EA009949B1 - 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

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

The level of technology

The active pharmaceutical ingredients (ΑΡΙ or APP (set)) in pharmaceutical compositions can be obtained in a variety of different forms. Such AVRs can be made to have a variety of different chemical forms, including chemical derivatives, solvates, hydrates, co-crystals, or salts. Such an AVR can also be obtained to have various physical forms. For example, ARNs can be amorphous, they can have different crystalline polymorphs, or they can exist in different states of solvation or hydration. By changing the forms ΑΡΙ, you can change its physical properties. For example, crystalline polymorphs usually have solubilities that differ from each other, so that a more thermodynamically stable polymorph is less soluble than a less thermodynamically stable polymorph. Pharmaceutical polymorphs can also vary in properties, such as shelf life, bioavailability, morphology, vapor pressure, density, color, and compressibility. Accordingly, a change in the crystalline state of ΑΡΙ is one of many ways to modulate its physical properties.

It would be beneficial to have new forms of these ARCs that have improved properties, in particular in the form of oral medications. It is particularly desirable to identify improved forms of ARI, which exhibit significantly improved properties, including increased water solubility and stability. In addition, it is desirable to improve the processability or the production of pharmaceutical preparations. For example, needle-like crystalline forms or ARI habits can cause aggregation, even in compositions in which AP1 is mixed with other substances, so that a heterogeneous mixture is obtained. Needle-like morphologies can also cause problems with filtering (see, for example, M1TeitaYy c1 a1. 1. Ryatt. 8c1. Vo1. 93, No. 7, pp. 1692-1700, 2004). It is also desirable to increase the dissolution rate of AP1-containing pharmaceutical compositions in water, to increase the bioavailability of orally administered compositions and to provide a more rapid onset of therapeutic action. It is also desirable to have the form of AP1, which, when administered to a subject, quickly reaches a peak plasma level, has a more prolonged therapeutic plasma concentration and a stronger overall effect compared with equivalent amounts of AP1 in its currently known form.

Modafinil, AP1, used to treat subjects with narcolepsy, is practically insoluble in water. Modafinil (CA8 registration number: 68 693-11-8) is represented by structure (I)

Modafinil is a chiral molecule due to the chiral group 8 = 0. Therefore, modafinil exists as two isomers, K .- (-) - modafinil and 8 - (-) - modafinil. It would be beneficial to have new forms of modafinil that have improved properties, especially in the form of oral medications. It is especially desirable to identify improved forms of modafinil that exhibit significantly increased water solubility and both chemical stability and form stability. It is also desirable to increase the dissolution rate of AP1-containing pharmaceutical compositions in water, to increase the bioavailability of orally administered compositions and to provide a more rapid onset of therapeutic action. It is also desirable to have the form of AP1, which, when administered to a subject, quickly reaches a peak plasma level and / or has a longer persistent therapeutic plasma concentration and a stronger overall effect compared with equivalent amounts of AP1 in its currently known form.

Summary of Invention

It has now been discovered that polymorphs and modafinil solvates can be obtained. Some of them may have properties different from those of the free form of AP1.

The present invention relates to a pharmaceutical composition comprising a mixture of 2: 1 K. - (-) modafinil: 8 - (+) - modafinil. More specifically, the proposed composition is characterized by (a) an x-ray powder diffraction pattern that includes peaks corresponding to degrees of angles 2-θ, where:

(ί) the indicated composition is a 2: 1 K mixture. - (-) - modafinil: 8 - (+) - modafinil and the indicated radiograph includes peaks corresponding to 8.97, 10.15, and 20.39 °; or (s) this composition is a mixture of 2: 1 K .- (-) - modafinil: 8 - (+) - modafinil and yak

- 1 009949 This radiograph includes peaks corresponding to 8.97 and 18.19 °; or (ίίί) the specified composition is a mixture of 2: 1 K - (-) - modafinil: 8 - (+) - modafinil and the indicated radiograph includes peaks corresponding to 10.15 and 20.39 °; or (ίν) the specified composition is a mixture of 2: 1 K - (-) - modafinil: 8 - (+) - modafinil and the indicated radiograph includes peaks corresponding to 15.77 and 19.25 °; or (ν) the indicated composition is a mixture of 2: 1 K - (-) - modafinil: 8 - (+) - modafinil and the indicated radiograph includes a peak corresponding to 8.97 °; or (b) a DSC thermogram, where the specified composition is a 2: 1 K - (-) - modafinil: 8 - (+) modafinil mixture and the DSC thermogram includes an endothermic transition approximately in the 167 ° C region. In a preferred embodiment, the proposed composition further includes a diluent, excipient or carrier.

The following embodiment of the present invention proposes a method of obtaining 2: 1 V - (-) - modafinil: 8 - (+) - modafinil, including:

(a) provision of B - (-) - modafinil and forms of 8-isomer modafinil; and (b) crystallization of a mixture of 2: 1 V - (-) - modafinil: 8 - (+) - modafinil from a solvent or mixture of solvents.

The description also contains information about the new polymorph I - (-) - modafinil, in particular, about such forms as forms III, IV and V I - (-) - modafinil. A method for preparing B - (-) - modafinil is described, which includes (a) providing K - (-) - and (b) crystallization of the polymorph B - (-) - modafinil from a suitable solvent.

In particular, the polymorph I - (-) - modafinil is crystallized from an organic solvent. In specific embodiments, the organic solvent can be acetonitrile, dimethylformamide (DMF), methanol, methyl ethyl ketone, Ν-methylpyrrolidone, 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. According to the invention, both individual solvents and mixed solvents are considered as an organic solvent. In a specific embodiment, the organic solvent is ethanol. In another embodiment, a mixed solvent system is used to crystallize the polymorph K - (-) modafinil. Mixed solvent systems can be, for example, ethanol and isopropyl alcohol or ethyl acetate and ethanol. In a further embodiment, the crystallization in step (b) is completed by thermal crystallization. In a further embodiment, the crystallization in step (b) is completed by evaporation of the solvent.

The pharmaceutical composition according to the invention has a modified profile. The modified release profile may include, for example, two or more plasma concentration peaks, for example, a double release profile.

Described drug, which includes polymorph or solvate of modafinil, and methods for its preparation. Typically, the drug additionally includes one or more pharmaceutically acceptable carriers, diluents or excipients. Medicines are described in more detail below.

Describes a method for treating a subject, preferably a human subject, suffering from daytime sleepiness associated with narcolepsy, fatigue associated with multiple sclerosis, infertility, appetite disturbances, and hyperactivity disorder leading to attention disorder (ΑΌΗΌ), Parkinson’s disease, incontinence, sleep apnea, or myopathy, where modafinil is an effective pharmaceutical agent for this disorder. The method includes administering to the subject a therapeutically effective amount of a modafinil polymorph or solvate.

A method of treating a subject suffering from one or more of the above conditions or disorders is described, including, but not limited to, sleep disorders such as narcolepsy, where the method includes administering to the subject a therapeutically effective amount of Form III B - (-) - Modafinil, Form IV I - (-) - Modafinil or Form V K - (-) Modafinil.

Brief Description of the Drawings

FIG. 1 - X-ray diffraction pattern of polymorph 2: 1 K - (-) - modafinil: 8 - (+) - modafinil;

FIG. 2 - DSC thermogram of polymorph 2: 1 V - (-) - modafinil: 8 - (+) - modafinil;

FIG. 3 - X-ray diffraction pattern of polymorph K - (-) - modafinil (form III);

FIG. 4 - DSC thermogram of polymorph K - (-) - modafinil (form III);

FIG. 5 - X-ray diffraction pattern of polymorph K - (-) - modafinil (form III); FIG. 6 - X-ray diffraction pattern of polymorph K - (-) - modafinil (form IV); FIG. 7 - DSC thermogram of polymorph K - (-) - modafinil (form IV);

FIG. 8 - X-ray diffraction pattern of polymorph K - (-) - modafinil (form IV);

- 009949 FIG. 9 - diffractogram ΡΧΚΌ of polymorph K - (-) - modafinil (form V); FIG. 10 - diffractogram ΡΧΚΌ of polymorph K - (-) - modafinil (form V); FIG. 11 - diffractogram ΡΧΚΌ 2: 1 K - (-) - modafinil: 8 - (+) - modafinil; FIG. 12 - DSC thermogram 2: 1 K - (-) - modafinil: 8 - (+) - modafinil;

FIG. 13 - diffractogram ΡΧΚΌ of form IV K - (-) - modafinil;

FIG. 14 - diffractogram ΡΧΚΌ of the form V K - (-) - modafinil;

FIG. 15 - DSC thermogram of the form V K - (-) - modafinil;

FIG. 16 - diffractogram ΡΧΚΌ of the solvate of K - (-) - modafinil with chloroform;

FIG. 17 - TGA thermogram of the solvate of K - (-) - modafinil with chloroform;

FIG. 18 - diffractogram ΡΧΡΩ of the solvate of K - (-) - modafinil with chlorobenzene;

FIG. 19 - diffractogram ΡΧΡΩ of the channel solvate of racemic modafinil with ethyl acetate; FIG. 20 - TGA thermogram of a channel solvate of racemic modafinil with ethyl acetate;

FIG. 21 - diffractogram ΡΧΡΌ of the solvate of K - (-) - modafinil with acetic acid;

FIG. 22 - thermogram TGA of the solvate K - (-) - modafinil with acetic acid; FIG. 23 - DSC thermogram of solvate K - (-) - modafinil with acetic acid.

