for crystallization of one or more polymorphs of R-(-)-modafinil include, but are not limited to, acetonitrile, dimethylformamide (DMF), methanol, methyl ethyl ketone , N-methylpyrrolidone, ethanol, isopropanol, isobutanol, formamide, isobutyl acetate, 1,4-dioxane, tetrahydrofuran (THF), ethyl acetate, o-xylene, acetic acid Isopropyl ester, methylene chloride, propylene glycol, acetic acid, water, acetone, nitromethane, toluene, and benzyl alcohol. Pure solvents and mixtures of solvents can be used for the crystallization of one or more polymorphs of R-(-)-modafinil.

Form III R-(-)-modafinil

Anhydrous ammonia gas was bubbled through a solution of R-benzhydrylsulfinylmethyl ester (8.3 g, 0.0288 mol) in methanol (75 mL) for 10 min. The reaction was then stirred in an ice bath at 5 °C for 1 hour and ammonia gas was bubbled through for an additional 10 minutes. Stirring was continued for an additional 2 hours and ammonia gas was bubbled through again for 10 minutes. After stirring for another hour, a precipitate (575 mg) formed and was collected. The filtrate was then neutralized using concentrated HCl, forming another precipitate which was collected. The solid residue was then recrystallized from a 1:1 v/v mixture of ethanol and isopropanol by heating the mixture until boiling and then cooling it to room temperature to afford Form III R-(-)-modafinil as Colorless solid (1.01 g).

Form III R-(-)-modafinil can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 3, which include But not limited to 7.21, 10.37, 17.73, 19.23, 21.17, 21.77, and 23.21 degrees 2Θ (Rigaku PXRD, directly collected data).

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

A second batch of Form III R-(-)-modafinil was prepared for further analysis by thermal microscopy and PXRD. Solubility data were also obtained. These data are discussed below.

The solubility of Form III R-(-)-modafinil is equal to 6.1-7.0 mg/mL. Solubility was measured from stirred isopropyl acetate slurries at 25°C. Solubility measurements were performed by HPLC. The solids from the solubility samples were dried under nitrogen and characterized by PXRD and thermal microscopy. No form conversion was observed during the workup.

Thermal (hot stage) microscopy was performed at a heating rate of 10°C/min to measure the melting point of Form III R-(-)-modafinil, which was determined to be about 156-158°C.

Form III R-(-)-modafinil can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 5, which include But not limited to 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 degrees 2Θ (Rigaku PXRD, data with background removed).

Form IV R-(-)-modafinil

Anhydrous ammonia gas was bubbled through a solution of R-benzhydrylsulfinylmethyl ester (8.3 g, 0.0288 mol) in methanol (75 mL) for 10 min. The reaction was then stirred in an ice bath at 5 °C for 1 hour and ammonia gas was bubbled through for an additional 10 minutes. Stirring was continued for an additional 4 hours. After stirring for a further hour, a precipitate (422 mg) formed and was collected. The filtrate was then neutralized using concentrated HCl, forming another precipitate which was collected. The solid material (3 g) was passed through a column (silica gel, grade 9385, 230-400 mesh, 60 Angstroms) using 3:1 v/v ethyl acetate and hexane as eluent. The column was then rinsed with ethyl acetate (250 mL). The filtrates were combined and concentrated under reduced pressure to afford R-(-)-modafinil Form IV as a colorless solid (590 mg).

Form IV R-(-)-modafinil can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 6, which include But not limited to 7.79, 10.31, 11.77, 16.49, 17.33, 19.47, and 23.51 degrees 2Θ (Rigaku PXRD, directly collected data).

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

A second batch of R-(-)-modafinil Form IV was prepared for further analysis by thermal microscopy and PXRD. Solubility data were also obtained. These data are discussed below.

The solubility of R-(-)-modafinil Form IV is equal to 3.5-4.0 mg/mL. Solubility was measured from stirred isopropyl acetate slurries at 25°C. Solubility measurements were performed by HPLC. The solids from the solubility samples were dried under nitrogen and characterized by PXRD and thermal microscopy. No form conversion was observed during the workup.

Thermal (hot stage) microscopy was performed at a heating rate of 10°C/min to measure the melting point of R-(-)-modafinil Form IV, which was determined to be about 147-158°C.