Detailed Description of the Invention

The structure of modafinil includes a stereocenter and therefore it can exist as a racemate, one of two pure isomers, or a pair of two isomers in any ratio. The chemical name for racemic modafinil is (±) -2 - [(diphenylmethyl) sulfinyl] acetamide. Isomeric pairs of racemic modafinil are K - (-) - 2 - [(diphenylmethyl) sulfinyl] acetamide or K - (-) modafinil and 8 - (+) - 2 - [(diphenylmethyl) sulfinyl] acetamide or 8 - (+) - modafinil.

The term as used herein, unless otherwise indicated, “enantiomerically pure” includes a composition that is substantially enantiomerically pure and includes, for example, a composition with an enantiomeric excess equal to or greater than about 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%. The enantiomeric excess is determined by the percentage of enantiomer A - the percentage of enantiomer B or by the formula its percentage = 100x ([K] - [8] / ([K] + [8])), where K is the number of moles K - (-) - modafinil and 8 is the number of moles of 8 - (+) modafinil.

The term “modafinil” as used herein includes the racemate, other mixtures of K- and 8-isomers, and individual enantiomers, but can be specifically defined as racemate, K-isomer, 8-isomer, or any mixture of both K- and 8-isomers .

The term “racemic,” as used herein, unless otherwise indicated, refers to a substance (eg, a polymorph or a solvate) that consists of an equimolar mixture of modafinil enantiomers, a solvent, or both. For example, a solvate comprising modafinil and a non-stereoisomeric solvent molecule is a racemic solvate only when an equimolar mixture of modafinil enantiomers is present. Similarly, a solvate comprising modafinil and a stereoisomeric solvent molecule is a racemic solvate only when there is an equimolar mixture of modafinil enantiomers and the enantiomers of the solvent molecule.

As used herein, unless otherwise indicated, “enantiomerically pure” refers to a substance that consists of modafinil and optionally a stereoisomeric or non-stereoisomeric solvent molecule, where the enantiomeric excess of the stereoisomeric compound is greater than or equal to about 90% of it (enantiomeric excess).

For the purposes of the present invention, the chemical and physical properties of modafinil in the form of a solvate or polymorph can be compared with a reference compound, which is modafinil in another form. The reference compound can be defined as a free form or, more specifically, an anhydrate (anhydrous compound) or a free form hydrate, or, more specifically, for example, a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate; or a free form solvate. The reference compound can also be defined as crystalline or amorphous. The reference compound can be defined as crystalline or amorphous. The reference compound can also be defined as the most stable known polymorph of a specific form of the reference compound.

Modafinil and some solvents molecules of the present invention have one or more chiral centers and may exist in various stereoisomeric configurations. As a result of these chiral centers, modafinil and several solvates of the present invention exist as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All such racemates, enantiomers and diastereomers are within the scope of the present invention, including, for example, cis and trans isomers, K- and 8-enantiomers and () - and (b) -isomers. The solvates of the present invention may include isomeric forms of either modafinil, solvent molecules, or both. The isomeric forms of modafinil and solvent molecules include, but are not limited to, stereoisomers, such as enantiomers and diastereomers. In one embodiment, the solvate includes racemic modafinil and

- 3 009949 solvent molecule. In another embodiment, the solvate comprises an enantiomerically pure B-or 8-modafinil and a solvent molecule. In another embodiment, the solvate of the present invention includes modafinil and / or a solvent molecule with 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%, more than 99% or any intermediate value. In another embodiment, the polymorph or solvate of the present invention may include modafinil with 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%, more than 99% or any intermediate value.

“Enriched” modafinil according to the present invention includes both the B - (-) - and 8 - (+) - isomers of modafinil in amounts equal to or greater than about 5, 6, 7, 8, 9 or 10 wt.% , or equal to or less than 90, 91, 92, 93, 94 or 95 wt.%. For example, a composition comprising 67% by weight of B - (-) - modafinil and 33% by weight of 8 - (+) - modafinil is an enriched composition of modafinil. In this example, the composition is neither racemic nor enantiomerically pure. The term enriched B - (-) - modafinil can be used to describe the composition of modafinil with more than 50% B - (-) - modafinil and less than 50% 8 - (+) - modafinil. Similarly, the term enriched with 8 - (+) - modafinil can be used to describe the composition of modafinil with more than 50% 8 - (+) - modafinil and less than 50% B - (-) - modafinil.

The terms “B - (-) - modafinil” and “8 - (+) - modafinil” can be used to describe enriched modafinil, enantiomerically pure modafinil or essentially enantiomerically pure modafinil, but may also specifically include enriched modafinil, enantiomerically pure modafinil and / or essentially enantiomerically pure modafinil.

Solvates and polymorphs that include enantiomerically pure and / or enantiomerically enriched components (for example, modafinil or a solvent molecule) can cause chemical and / or physical properties that are modulated with respect to such properties of the corresponding form, including the racemic component.

Polymorphs and solvates of modafinil can be obtained with racemic modafinil, enantiomerically pure modafinil, or with any mixture of B - (-) - and 8 - (+) - modafinil (for example, enriched modafinil) according to the present invention.

In another embodiment, the compositions or drugs, including the solvates and polymorphs of the present invention, can be compared with the free form of modafinil, such as РВОУУШ® (Serialop, 1ps.). (See US replacement patent number BE37516).

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

Pharmaceutically acceptable forms can be administered by controlled or sustained release methods. Pharmaceutical products with controlled release have the overall goal of improving drug therapy compared to therapy achieved by their counterparts without controlled release. In the ideal case, the use of an optimally developed drug with a controlled release with conservative treatment is characterized by the minimum amount of drug used to treat or eliminate the condition in the shortest possible time. The benefits of controlled release formulations include: 1) enhanced drug activity; 2) reduced frequency of dosing; 3) increased patient susceptibility; 4) use a smaller total amount of the drug; 5) reduction of local or systemic side effects; 6) minimization of drug accumulation; 7) reducing fluctuations in blood levels; 8) increasing the effectiveness of treatment; 9) decrease in potentiation or loss of drug activity; and 10) increase in the rate of suppression of diseases or conditions. (K1sh, Segpd-shch. Sop1go11eb K.eleagazhe Eo ^ hell Rogsh Eedp, 2 Tesypot1s RiIkIpd, Lapsayeg, Pa .: 2000).

Conventional dosage forms typically provide for the rapid or immediate release of a drug from a preparation. Depending on the pharmacology and pharmacokinetic characteristics of a drug, the use of conventional dosage forms can lead to wide variations in drug concentrations in the blood and other tissues of the patient. These fluctuations can affect a number of parameters, such as dose frequency, onset of action, duration of effectiveness, maintenance of therapeutic blood levels, toxicity, side effects, and the like. The controlled release formulations may advantageously be used to control the onset of action, duration of action, plasma levels within the therapeutic window and peak blood levels of the drug. In particular, controlled or sustained release dosage forms or preparations can be used to ensure that the maximum efficacy of the drug is achieved while minimizing potential negative effects and safety concerns that may occur due to an inadequate dose of the drug (ie acting at a level below the minimum therapeutic levels) and exceeding the level of toxicity for the drug.

- 4 009949

Most controlled-release drugs are designed for the initial release of a quantity of a drug (active ingredient) that quickly causes the desired therapeutic effect, and a gradual and continuous release of other quantities of the drug to maintain this level of therapeutic or prophylactic effect over a long period of time. To maintain this 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 the drug that is metabolized and excreted from the body. The controlled release of the active ingredient can be stimulated by various conditions including, but not limited to, pH, ionic strength, osmotic pressure, temperature, enzymes, water, and other physiological conditions or compounds.

For use with solvates, polymorphs, and compositions of the invention, various known dosage forms, formulations, and devices with controlled or sustained release can be adapted. Examples include, but are not limited to, examples described in US Pat. No. 3,845,770; 3,916,899; 3536809; 3598123; 4008719; 5674533; 5059595; 5591767; 5,120,548; 5073543; 5639476; 5354556; 5,733,566 and 6365185 B1; each of which is incorporated herein by reference. These dosage forms can be used to provide slow or controlled release of one or more active ingredients using, for example, hydroxypropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems (such as ΘΚΌ8® (Αίζα Sogrogog, MoiShat Υίο. SaIG. I8A) ), multi-layer coatings, microparticles, liposomes or microspheres, or combinations thereof, to provide the desired release profile in varying proportions. In addition, ion-exchange materials can be used to obtain immobilized, absorbed polymorphs, and thus the implementation of controlled drug delivery. Examples of specific anion exchangers include, but are not limited to, Duolit® A568 and Duolit® AP143 (Voight & Naak, 8epp Noche, PA. I8A).

One embodiment of the invention includes a unit dosage form that includes a pharmaceutically acceptable solvate, hydrate, dehydrate, anhydrous or amorphous form, and one or more pharmaceutically acceptable excipients or diluents, where the pharmaceutical composition, drug, or dosage form is manufactured for controlled release. . In specific dosage forms, an osmotic drug delivery system is used.

A specific and well-known osmotic drug delivery system is called OKO8® (Αίζα Sigrotiop, Moip1U U | e \\\ SaIG. I8A). This technology can be easily adapted to deliver the compounds and compositions of the invention. Various aspects of the technology are described in US Pat. No. 6,375,978 B1; 6368626 B1; 6342249 B1; 6333050 B2; 6287295 B1; 6283953 B1; 6270787 B1; 6245357 B1 and 6132420, each of which is incorporated herein by reference. Specific 0KO8® adaptations that can be used to administer the compounds and compositions of the invention include, but are not limited to, 0KO8® Pu8y-Pu11 ™ systems, Eilebay Rshy-Rii ™, Mishbauge Pu8y-Pu11 ™ and Rikey-Ziisk ™, all of which are well known. See, for example, 1Shr: // \\ l \ l \ '.aAa.sot. Additional 0KO8® systems that can be used for controlled oral delivery of the compounds and compositions of the invention include 0K08®-CT and B-0B08®. Ibid; see also E111egu T1te8, yo1. II, 188 II (Aka Sogrogayots).

Conventional oral dosage forms 0B08® are prepared by compressing the drug powder into a solid tablet, coating the tablet with cellulose derivatives to form a semipermeable membrane and then drilling holes in the coating (for example, with a laser). K1t, Sjetd -_) and, Soygoybe Belee5e Eokade Rott Oeidp, 231-238 (Tesiotk RiIeIdd, Lapsieg, Pa .: 2000). The advantage of such dosage forms is that the rate of drug delivery is not affected by physiological or experimental conditions. Even a drug with pH-dependent solubility can be delivered at a constant speed, regardless of the pH of the delivery medium. But due to the fact that these advantages are provided by the creation of osmotic pressure inside the dosage form after the introduction of conventional drug delivery systems, 0B08® cannot be used for effective drug delivery with low water solubility. In the same place p.234.

A specific dosage form according to the invention includes a cavity defined by the wall, a wall having an outlet opening formed or formed therein, wherein at least part of the wall is semipermeable; an expandable layer located inside the cavity, remote from the outlet orifice and connected with the semi-permeable wall part by means of a liquid; a drug layer in a dry or substantially dry state, placed in this cavity near the outlet and in direct or indirect contact with an expandable layer, and a flow activating layer located between the inner wall surface and at least the outer surface of the drug layer located in the cavity where

- 5 009949 drug layer includes a polymorph or its solvate, hydrate, dehydrate, anhydrous or amorphous form. See US Patent No. 6,368,626, which is incorporated herein in its entirety by reference.

Another specific dosage form of the invention includes a cavity defined by the wall, a wall having an outlet opening formed or formed therein, wherein at least part of the wall is semipermeable; an expandable layer located inside the cavity, remote from the outlet orifice and connected with the semi-permeable wall part by means of a liquid; a layer of the drug placed in this cavity near the outlet and in direct or indirect contact with the expandable layer; a drug layer comprising the composition of the liquid active agent absorbed into the porous particles, the porous particles adapted to resist the pressing forces to form a compressed drug layer without significantly isolating the composition of the liquid active agent, and the dosage form optionally has a placebo layer between the exit orifice and drug layer, where the drug layer includes a polymorph or its solvate, hydrate, dehydrate, anhydrous and and an amorphous form. See US Patent No. 6,342,249, which is incorporated herein in its entirety by reference.

In another embodiment, the pharmaceutical composition or drug comprises a mixture of a novel form of modafinil of the present invention (for example, a polymorph or a solvate) and racemic modafinil. This embodiment can be used, for example, as a controlled, continuous, or sustained release dosage form. In another embodiment, the sustained release dosage form includes racemic modafinil and the polymorph or solvate of the present invention.

In another embodiment, the pharmaceutical composition or drug has a modified release profile of one or more components from racemic modafinil, B - (-) - modafinil and 8 - (+) - modafinil. The modified release profile may include, for example, two or more plasma concentration peaks, such as a double release profile. Such a modified release profile can help, for example, treat a patient with a composition or drug that suffers a loss of wakefulness in the afternoon. A second “splash” or release of ΑΡΙ at least 2, 3, 4, 5, or 6 hours after administration may help overcome this effect. In another embodiment, a pharmaceutical composition or drug can be applied, which includes a small loading dose released immediately after administration, followed by a release of проф over a profile of approximately zero order over the next 2, 3, 4, 5, or 6 hours. peak plasma levels can be reached at around noon.

In another embodiment, the pharmaceutical composition or drug having a modified modafinil release profile may include K .-- (-) modafinil and 8 - (+) - modafinil, where K. - (-) - modafinil provides an initial boost (initial WITH _max , due to B - (-) - modafinil) plasma concentrations and 8 - (+) - modafinil provides a delayed increase (subsequent C ,,,., ·. due to 8 - (+) - modafinil) plasma concentrations. Slow rise in C _max due to 8 - (+) - modafinil, maybe 2, 3, 4, 5, 6 or more hours after the initial increase in C _max , due to K .- (-) - modafinil. In another embodiment, the delayed With _t ,,, · is approximately equal to the initial C _t ,,, ·. In another embodiment, the delayed With _t ,,, · more than the initial C _max . In another embodiment, the delayed With _max less than initial C ' _t ,,, ·. In another embodiment, the delayed C ' _t ,,, · due to racemic modafinil instead of 8 - (+) - modafinil. In another embodiment, the delayed Sta, due to K .- (-) - modafinil instead of 8 - (+) - modafinil. In another embodiment, the initial With _max due to racemic modafinil instead of K .- (-) - modafinil. In another embodiment, the initial With _max due to 8 - (+) - modafinil instead of K .- (-) - modafinil. In another embodiment, the modified release profile has 3, 4, 5, or more “splashes” of plasma concentration.

In another embodiment, the pharmaceutical composition or drug has a modified modafinil release profile when one or more of the components from racemic modafinil, K .- (-) - modafinil or 8 - (+) - modafinil are present in the form of a solvate or polymorph.

In another embodiment, the pharmaceutical composition or drug has a modified release profile when B - (-) - modafinil is used in an oral formulation. Such a composition can minimize the first-pass metabolism of modafinil to the sulfone. In another embodiment, the pharmaceutical composition or drug has a modified release profile when racemic modafinil is used in an oral formulation. In another embodiment, the pharmaceutical composition or drug has a modified release profile when 8 - (+) - modafinil is administered orally

- 6 009949 preparation. In another embodiment, the pharmaceutical composition or drug has a modified release profile when racemic modafinil and K .- (-) - modafinil are used in an oral formulation. In another embodiment, the pharmaceutical composition or drug has a modified release profile when racemic modafinil and 8 - (+) - modafinil are used in an oral formulation. In another embodiment, the pharmaceutical composition or drug has a modified release profile when 8 - (+) - modafinil and K. - (-) - modafinil is used in an oral formulation. In another embodiment, the pharmaceutical composition or drug has a modified release profile when the racemic modafinil, 8 - (+) - modafinil, and K. - (-) - modafinil are used in the oral formulation.

In another embodiment, the pharmaceutical composition or drug having a modified modafinil release profile is administered transdermally. Such transdermal (ΤΏ) delivery may prevent first-pass metabolism. In addition, a pill-patch strategy can be applied in which only a fraction of the daily dose is delivered through the skin to provide basic systemic levels to which oral dose therapy is added in order to provide a wakeful effect.

Excipients used in pharmaceutical compositions and drugs may be solid, semi-solid, liquid, or combinations thereof. Preferably, the excipients are solid. Compositions and drugs of the invention containing excipients can be obtained by a known pharmacy technique, which includes mixing the excipient with ΑΡΙ or a therapeutic agent. The pharmaceutical composition or drug of the invention contains the required amount of ΑΡΙ per standard dose and, if it is intended for oral administration, may be in the form of, for example, a tablet, small capsule, pill, hard or soft capsule, pellet, starch capsule, metered powder, granules , suspension, elixir, dispersion, liquid or any other form sufficiently adapted for such administration. If the composition is intended for parenteral administration, it may be in the form of, for example, a suspension or a transdermal patch. If the composition is intended for rectal administration, it may be in the form of, for example, a suppository. Currently preferred are oral dosage forms that are discrete unit doses, each containing a predetermined amount of, such as tablets or capsules.

The following are non-limiting examples of excipients that can be used to prepare pharmaceutical compositions or medicaments of the invention.

The pharmaceutical compositions and medicaments of the invention optionally include one or more pharmaceutically acceptable carriers or diluents as excipients. Suitable carriers or diluents illustratively include, but are not limited to, listed, either individually or in combination, lactose, including anhydrous lactose and lactose monohydrate; starches, including directly compressible starch and hydrolyzed starches (for example, Cetila ™ and Eshbeh ™); mannitol; sorbitol; xylitol; dextrose (e.g., Ceto8e ™ 2000) and dextrose monohydrate; calcium hydrophosphate dihydrate; sucrose-based diluents; confectionery sugar; calcium sulfate monohydrate; calcium sulfate dihydrate; granulated calcium lactate trihydrate; dextrates; inositol, hydrolyzed cereal solids; amylose; cellulose, including microcrystalline cellulose, alpha cellulose, and amorphous cellulose from food grade sources (for example, C. y. 1), powdered cellulose, hydroxypropyl cellulose (LDC), and hydroxypropyl methyl cellulose (HPMC); calcium carbonate; glycine; bentonite; block copolymers; polyvinylpyrrolidone and the like. Such carriers or diluents, if present, constitute in total from about 5 to about 99%, preferably from about 10 to about 85%, and more preferably from about 20 to about 80% of the total weight of the composition. The selected carrier, carriers, diluent or diluents preferably exhibit suitable flow characteristics and compressibility when tablets are required.