Form IV R-(-)-modafinil can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 8, which include But not limited to 7.77, 10.33, 11.75, 16.53, 19.43, 19.89, 21.87, 23.49, and 26.69 degrees 2Θ (Rigaku PXRD, data with background removed).

V-shaped R-(-)-modafinil

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 V-form R-(-)-modafinil.

V-shaped R-(-)-modafinil can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 9, which include But not limited to 6.61, 10.39, 13.99, 16.49, 17.73, 19.03, 20.87, 22.31, and 25.99 degrees 2Θ (Rigaku PXRD, directly collected data).

A second batch of V-form R-(-)-modafinil was prepared for further analysis by thermal microscopy and PXRD. Solubility data were also obtained. These data are discussed below.

The solubility of Form V R-(-)-modafinil is equal to 2.1-2.6 mg/mL. Solubility was measured from stirred isopropyl acetate slurries at 25°C. Solubility measurements were performed by HPLC. The solids from the solubility samples were dried under nitrogen and characterized by PXRD and thermal microscopy. No form conversion was observed during the workup.

Thermal (hot stage) microscopy was performed at a heating rate of 10°C/min to measure the melting point of Form V R-(-)-modafinil, which was determined to be approximately 159°C.

V-shaped R-(-)-modafinil can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 10, which include But not limited to 6.53, 10.19, 13.90, 16.56, 17.35, 17.62, 18.99, 20.93, 22.08, 23.36, and 25.91 degrees 2Θ (Bruker PXRD, directly collected data).

Polymorphs of R-(-)-modafinil according to the diffraction of the corresponding III, IV, and V forms of racemic modafinil in U.S. Patent Application 20020043207 published on April 18, 2002 Similarities in those PXRD diffraction patterns found in the figure are named III, IV, and V shapes.

Example 3

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

A solution containing R-(-)-modafinil (80.16 mg, 0.293 mmol) and racemic modafinil (20.04 mg, 0.0366 mmol) in ethanol (2 mL) was prepared. The mixture was heated to boiling to dissolve all solids, then cooled to room temperature (25°C). After 15 minutes at room temperature, the solution was allowed to stand overnight at 5°C. The solution was then decanted off and the remaining crystals were dried under nitrogen flow and characterized using HPLC, PXRD, DSC, and thermal microscopy.

The resulting crystals contained about 63 to about 67% R-(-)-modafinil, with the remainder of the crystals being S-(+)-modafinil. HPLC analysis showed that the crystals were a 2:1 phase containing two R-(-)-modafinil molecules per S-(+)-modafinil molecule.

PXRD was performed on single crystal samples of 2:1 R-(-)-modafinil:S-(+)-modafinil. 2:1 R-(-)-modafinil: S-(+)-modafinil can pass any one, any two, any three, any four, any five, Or any six or more peak characterizations, including but not limited to 8.95, 10.17, 11.87, 14.17, 15.11, 17.39, 18.31, 20.39, 21.09, 24.41, and 26.45 degrees 2θ (Rigaku PXRD, obtained for direct collection data).

The DSC of 2:1 R-(-)-modafinil:S-(+)-modafinil characterized in Figure 12 exhibited an endothermic transition at about 168°C.

Thermal (hot stage) microscopy was performed at a heating rate of 5 °C/min to measure the melting point of the 2:1 R-(-)-modafinil:S-(+)-modafinil determined to be ca. 160-166°C.

Example 4

Form IV R-(-)-modafinil

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

Form IV R-(-)-modafinil can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 13, which include But not limited to 7.64, 10.17, 11.61, 16.41, 19.34, 21.71, 22.77, and 23.36 degrees 2Θ (Bruker PXRD, directly collected data).

Form IV R-(-)-modafinil was recovered by thermodynamic recrystallization from ethanol and by slow evaporation of the solvent from ethanol.

Example 5

V-shaped R-(-)-modafinil

107.7 mg of R-(-)-modafinil was dispersed in 3 mL of ethyl acetate. The suspension was heated on a hot plate (60°C) to dissolve the solids. About one-third to one-half of the heated solvent was evaporated with a stream of nitrogen. The mixture was then cooled to room temperature (25°C). Solids are separated from liquids using a centrifugal filter. The resulting solid was analyzed by PXRD and DSC and determined to be Form V R-(-)-modafinil (Figures 14 and 15).

V-shaped R-(-)-modafinil can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 14, which include But not limited to 6.52, 10.23, 13.93, 16.37, 17.61, 18.97, 20.74, 22.21, 23.36, and 25.90 degrees 2Θ (Bruker PXRD, directly collected data).