Lactose, mannitol, sodium hydrogen phosphate, and microcrystalline cellulose (especially microcrystalline cellulose AVtseltl PH, such as Avtitsel PH 101), either individually or in combination, are the preferred diluents. These diluents are chemically compatible with ΑΡΕ. Extragranular microcrystalline cellulose (i.e., microcrystalline cellulose added to the granular composition) can be used to increase hardness (for tablets) and / or disintegration time. Lactose, especially lactose monohydrate, is particularly preferred. Lactose typically provides compositions having suitable release rates of выс. stability, flowability before pressing and / or drying properties at a relatively low cost of thinner. It provides a high-density substrate that helps compaction during granulation (when wet granulation is used) and, therefore, improves the flow properties of the mixture and the properties of the tablet.

Pharmaceutical compositions and medicaments of the invention optionally include one or more pharmaceutically acceptable disintegrating agents as excipients.

- 7 009949 ents, especially for drugs in the form of tablets. Suitable disintegrants include, but are not limited to, listed, either individually or in combination, starches, including sodium starch glycolate (for example, Expro! Ab ™ or Rep. UX1) and pre-gelatinized corn starch (for example, Iylyupa ™ 1551 about £ Ναΐίοηαΐ 81atsy apb Syet1sa1 Sotrapu, Ilyupa1 ™ 1550, apb So1osogp ™ 1500), clays (for example, Uedit ™ OU about £ K.T.T. sodium salt carboxymethylcellulose, croscarmellose sodium (for example, Ls-O1-8o1 ™ o £ EMC), alginates, crospovidone, and gums, such as agar, locust bean gum, locust bean gum, karaya gum, pectin, and tragacanth gum.

Disintegrants may be added at any suitable stage during the preparation of the composition, especially before granulation or during the lubrication step before compression. Such disintegrating agents, if present, constitute in total from about 0.2 to about 30%, preferably from about 0.2 to about 10%, and more preferably from about 0.2 to about 5% of the total weight of the composition.

Croscarmellose sodium is a preferred disintegrant for disintegrating a tablet or capsule and, if present, is preferably from about 0.2 to about 10%, more preferably from about 0.2 to about 7% and even more preferably from about 0.2 to about 5% of the total weight of the composition. Croscarmellose sodium salt gives the best intragranular disintegration characteristics of the granular pharmaceutical compositions and drugs of the present invention.

The pharmaceutical compositions and medicaments of the invention optionally include one or more pharmaceutically acceptable binding agents or adhesives as excipients, especially for tablets. Such binding agents and adhesives preferably impart sufficient cohesion to the powder, which is tableted to allow normal processing operations, such as sizing, lubrication, pressing and packaging, but still allow the tablet to disintegrate and the compositions to be absorbed after ingestion.

Such binding agents may also prevent or inhibit the crystallization or recrystallization of AP1 of the present invention after the salt has dissolved in the solution. Suitable binding agents and adhesives include, but are not limited to, listed, either individually or in combination, acacia; tragacanth gum; sucrose; gelatin; glucose; starches, such as, but not limited to, pre-gelatinized starches (eg, Ialipa1 ™ 1511 apb Ialipa1 ™ 1500); cellulose, such as, but not limited to, methylcellulose and carmellose sodium (for example, Tuloke ™); alginic acid and alginic acid salts; magnesium aluminum silicate; PEG; carob gum; polysaccharide acids; bentonites; povidone, for example, povidone K-15, K-30 and K-29/32; polymethacrylates; HPMC; hydroxypropylcellulose (for example, K1is1 ™ o £ Ac. | Ia1op); and ethylcellulose (for example, Euroce1 ™ about £ 1st Eo \\ 'Syka1 Sotrapu). Such binding agents and / or adhesives, if present, constitute in total from about 0.5 to about 25%, preferably from about 0.75 to about 15%, and more preferably from about 1 to about 10% of the total weight of the pharmaceutical composition or drug facilities.

Many of the binding agents are polymers comprising the amide, ester, ether, alcohol or ketone groups, and as such are preferably incorporated into the pharmaceutical compositions and medicaments of the present invention. Polyvinylpyrrolidones, such as povidone K-30, are particularly preferred. Polymeric binding agents can have different molecular weights, degrees of crosslinking and polymer grades. Polymeric binding agents can also be copolymers, such as block copolymers, which contain mixtures of ethylene oxide and propylene oxide units. The change in the relationship of these links in a given polymer affects the properties and characteristics. Examples of block copolymers with variable composition of block units are poloxamer 188 and poloxamer 237 (BA8E CompoteNoop).

The pharmaceutical compositions and medicaments of the invention optionally include one or more pharmaceutically acceptable wetting agents as excipients. Such wetting agents are preferably selected to maintain AP1 in close association with water, a condition that is thought to increase the bioavailability of the composition.

Non-limiting examples of surfactants that can be used as wetting agents in pharmaceutical compositions and medicaments of the invention include citrate ammonium compounds, for example, benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride, dioctylsulfosuccinate sodium, polyoxyethylenealkylphenyl sulfates, sulfates, polyoxyethylene, phenylmethyl sulfonate, sulfonic acid nonoxynol 9, nonoxynol 10 and octoxynol 9, poloxamer (polyoxyethylene and polyoxypropylene block copolymers), polyoxyethylene glyceride s acids and oils, e.g., mono- and diglycerides, polyoxyethylene (8) caprylic / capric acids (e.g., about atako1 ™ £ SaIeGokke). polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor

- 8 009949 all over oil; polyoxyethylene alkyl ethers, for example, polyoxyethylene (20) cetostearyl ether, polyoxyethylene fatty acid esters, for example polyoxyethylene (40) stearate, polyoxyethylene sorbitan esters, for example polysorbate 20 and polysorbate 80 (for example, Tefti ™ 80 1C1), esters of polyoxyethylene sorbitan, for example, polysorbate 20 and polysorbate 80 (for example, Tefti ™ 80 1C1), esters of polyoxyethylene sorbitan, for example, polysorbate 20 and polysorbate 80 (for example, Tefti ™ 80 1C1) Propylene glycol laurate (for example, LAIGOD1USO1 ™ OH SayGo55e). sodium lauryl sulfate, fatty acids and their salts, for example oleic acid, sodium oleate and triethanolamine oleate, glyceryl esters of fatty acids, for example glyceryl monostearate, sorbitan esters, for example, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, and a graphist, and a graphite, monostry, monostate, monostrum, and monostrum; Such moisturizers, if present, constitute in total from about 0.25 to about 15%, preferably from about 0.4 to about 10%, and more preferably from about 0.5 to about 5% of the total weight of the pharmaceutical composition or drug.

Preferred wetting agents are anionic surfactants. A particularly preferred wetting agent is sodium lauryl sulfate. Lauryl sulfate, if present, is from about 0.25 to about 7%, more preferably from about 0.4 to about 4%, and even more preferably from about 0.5 to about 2% of the total weight of the pharmaceutical composition or drug.

The pharmaceutical compositions and medicaments of the invention optionally include one or more pharmaceutically acceptable lubricants (including anti-adhesion agents and / or glidants) as excipients. Suitable lubricants include, but are not limited to, listed, either individually or in combination, glycerylbegapat (for example, Sotrgyo1 ™ 888 OH OyeGokke); stearic acid and its salts, including magnesium, calcium and sodium stearates; hydrogenated vegetable oils (for example, 81! ex ™ OH AY1e), colloidal silicon dioxide; talc; waxes; boric acid; sodium benzoate; sodium acetate; sodium fumarate; sodium chloride; O-leucine; PEG (for example, Sago ^ ah ™ 4000 aib Sagoho \ gah ™ 6000 oG 1Pe Eo \ y Syet1s1 Sotrupa); sodium oleate; sodium lauryl sulfate and magnesium lauryl sulfate. Such lubricants, if present, comprise from about 0.1 to about 10%, preferably from about 0.2 to about 8%, and more preferably from about 0.25 to about 5% of the total weight of the pharmaceutical composition or drug.

Magnesium stearate is the preferred lubricant used, for example, to reduce friction between the equipment and the granulated mixture during pressing to obtain drugs in the form of tablets.

Suitable anti-sticking agents include, but are not limited to, talc, corn starch, EB-leucine, sodium lauryl sulfate, and metal stearates. Talc is the preferred anti-sticking agent or gliding agent used, for example, to reduce the sticking of a drug to equipment surfaces, as well as to reduce static in a mixture. Talc, if present, is from about 0.1 to about 10%, more preferably from about 0.25 to about 5%, and even more preferably from about 0.5 to about 2% of the total weight of the pharmaceutical composition or drug.

Slip agents can be used to promote the flowability of a powdered solid preparation. Suitable glidants include, but are not limited to, colloidal silicon dioxide, starch, talc, calcium phosphate, powdered cellulose, and magnesium trisilicate. Colloidal silicon dioxide is particularly preferred.

Other excipients, such as coloring agents, flavoring agents and sweeteners, are known in the pharmaceutical field and can be used in the pharmaceutical compositions and medicaments of the present invention. Tablets may be coated, for example with an enteric coating, or may be uncoated. Compositions of the invention may further include, for example, buffering agents.

Optionally, one or more agents may be used to provide effervescence as disintegrating agents and / or to enhance the organoleptic properties of the pharmaceutical compositions or drugs of the invention. When one or more effervescent agents are present in pharmaceutical compositions or drugs to facilitate the disintegration of dosage forms, they are preferably present in a total amount from about 30 to about 75% by weight and preferably from about 45 to about 70% by weight, for example, approximately 60% by weight of the pharmaceutical composition or drug.

According to a particularly preferred embodiment of the invention, an effervescent agent present in a solid dosage form in an amount less than that

- 9 009949 effective to promote the disintegration of the dosage form, provides increased dispersion ΑΡΙ in the aquatic environment. Without being bound by theory, it is believed that an effervescent agent is effective to accelerate dispersion of ΑΡΙ from the dosage form into the gastrointestinal tract, thereby further enhancing absorption and ensuring a rapid onset of therapeutic action. When an effervescent agent is present in a pharmaceutical composition or medicament of the invention to facilitate dispersion in the gastrointestinal tract, but not to increase disintegration, it is preferably present in an amount from about 1 to about 20% by weight, more preferably from about 2.5 to about 15 wt.% and even more preferably from about 5 to about 10 wt.% of the pharmaceutical composition or drug.

An “bubbling agent” is here an agent that includes one or more compounds that, acting together or separately, release gas when in contact with water. The gas emitted is usually oxygen or, most often, carbon dioxide. Preferred effervescent agents include an acid and a base, which react in the presence of water to release carbon dioxide gas. Preferably, the base comprises an alkali metal or alkaline earth metal carbonate or bicarbonate and the acid includes an aliphatic carboxylic acid.

Non-limiting examples of suitable bases as components of effervescent agents suitable for the invention include carbonate salts (eg, calcium carbonate), bicarbonate salts (eg, sodium bicarbonate), semi-carbonate salts, and mixtures thereof. Calcium carbonate is the preferred base.

Non-limiting examples of suitable acids as components of agents for imparting effervescence and / or solid acids suitable for the invention include citric acid, oxalic acid (0-, L- or / L-oxalic acid), malic acid, maleic acid, fumaric acid, adipic acid, succinic acid, acid anhydrides of such acids, acid salts of such acids, and mixtures thereof. Citric acid is the preferred acid.

In a preferred embodiment of the invention, in which 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 more preferably from about 1:10 to about 10: 1. In a further preferred embodiment of the invention, in which the effervescent agent includes an acid and a base, the ratio of acid to base is approximately stoichiometric.

Excipients that dissolve metal salts ΑΡΚ usually have both hydrophilic and hydrophobic regions, or are preferably amphiphilic or have amphiphilic regions. One type of amphiphilic or partially amphiphilic excipient includes an amphiphilic polymer or is an amphiphilic polymer. A particular amphiphilic polymer is polyalkylene glycol, which typically consists of ethylene glycol and / or propylene glycol subunits. Such polyalkylene glycols can be esterified in their terminal positions with a carboxylic acid, ester, carboxylic anhydride, or other suitable part. Examples of such excipients include poloxamers (symmetrical block copolymers of ethylene glycol and propylene glycol, for example, poloxamer 237), polyalkylene glycol esters of tocopherol and glycerol-glycol glycol glycol glycol glycol glycol glycol glycol glycol glycol glycol glycol glycol polystyrene block copolymers; (oils obtained by alcoholysis and esterification of polyalkylene glycol to form a mixture of mono-, di-, and triglycerides and mono- and diesters; for example, stearyl macrogol-32 glycerides). Such pharmaceutical compositions and drugs are preferably administered orally.

Pharmaceutical compositions and drugs of the present invention may include from about 10 to about 50 wt.%, From about 25 to about 50 wt.%, From about 30 to about 45 wt.% Or from about 30 to about 35 wt.% ΑΡΙ, from about 10 to about 50 wt.%, From about 25 to about 50 wt.%, From about 30 to about 45 wt.%, Or from about 30 to about 35 wt.% Excipient that inhibits crystallization, and from approximately 5 to about 50 wt.%, From about 10 to about 40 wt.%, From about 15 to about 35 wt.%, Or from about 30 to about 35 wt.% Binder. In one example, the weight ratio of ΑΡΙ to excipient that inhibits crystallization to binding agent is about 1: 1.

Solid dosage forms of the invention can be obtained in any suitable way, not limited to the methods described here.

An exemplary method includes (a) a stage of mixing a salt of the invention with one or more excipients to form a mixture, and (b) a stage of tableting or encapsulating the mixture to form tablets or capsules, respectively.

- 10 009949

In a preferred method, solid dosage forms are prepared by a method comprising (a) a step of mixing a salt ΑΡΙ of the invention with one or more excipients to form a mixture, (b) a stage of granulating the mixture to form a granulate and (c) a stage of tableting or encapsulating the mixture to form tablets or capsules, respectively. Stage (b) can be performed by any method of dry or wet granulation, known in this field, but the preferred stage is dry granulation. The salt of the present invention is preferably granulated to form particles from about 1 to about 100 microns, from about 5 to about 50 microns, or from about 10 to about 25 microns. Preferably add one or more diluents, one or more disintegrating agents and one or more binding agents, for example, at the mixing stage, you can optionally add a wetting agent, for example, at the granulation stage and, preferably, add one or more disintegrating agents after granulation, but before tabletting or encapsulation. The lubricant is preferably added before tabletting. Mixing and granulation can be carried out independently with low or high shear. Preferably, a method is selected in which a granulate is formed which is uniform in content ΑΡΙ, which is easily disintegrating, which is quite easily flowable, so that the weight change can be easily adjusted during capsule filling or tableting, and which is sufficiently dense in mass, so that the load can be processed in the selected equipment and individual doses filled into specific capsules or pellets for tableting.

In an alternative embodiment, solid dosage forms are prepared in a manner that includes a spray drying step in which ΑΡΙ is suspended with one or more excipients in one or more sprayed fluids, preferably non-proton (for example, non-aqueous or non-alcoholic) sprayed fluid, and then quickly spray dried over a stream of warm air.

The granulate or spray-dried powder obtained by any of the above illustrative methods can be pressed or molded to form tablets or encapsulate to form capsules. Conventional tableting and encapsulation methods known in the art can be used. When coated tablets are required, conventional coating methods are suitable.

Excipients for tablet compositions of the invention are preferably chosen to provide a disintegration time of less than about 30 minutes, preferably about 25 minutes or less, more preferably about 20 minutes or less, and even more preferably about 15 minutes or less in a standard disintegration analysis.

In another embodiment of the present invention, a pharmaceutical composition or drug can be obtained, including modafinil and an additional ΑΡΙ. Modafinil and supplemental ΑΡΙ may be included as a mixture or combination of active pharmaceutical ingredients. For example, the composition may include modafinil and caffeine as a combination. A composition comprising modafinil and caffeine can be used as a therapeutic agent for treating the same conditions for which modafinil is used. In such a composition, including modafinil and caffeine, caffeine can provide a quick release characteristic (small T _max relative to modafinil) for the dissolution profile, whereas modafinil causes a therapeutic effect that lasts for hours after administration. For example, T _max 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 of the T value _max modafinil Combination therapies include the administration of two or more ΑΡΙδ in the same preparation or in two or more co-administered drugs. ΑΡΙδ can be entered together at the same time or separately at specific time intervals.

In the following embodiment, the present invention proposes a new polymorph K - (-) - modafinil. In a specific embodiment, the present invention provides Forms III, IV, and V of K - (-) - modafinil. The present invention also provides a method for producing polymorph K - (-) - modafinil.

In the following embodiment of the present invention proposes a method of producing polymorph K - (-) - modafinil, including:

(a) provision of K - (-) - modafinil;

(b) crystallization of the polymorph K - (-) - modafinil from a suitable solvent.

In a further embodiment of the invention, the K - (-) - modafinil polymorph is crystallized from an organic solvent. In a specific embodiment, the organic solvent is ethanol. In another embodiment, a mixed solvent system is used to crystallize the polymorph K - (-) modafinil. Mixed solvent systems can be, for example, ethanol and isopropyl alcohol or ethyl acetate and ethanol. In a further embodiment, the crystallization in step (b) is completed by thermal recrystallization. In another embodiment, the crystallization in step (b) is completed by evaporation of the solvent.

- 11 009949

Applications of modafinil are well known in the art and include the treatment of narcolepsy associated with multiple sclerosis of fatigue, infertility, appetite disturbances, and hyperactivity disorder leading to attention disorder (ΆΌΗΌ), Parkinson's disease, incontinence, sleep apnea or myopathy. In another embodiment, one or more of the modafinil compositions of the present invention can be used in the treatment of one or more of the above conditions. The dose and administration for modafinil compositions of the present invention can be determined using standard methods in the art, but it is usually reduced to between about 50 and about 700 mg / day.

In another embodiment, a method is provided for treating a subject suffering from one or more of the above conditions or disorders, including, but not limited to, sleep disorders such as narcolepsy, where the method includes administering to the subject a therapeutically effective amount of Form III K - (- ) -modafinil, forms IV th - (-) modafinil or form V K - (-) - modafinil.