DSC was performed on the V-shaped R-(-)-modafinil. Figure 15 shows an endothermic transition at about 161-162 (161.57) °C.

Example 6

R-(-)-modafinil chloroform solvate

200 microliters of chloroform was added to 30.5 mg of R-(-)-modafinil. The mixture was heated at 75°C for 30 minutes before adding an additional 200 microliters of chloroform. After an additional 30 minutes, the solids had completely dissolved. The samples were heated for an additional 2 hours. After heating, the sample was cooled to 5°C at a rate of about 1 degree/minute. Upon reaching 5°C, the sample was still a homogeneous liquid solution. The sample was then placed under a stream of nitrogen for one minute to initiate crystal formation. Samples were re-incubated at 5°C and more solids precipitated. The samples were then dried under nitrogen flow and characterized by PXRD and TGA.

PXRD was performed on R-(-)-modafinil chloroform solvate. R-(-)-modafinil chloroform solvate can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 16, These include, but are not limited to, 8.97, 12.07, 14.20, 16.91, 17.49, 18.56, 20.87, 21.45, 23.11, and 25.24 degrees 2Θ (Bruker PXRD, directly collected data).

TGA was performed on R-(-)-modafinil chloroform solvate. Figure 17 shows a 15% weight loss between about 25°C and about 150°C.

Example 7

R-(-)-modafinil chlorobenzene solvate

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

PXRD was performed on R-(-)-modafinil chlorobenzene solvate. R-(-)-modafinil chlorobenzene solvate can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 18 , which include, but are not limited to, 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 degrees 2Θ (Rigaku PXRD, directly collected data).

Example 8

Ethyl acetate channel solvate of racemic modafinil

The ethyl acetate channel solvate of racemic modafinil was prepared by dissolving racemic 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. Once cooled, the solution was crystallized seeded with a ground co-crystal of R-(-)-modafinil: 1-hydroxy-2-naphthoic acid (see Example 17 of PCT/US2004/29013).

PXRD was performed on the ethyl acetate channel solvate of racemic modafinil. The ethyl acetate channel solvate of racemic modafinil can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in Figure 19 , including but not limited to 8.88, 14.09, 19.83, 21.59, 23.04, and 25.94 degrees 2Θ (Bruker PXRD, directly collected data).

TGA was performed on the ethyl acetate channel solvate of racemic modafinil. Figure 20 shows a 3.6% weight loss between about 25 and about 150°C.

Example 9

R-(-)-Modafinil acetic acid solvate

R-(-)-modafinil acetic acid was formed by grinding R-(-)-modafinil (105.5 mg) in 0.066 mL of acetic acid in a stainless steel cylinder with a Wig-L-Bug grinder/mixer solvates. The powders were then analyzed by DSC, TGA, and PXRD.

PXRD was performed on R-(-)-modafinil acetic acid solvate. R-(-)-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 21, These include, but are not limited to, 9.17, 10.20, 16.61, 17.59, 18.90, 21.11, and 24.11 degrees 2Θ (Bruker PXRD, directly collected data).

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

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

Claims (7)

1. Compositions comprising V-shaped R-(-)-modafinil, wherein V-shaped R-(-)-modafinil is characterized in that under Rigaku PXRD test conditions, derivative peaks include 6.61, 10.39, 13.99 , 16.49, 17.73, 19.03, 20.87, 22.31, 25.99 ± 0.1 degrees of 2θ. 2. The composition of claim 1, wherein the composition is a pharmaceutical composition. 3. the method for producing the V-shaped R-(-)-modafinil of claim 1, the method comprising: (a) provide R-(-)-modafinil; and (b) Crystallization of Form V R-(-)-modafinil from ethyl acetate. 4. The V-shaped R-(-)-modafinil of claim 1 is used for the treatment of excessive daytime sleepiness associated with narcolepsy, fatigue associated with multiple sclerosis, infertility, eating disorders, Drug use in subjects with attention deficit hyperactivity disorder, Parkinson's disease, incontinence, sleep apnea, or myopathy. 5. The use of claim 4, wherein the subject is a human subject. 6. Use according to claim 4 for the treatment of excessive daytime sleepiness or sleep apnea associated with narcolepsy. 7. The application of claim 4 for the treatment of attention deficit hyperactivity disorder.

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