In another embodiment, the composition of the present invention can be administered to a mammal by injection. Injections include, but are not limited to, intravenous, subcutaneous, and intramuscular injections. In another embodiment, the composition of the present invention is made for injection to a mammal in need of therapeutic action.

Examples Analytical Methods

Differential scanning calorimetric analyzes (DSC) of the samples were carried out using a differential scanning calorimeter 01000 (TA PgDgitspK No. \ ν Ca ‡ 11e, IE, I.8.A.), which takes advantage of 0 \ U-8epe5. Augusta 1.0.0.78, Tietta1 AbuSacade CelesaGe 2.0 (2001 TA [p51ngspech5- \ utergu LBC). In addition, the software used for the analysis was Ishuyeg-8a1a8182000 yogi \\\\\\\\\\\\\\\\\\\\\\\\\\\\\\; Higher 3.1.0.40 (2001 TA I η 8 ί ΐ and η ΐ 8 \ a! Et bs).

For DSC analysis, the purge gas used was dry nitrogen, the reference material was an empty cup made of corrugated aluminum, and the sample was blown at 50 ml / min.

DSC sample analysis was performed by placing the modafinil sample in an aluminum cup with a lid for a corrugated cup. The initial temperature was usually 20 ° C with a heating rate of 10 ° C / min and the final temperature was 200 ° C. All of the above transitions (phase) DSC represent the temperature of the endothermic or exothermic transition at their respective peaks with an error of +/- 2 ° C, unless otherwise specified.

Thermogravimetric analysis (TGA) of the samples was carried out using a thermogravimetric analyzer 0500 (TA Iη8ί ^ iteηΐ8, № \ ν Sajle, IE, and.8.A.), which takes advantage of 0 \ -8g1е5, éguayup 1.0.0.78, T11gsha1 Abuasad K .eakee 2.0 (2001 TA Iη8ΐ ^ and ithΐΐ8- \ aΐe ^ bc). In addition, the analysis software used was шшуег5а1 Ап1у818 2000 yogi \\ MSW 95/98/2000 / KT, gug 3.1E; Higher 3.1.0.40 (2001 TA Iη8 ^ and iteηΐ8-Vаΐе ^ ЬЬС).

For the TGA experiments, the purge gas used was dry nitrogen, purging to achieve equilibrium was carried out at 40 ml / min мин ₂ , and the sample was purged at 60 ml / min. ₂ .

TGA was performed on the sample by placing the sample modafinil in a platinum cup. The initial temperature was typically 20 ° C at a heating rate of 10 ° C / min and the final temperature was 300 ° C.

Powder X-ray (RHYI) for samples was obtained using Ό / Max Yar1b, Sop1ae1 (K1daki / M8C, Tye \ ob1apb§, TX, E.8.A), which uses K.UT1 Karlb Sop1to1 as its control software. 8th ^ Ate, Shdaki Yar1b / HVI, Vegayup 1.0.0 (1999 Shdaki So). In addition, the software used for analysis was K.YuT K.ar1b11r1au koShat, ugayup 1/18 (K1daki / M8S) and 1AIE ΧΒΌ Raietp Rotosecpd, ugayupk 5.0 apb 6.0 (1995-2002, Maileyak Iaa, Shs).

For the analysis of RCXI, the parameters for data collection were as follows: the source was C with the line K y of 1.5406 A; the xy stage was manual; collimator size was 0.3 mm; the capillary tube (Syayek 8irreg Sotrapu, SHOK, MA, I.8.A.) had a GO (internal diameter) 0.3 mm; used the method of reflection; the power for the x-ray tube was 46 kV; the current for the x-ray tube was 40 mA; omega-axis oscillated in the range of 0-5 ° at a speed of 1 ° / min; The fi-axis was rotated at an angle of 360 ° at a speed of 2 ° / s; 0.3 mm collimator; the collection time was 60 minutes, the temperature was room temperature and the heater was not used. The sample was exposed to an x-ray source in a capillary made of glass rich in boron.

In addition, the analysis parameters were as follows: The 2-theta integration range was 2-60 °; The integration range was 0-360 °; the number of chi-segments was 1; the step size used was 0.02; the effectiveness of the integration was Subs; used normalization; dark count rates were 8; Omegasdvig was 180 and Hi and Fi shifts were 0.

DXR diffraction patterns were also obtained using a Vgikeg AX8 I8 I18 X-ray X-ray diffractometer. This tool was supplied with OJSCI8 ™ (Opeta1 Agea Iyytasyop Ieles1yup 8yuyet), detekto

- 12 009949 rum of Vgikeg AH8 H1-81at area at a distance of 15.05 cm according to the system calibration, a copper radiation source (Cu / K 1.54056 A), an automated xy-ζ stage and a collimator of 0.5 mm. The sample was pressed into a ball shape and set at the stage xy-ζ. The diffraction pattern was obtained under ambient conditions (25 ° C) with a determination of the power of 40 kV and 40 mA in the reflection method, while the sample remained in a steady state. The exposure time was changed and determined for each sample. The resulting diffractogram was subjected to a spatial transformation procedure to calculate the geometric pincushion distortion of the area detector, then integrated along the shea angle from -118.8 to -61.8 ° and 2-theta angle of 2.1-37 ° with a step size of 0.02 ° with the establishment normalization to normalize the drive.

The relative intensity of the peaks in the diffraction pattern is not necessarily a limitation of the CXMR pattern, since the intensity of the peaks may vary from sample to sample, for example, due to crystalline impurities. In addition, the angles of each peak can vary by approximately +/- 0.1 °, preferably +/- 0.05 °. The entire X-ray pattern or most of the picture peaks can also shift from about +/- 0.1 ° to about +/- 0.2 ° due to differences in calibration, adjustments and other changes from instrument to instrument and from operator to operator. All of the CECP peaks shown in the figures, in the examples and elsewhere here, are indicated with an error of approximately ± 0.1 ° 2 theta.

Based on the CCD data provided here, including the tables and figures, each composition of the present invention may be characterized by any one, any two, any three, any four, any five, any six, any seven, or any eight or more 2-theta peaks. . Any one, two, three, four, five, or six DSC phase transitions can also be used to characterize the compositions of the present invention. Any one, any two, three, four, five or six DSC transitions can also be used to characterize the compositions of the present invention. Various combinations of the peaks of RHRE and DSC phase transitions can also be used to characterize the compositions.

A thermal (with a heating table) microscopy was performed on a 2е188 Ahyur1ap 2 microscope equipped with a Meilet Tоébobo PP90 regulator. The heating table used was Me111et Tolebo PP82NT. All melting point determinations were performed by placing the sample on a microscope slide and coating it with a cover glass. The initial temperature was set at 30 ° C and the temperature was raised at a rate of 10 ° C / min. Melting was observed through a 5x microscope objective.

HPLC method (adapted from the Eopouap method! A1. Tyetareye Egid Mopioppd 25: 197-202): column: Ayes Susioi I 2000 B8P, 250x4.6 mm (Reg! № 411121), mobile phase A: 20 mM sodium phosphate, pH 3.0, B: mixture 70:30 mobile phase A: acetonitrile, flow rate: 1.0 ml / min (~ 1500 psi), flow program: gradient, test time: 35 min.

Detection: UV @ 225 nm.

Injection volume: 10 μl.

Column temperature: 30 +/- 1 ° C.

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

Washing the needle: acetonitrile.

Cleaning Solvent & Wash Fluid for Sealing Material: 90:10 (v / v) mixture water: acetonitrile.

Getting the mobile phase:

1. Preparation of 1M sodium dihydrogen phosphate: 120 g of sodium dihydrogen phosphate are dissolved in water and the volume is made up to 1000 ml, the solution is filtered.

2. Preparation of mobile phase A (20 mM sodium phosphate, pH 3.0): for each liter, 20 ml of 1M sodium phosphate is diluted to 1000 ml with water, the pH is adjusted to 3.0 with phosphoric acid.

3. Preparation of mobile phase B (70:30 (v / v) mixture 20 mM sodium phosphate, pH 3.0: acetonitrile): 700 ml of mobile phase A and 300 ml of acetonitrile are mixed to make each liter.

Sample receipt:

1. Samples are dissolved in a mixture of 90:10 (v / v) 20 mM sodium phosphate, pH 3.0: acetonitrile to an approximate concentration of 20 μg / ml.

Removing Raman Spectra

The sample was either left in a glass tube in which it was prepared, or an aliquot of the sample was transferred to a glass slide. A glass tube or slide was placed in the sample chamber. The measurements were carried out using the A1Ted ™ Echretiyu Pa et η system (A1TED ™ Eeschregschee Ratap, Tiegto-Solo1, 5225 Negome Roab. MabTsop, XVI 53711-4495) equipped with a laser source with 785 nm. The sample is manually adjusted to focus using a microscopic part of the device with a 10x objective magnification (unless otherwise indicated), thus directing the laser to the sample surface. The spectrum is taken using the parameters listed in Table A. (Time

- 13 009949 exposures and the number of exposures may vary; changes for parameters will be indicated for each spectrum removal).

Table A

Raman Spectra Removal Parameters

Parameter Used parameter value Exposure time (sec) 2.0 Number of exhibits ten Wavelength of a laser source (nm) 785 Laser power (%) 100 Hole shape Pinhole Hole size (µm) 100 Spectral region 104-3428 Diffraction Grid Position Separate Spectrum removal temperature (degrees C) 24.0

Removal of IR spectra.

The IR spectrum was obtained using χοχιΐδ TM 470-ΙΚ, Tietto-So1e1, 5225 Uétopa Coab, Mab15op. VI 53711-4495 and analyzed using control and analysis software::, Veg51op 6.0a, (C) Tietto-So1e1, 1995-2004.

Example 1. A mixture of 2: 1 (K) - (-) - modafinil: (8) - (+) - modafinil

Anhydrous ammonia gas was bubbled through a solution containing K-benzhydrylsulfinylmethyl ester (8.62 g, 0.0299 mol, mixture with a mass ratio of approximately 80:20 K-isomer: 8-isomer) in methanol, for 10 minutes. The pressure generated by the reaction causes sodium bicarbonate to flow back from the trap into the reaction mixture. The reaction is stopped and the precipitate is collected. The filtrate is concentrated under reduced pressure, thus obtaining a yellow solid residue (2.8 g). The yellow solid is passed through a column (silica gel, grade 9385, 230-400 mesh, 60 A) using a 3: 1 v / v mixture. ethyl acetate: hexane as eluent. The filtrates are then combined and concentrated under reduced pressure, thus obtaining a light yellow solid (most of the yellow coloration remains on the column). The solid is then recrystallized from ethanol by heating the mixture to boil it and then cooling it to room temperature, thus obtaining a mixture of 2: 1 K - (-) - modafinil: 8 - (+) - modafinil as a colorless solid (580 mg). Analysis ΡΧΌΚ and DSC were performed with the obtained solid and found that the solid is a pure form of K - (-) - modafinil and 8 - (+) - modafinil in approximately a 2: 1 ratio by weight.

A solid mixture of 2: 1 K - (-) - modafinil: the 8 - (+) - modafinil obtained above can be characterized by any one, any two, any three, any four, any five or any six or more peaks in FIG. 1, including, but not limited to, peaks at 8.97, 10.15, 12.87, 14.15, 15.13, 15.77, 18.19, and 20.39 ° 2-theta (obtained data without processing).

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

Example 2. Polymorphs K - (-) - modafinil

Investigated several polymorphs of K - (-) - modafinil, each characterized ΡΧΚΌ. FIG. 3, 6, and 9 show these diffraction patterns ΡΧΚΌ (data obtained without processing) of polymorphs of form III, form IV, and form V.

It has been proven that recrystallization is an effective way to obtain and detect polymorphs of K - (-) - modafinil. Suitable solvents for the crystallization of one or more polymorphs of K - (-) - modafinil include, but are not limited to, acetonitrile, dimethylformamide (DMF), methanol, methyl ethyl ketone, Ν-methylpyrrolidone, ethanol, isopropanol, isobutanol, formamide, isobutyl acetate, , 4-dioxane, tetrahydrofuran (THF), ethyl acetate, o-xylene, isopropyl acetate, dichloromethane, propylene glycol, acetic acid, water, acetone, nitromethane, toluene, and benzyl alcohol. Separate solvents or solvent mixtures can be used to crystallize one or more polymorphs of K - (-) - modafinil.

Form III K - (-) - modafinil.

Anhydrous ammonia gas was bubbled through a solution containing Kbenzhydrylsulfinylmethyl ester (8.3 g, 0.0288 mol) in methanol (75 ml) for 10 minutes. The reaction mixture was then stirred in an ice bath at 5 ° C for 1 hour and ammonia gas was bubbled through the solution for an additional 10 minutes. Stirring was continued for an additional 2 hours and ammonia was bubbled through the solution again for 10 minutes. After stirring for another hour, a precipitate formed (575 mg), which was collected. The filtrate is then her

- 14 009949 were concentrated using concentrated HC1 and the additional precipitate was collected. The solid residue is then recrystallized from 1: 1 v / v. ethanol and isopropyl alcohol by heating the mixture to boil it and then cooling it to room temperature, thus obtaining Form III K - (-) - modafinil as a colorless solid (1.01 g).

Form III K - (-) - modafinil can be characterized by any one, any two, any three, any four, any five or any six or more peaks in FIG. 3, including, but not limited to, peaks at 7.21, 10.37, 17.73, 19.23, 21.17, 21.77, and 23.21 ° 2-theta (K1daki киΩ. Data obtained without treatment).

DSC Form III K - (-) - modafinil, characterized in FIG. 3, found an endothermic phase transition at approximately 161 ° C.

A second batch of Form III K - (-) - modafinil was obtained for additional analysis using thermal microscopy and ΡΧΡΩ. Solubility data was also obtained. These data are discussed below.

The solubility of Form III K - (-) - modafinil was approximately 6.1–7.0 mg / ml. The solubility was measured in suspension in isopropyl acetate, stirred at 25 ° C. The measurement of the solubility was performed using HPLC. The solids from the solubility samples were dried under a nitrogen atmosphere and characterized by ΡΧΡΌ and thermal microscopy. During analyzes, no form conversion was observed.

Thermal (with a heating table) microscopy was used at a heating rate of 10 ° C / min to measure the melting point of Form III K - (-) - modafinil, which, as determined, was approximately 156-158 ° C.

Form III K - (-) - modafinil can be characterized by any one, any two, any three, any four, any five or any six or more peaks in FIG. 5, including, but not limited to, peaks at 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 (K1 daki ΡΧΡΩ, data with background subtracted).

Form IV K - (-) - modafinil.

Anhydrous ammonia gas was bubbled through a solution containing Kbenzhydrylsulfinylmethyl ester (8.3 g, 0.0288 mol) in methanol (75 ml) for 10 minutes. The reaction mixture was then stirred in an ice bath at 5 ° C for 1 hour and ammonia gas was bubbled through the solution for an additional 10 minutes. After stirring for another hour, a precipitate formed (422 mg), which was collected. The filtrate was then neutralized using concentrated HC1 and the additional precipitate formed was collected. A solid (3 g) was passed through a column (silica gel, grade 9385, 230-400 mesh, 60 A) using a 3: 1 v / v mixture. ethyl acetate and hexane as eluent. The column was then flushed with ethyl acetate (250 ml). The filtrates were combined and concentrated under reduced pressure, thus obtaining the form IV K - (-) - modafinil as a colorless solid (590 mg).

Form IV K - (-) - modafinil can be characterized by any one, any two, any three, any four, any five or any six or more peaks in FIG. 6, which include, but are not limited to, the peaks at 7.79, 10.31, 11.77, 16.49, 17.33, 19.47, and 23.5 ° 2-theta (K1 changes киΩ, data obtained without treatment).

DSC Form IV K - (-) - modafinil, characterized in FIG. 7, found an endothermic phase transition at approximately 147 ° C.

Received the second portion of form IV K - (-) - modafinil for additional analysis using thermal microscopy and ΡΧΡΌ. Solubility data is also obtained. These data are discussed below.

The solubility of Form IV K - (-) - modafinil was approximately 3.5-4.0 mg / ml. The solubility was measured in suspension in isopropyl acetate, stirred at 25 ° C. The measurement of the solubility was performed using HPLC. The solids from the solubility samples were dried under a nitrogen atmosphere and characterized by ΡΧΡΌ and thermal microscopy. During the analysis, no form transformation was observed.

Thermal (with a heating table) microscopy was used at a heating rate of 10 ° C / min to measure the melting point of form IV K - (-) - modafinil, which, as determined, was approximately 147-158 ° C.

Form IV K - (-) - modafinil can be characterized by any one, any two, any three, any four, any five or any six or more peaks in FIG. 8, including, but not limited to, peaks at 7.77, 10.33, 11.75, 16.53, 19.43, 19.89, 21.87, 23.49 and 26.69 ° 2 -teta (K1daki ΡΧΡΩ, data with background subtracted).

Form V K - (-) - modafinil.

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

- 15 009949

Form V I - (-) - modafinil can be characterized by any one, any two, any three, any four, any five or any six or more peaks in FIG. 9, including, but not limited to, peaks at 6.61, 10.39, 13.99, 16.49, 17.73, 19.03, 20.87, 22.31 and 25.99 ° 2 -teta (Cgdaki RHRE, the data obtained without processing).

Received the second portion of the form V K - (-) - modafinil for additional analysis using thermal microscopy and RHKE. Solubility data was also obtained. These data are discussed below.

The solubility of form V I - (-) - modafinil was approximately 2.1-2.6 mg / ml. The solubility was measured in suspension in isopropyl acetate, stirred at 25 ° C. The measurement of the solubility was performed using HPLC. The solids from the solubility samples were dried under a nitrogen atmosphere and characterized by RHRE and thermal microscopy. During the analysis, no form transformation was observed.

Thermal (with a heating table) microscopy was used at a heating rate of 10 ° C / min to measure the melting point of the form V I - (-) - modafinil, which, as determined, was approximately 159 ° C.

Form V I - (-) - modafinil can be characterized by any one, any two, any three, any four, any five or any six or more peaks in FIG. 10, including, but not limited to, peaks at 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 (Vgikeg RHRE, data obtained without processing).

Polymorphs B - (-) - modafinil are called forms III, IV and V based on the similarities found in their RHRE diffractograms with such diffractograms for the corresponding forms III, IV and V of racemic modafinil in US patent application No. 20020043207, published April 18, 2002.

Example 3. B - (-) - modafinil: 8 - (+) - modafinil, 2: 1

A solution containing B - (-) - modafinil (80.16 mg, 0.293 mmol) and racemic modafinil (20.04 mg, 0.0366 mmol) in ethanol (2 ml) was obtained. The mixture was heated to boil to dissolve all the solid and then cooled to room temperature (25 ° C). After keeping at room temperature for 15 minutes, the solution was kept at 5 ° C overnight. The solution was then decanted and the remaining crystals were dried under a stream of gaseous nitrogen and characterized using HPLC, RCTE, DSC and thermal microscopy.

The resulting crystals contained from about 63 to about 67% B - (-) modafinil, the rest of the crystals being 8 - (+) - modafinil. An HPLC analysis showed that the crystals were a 2: 1 phase containing two B - (-) - modafinil molecules for each one 8 - (+) modafinil molecule.

RHAV was carried out on a sample of a single crystal of B - (-) - modafinil: 8 - (+) - modafinil, 2: 1. Single crystal B - (-) - modafinil: 8 - (+) - modafinil, 2: 1, can be characterized by any one, any two, any three, any four, any five or any six or more peaks in FIG. 6, 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 ° 2-theta (Cgdaci RHCE, data obtained without processing).

DSC B - (-) - modafinil: 8 - (+) - modafinil, 2: 1, characterized in FIG. 12, found an endothermic transition at approximately 168 ° C.

Thermal (with a heating table) microscopy was used at a heating rate of 5 ° C / min to measure the melting point of B - (-) - modafinil: 8 - (+) - modafinil 2: 1, which, as determined, was approximately 160-166 ° WITH.

Example 4. Form IV K - (-) - modafinil

105.9 mg of B - (-) - modafinil was suspended in 1.5 ml of ethanol for 2 days. The liquid was filtered off and then dried over a stream of nitrogen gas. The resulting solid was analyzed by RHRE and it was determined that it is form IV B - (-) - modafinil (Fig. 13).

Form IV B - (-) - modafinil can be characterized by any one, any two, any three, any four, any five or any six or more peaks in FIG. 13, including, but not limited to, peaks at 7.64, 10.17, 11.61, 16.41, 19.34, 21.71, 22.77, and 23.36 ° 2-theta (Vgikeg RHRE, the data obtained without processing).

Form IV B - (-) - modafinil was also isolated by thermal recrystallization from ethanol and by slow evaporation of the ethanol solvent.

Example 5. Form V K - (-) - modafinil

107.7 mg of B - (-) - modafinil was suspended in 3 ml of ethyl acetate. The suspension was heated on a heating table (60 ° C) to dissolve the solid. Approximately one third to half of the heated solvent is evaporated with a stream of nitrogen gas. The mixture was then cooled to room temperature (25 ° C). A filter centrifuge was used to separate the solid from the liquid. The resulting solid was analyzed using CXA and DSC and found that it is a form of V B - (-) - modafinil (Fig. 14 and 15).

Form V B - (-) - modafinil can be characterized by any one, any two, any three,

- 16 009949 with any four, any five or any six or more peaks in FIG. 14, including, but not limited to, peaks at 6.52, 10.23, 13.93, 16.37, 17.61, 18.97, 20.74, 22.21, 23.36, and 25 , 90 ° 2-theta (Vgykeg ΡΧΚΌ, the data obtained without processing).

DSC analysis of the form V B - (-) - modafinil was performed. FIG. 15 shows the endothermic phase transition at approximately 161-162 (161.57) ° C.

Example 6. Solvate To - (-) - modafinil with chloroform

200 μl of chloroform was added to 30.5 mg of B - (-) - modafinil. The mixture was heated at 75 ° C for 30 minutes and then an additional 200 μl of chloroform was added. After an additional 30 minutes, the solid was completely dissolved. The sample was heated for an additional 2 hours. After heating, the sample was cooled to 5 ° at a rate of approximately 1 ° / min. After reaching 5 ° C, the sample was still a homogeneous liquid solution. The sample was then placed under a stream of nitrogen for one minute, thereby causing the onset of crystal formation. The sample was again incubated at 5 ° C and an additional solid was obtained. The sample was then dried under a stream of nitrogen and characterized by ΡΧΚΌ and TGA.

Analysis ΡΧΚΌ was performed for solvate B - (-) - modafinil with chloroform. The оль - (-) solvate with chloroform can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in FIG. 16, including, but not limited to, peaks at 8.97, 12.07, 14.20, 16.91, 17.49, 18.56, 20.87, 21.45, 23.11 and 25 , 24 ° 2-theta (Vgykeg ΡΧΚΌ, data obtained without processing).

Conducted TGA of the solvate of B - (-) - modafinil with chloroform. FIG. 17 shows that approximately 15% by weight was lost between approximately 25 and approximately 150 ° C.

Example 7. Solvate In - (-) - modafinil with chlorobenzene

In - (-) - modafinil (102.6 mg, 0.375 mmol) was suspended in chlorobenzene (5 ml) and the suspension was heated on a heating table at 60 ° C. The mixture was allowed to cool to approximately 25 ° C. The suspension was again heated and THF was added to dissolve all solids. The solution was then allowed to cool while being stored at room temperature for 4 days in a sealed vial. After storage, the resulting solid is collected by vacuum filtration and characterized by ΡΧΚΌ.

ΡΧΚΌ performed on the K - (-) - modafinil solvate with chlorobenzene. Solvate K - (-) - modafinil with chlorobenzene can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in FIG. 18, including, but not limited to, peaks at 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 (Vgikeg ΡΧΚΌ, data obtained without processing).

Example 8. Channel solvate of racemic modafinil with ethyl acetate

A channel solvate of racemic modafinil with ethyl acetate was obtained from a solution of 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, obtained by dissolving on a heating table at 60 ° C. After cooling, the solution was seeded with crushed cocrystals of K - (-) - modafinil: 1-hydroxy-2-naphthoic acid (see example 17 of application no.'Τ / υ82004 / 29013).

Analysis ΡΧΚΌ was performed with the channel solvate of racemic modafinil with ethyl acetate. A channel solvate of racemic modafinil with ethyl acetate can be characterized by any one, any two, any three, any four, any five, or any six or more peaks in FIG. 19, including, but not limited to, the peaks at 8.88, 14.09, 19.83, 21.59, 23.04 and 25.94 ° 2-theta (Vigkeg ΡΧΚΌ, data obtained without processing).

TGA of the channel solvate with racemic modafinil ethyl acetate was performed. FIG. 20 shows that approximately 3.6% by weight is lost between approximately 25 and approximately 150 ° C.

Example 9. Solvate K - (-) - modafinil with acetic acid

The K - (-) - modafinil solvate with acetic acid was obtained by grinding K - (-) - modafinil (105.5 mg) in 0.066 ml of acetic acid for 10 min in a stainless steel cylinder with a crusher / mixer U1d-b-Kind. The powder was then analyzed by DSC, TGA and ΡΧΚΌ.

Received ΡΧΚΌ solvate of P - (-) - modafinil with acetic acid. A solvate can be characterized by any one, any two, any three, any four, any five or any six or more peaks in FIG. 21, which include, but are not limited to, the peaks at 9.17, 10.20, 16.61, 17.59, 18.90, 21.11 and 24.11 ° 2-theta (Vgykeg, data obtained without treatment).

Conducted TGA solvate of P - (-) - modafinil with acetic acid. FIG. 22 shows that approximately 11% by weight is lost between approximately 25 and approximately 125 ° C.

Conducted DSC analysis of the P - (-) - modafinil solvate with acetic acid. FIG. 23 shows the endothermic transition at approximately 56 ° C.

- 17 009949

Claims (4)

CLAIM 1. A pharmaceutical composition comprising a mixture of 2: 1 K - (-) - modafinil: 3 - (+) - modafinil. 2. The pharmaceutical composition according to claim 1, where: (a) the composition is characterized by a powder x-ray, including peaks corresponding to degrees of 2-theta angles, where: (ί) said composition is a 2: 1 mixture of K - (-) - modafinil: 3 - (+) - modafinil and said radiograph includes peaks corresponding to 8.97, 10.15 and 20.39 °; (i) said composition is a 2: 1 mixture of K - (-) - modafinil: 3 - (+) - modafinil and said radiograph includes peaks corresponding to 8.97 and 18.19 °; (ΐϊϊ) said composition is a 2: 1 K - (-) - modafinil mixture: 3 - (+) - modafinil and said radiograph includes peaks corresponding to 10.15 and 20.39 °; (ίν) said composition is a 2: 1 K - (-) - modafinil mixture: 3 - (+) - modafinil and said radiograph includes peaks corresponding to 15.77 and 19.25 °; or (ν) said composition is a 2: 1 K - (-) - modafinil mixture: 3 - (+) - modafinil and said radiograph includes a peak corresponding to 8.97 °; or (b) the composition is characterized by a DSC thermogram, wherein said composition is a 2: 1 K - (-) - modafinil mixture: 3 - (+) - modafinil and said DSC thermogram includes an endothermic transition at approximately 167 ° C. 3. The composition of claim 2, wherein said composition further comprises a diluent, excipient, or carrier. 4. The method of obtaining the mixture 2: 1 K - (-) - modafinil: 3 - (+) - modafinil, including: (a) providing K - (-) - modafinil and a form of the δ-isomer of modafinil; and (b) crystallizing the mixture 2: 1 K - (-) - modafinil: 3 - (+) - modafinil from a solvent or mixture of solvents.