JP4842819B2 - Modafinil composition - Google Patents

Description

This application is related to US patent application Ser. No. 10 / 378,956 filed Mar. 3, 2003, US provisional application No. 60 / 463,962 filed Apr. 18, 2003, 2003 Patents filed on September 4, 2003, claiming the benefit of US Provisional Application No. 60 / 451,213 filed on May 28, and US Provisional Application No. 60 / 487,064 filed on July 11, 2003 This is a continuation-in-part of application No. PCT / US03 / 27772. Said US patent application Ser. No. 10 / 378,956 filed Mar. 3, 2003 claims the benefit of US Provisional Application No. 60 / 360,768 filed Mar. 1, 2002.

  This application is also a continuation-in-part of US patent application Ser. No. 10 / 660,202 filed Sep. 11, 2003 claiming the benefit of PCT / US03 / 27772 filed Sep. 4, 2003. . No. 10 / 660,202, filed Sep. 11, 2003, is also US provisional application No. 60 / 406,974, filed Aug. 30, 2002, U.S. application filed May 15, 2002. US patent application Ser. No. 10/232, filed Sep. 3, 2002, which claims the benefit of provisional application No. 60 / 380,288 and US Provisional Application No. 60 / 356,764 filed Feb. 15, 2002. Also claims the benefit of US Patent Application No. 10 / 637,829, filed August 8, 2003, which is a division of US Patent Application No. 10 / 295,995, filed November 18, 2002, which is a continuation of 589 To do. No. 10 / 660,202, filed Sep. 11, 2003, is also US provisional application No. 60 / 463,962, filed Apr. 18, 2003, US filed Jan. 31, 2003. Benefits of provisional application 60 / 444,315, US provisional application 60 / 439,282 filed January 10, 2003, and US provisional application 60 / 384,152 filed May 31, 2002 Is a continuation-in-part of US patent application Ser. No. 10 / 449,307, filed May 30, 2003. The aforementioned US patent application Ser. No. 10 / 660,202 filed on Sep. 11, 2003 is also a continuation-in-part of U.S. patent application Ser. No. 10 / 601,092 filed Jun. 20, 2003. The aforementioned US patent application 10 / 660,202 filed on September 11, 2003 is also referred to as US provisional application 60 / 451,213 filed February 28, 2003, US filed April 18, 2003. We also claim the benefit of provisional application 60 / 463,962 and US provisional application 60 / 487,064 filed July 11, 2003.

  This application also includes US Provisional Application No. 60 / 451,213 filed on Feb. 28, 2003, US Provisional Application No. 60 / 487,064 filed on Jul. 11, 2003, filed Sep. 4, 2003. Patent Application No. PCT / US03 / 27772, US Patent Application No. 10 / 660,202 filed on September 11, 2003, Patent Application No. PCT / US03 / 06662 filed on March 3, 2003, 2003 US Provisional Application No. 60 / 508,208 filed on October 2, US Provisional Application No. 60 / 542,752 filed on February 6, 2004, US Provisional Application No. 60 / filed on April 18, 2003 No. 463,962, US Patent Application No. 10 / 449,307 filed May 30, 2003, US Provisional Application No. 60 / 456,027, filed March 18, 2003, issued June 20, 2003 US Patent Application No. 10 / 601,092, Patent Application No. PCT / US03 / 19574 filed on June 20, 2003, and Patent Application No. PCT / US03 / 41273 filed on December 24, 2003. This is also a continuation-in-part of Patent Application No. PCT / US04 / 06288 filed on February 26, 2004.

This application also includes US Provisional Application No. 60 / 508,208, filed October 2, 2003, US Provisional Application No. 60 / 542,752, filed February 6, 2004, and filed April 6, 2004. US Provisional Application No. 60 / 560,411, filed May 21, 2004, US Provisional Application No. 60
US Provisional Application No. 60 / 579,176, filed June 12, 2004, US Provisional Application No. 60 / 581,992, filed June 22, 2004, July 9, 2004. We also claim the benefit of US Provisional Application No. 60 / 586,752 and US Provisional Application No. 60 / 588,236, filed July 15, 2004.

All of the above applications that benefit from them are incorporated herein by reference in their entirety.
The present invention relates to compositions containing APIs, pharmaceutical compositions comprising such APIs, and methods for their production.

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

  It would be advantageous to have new forms of these APIs with improved properties, especially as oral formulations. In particular, it is desirable to identify improved forms of API that exhibit significantly improved properties, including increased water solubility and stability. Furthermore, it is desirable to improve the processability, i.e. the manufacturing process of the pharmaceutical formulation. For example, the shape or tendency of API needle crystals can cause aggregation even in compositions where the API is mixed with other materials, resulting in a heterogeneous mixture. The needle-like form can also cause filtration problems (see, for example, Non-Patent Document 1). It is also desirable to increase the dissolution rate of pharmaceutical compositions containing API in water, increase the bioavailability of orally administered compositions, and provide a more rapid onset of therapeutic effect. . When administered to a subject, peak plasma concentrations are reached more quickly when compared to equivalent amounts of API in its currently known form, with longer lasting therapeutic plasma concentrations and higher overall exposure It is also desirable to have an API form.

  The API used to treat subjects with narcolepsy, modafinil, is virtually insoluble in water. Modafinil (CAS Registry Number: 68693-11-8) has the structure (I):

It is represented by Modafinil is a chiral molecule due to the chiral S = O group. Thus, modafinil exists as two isomers, namely R-(−)-modafinil and S-(+)-modafinil. It would be advantageous to have a new form of modafinil with improved properties, especially as an oral formulation. In particular, it is desirable to identify improved forms of modafinil that exhibit significantly increased water solubility and both chemical and morphological stability. It is also possible to increase the dissolution rate in water of pharmaceutical compositions containing APIs, increase the bioavailability of orally administered compositions, and provide a more rapid onset of therapeutic effect. desirable. When administered to a subject, the peak plasma concentration is reached more quickly when compared to its equivalent amount of API in its currently known form and / or the plasma concentration lasts longer at higher doses and higher overall It may also be desirable to have a form of API that has mechanical exposure.
Mirmehrabi et al. Pharm. Sci. Vol. 93, no. 7, pp. 1692-1700, 2004

[Summary of Invention]
It has now been found that modafinil co-crystals and solvates, many of which have different properties compared to the free form of the API.

  Accordingly, in the first aspect, the present invention provides that the co-crystal former is an ether, thioether, alcohol, thiol, aldehyde, ketone, thioketone, nitrate ester, phosphate ester, thiophosphate ester, ester, thioester, sulfate ester, Carboxylic acid, phosphonic acid, phosphinic acid, sulfonic acid, amide, primary amine, secondary amine, ammonia, tertiary amine, sp2 amine, thiocyanate, cyanamide, oxime, nitrile, diazo, organic halide, nitro, Provided is a co-crystal of modafinil which is S-heterocycle, thiophene, N-heterocycle, pyrrole, O-heterocycle, furan, epoxide, hydroxamic acid, imidazole or pyridine.

  The present invention further provides a pharmaceutical composition comprising a co-crystal of modafinil. Typically, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers, diluents or excipients. The pharmaceutical compositions of the present invention are described in further detail below.

In a further aspect, the present invention provides:
(A) providing modafinil;
(B) providing a co-crystal former compatible with the functional group of modafinil such that the co-crystal former and modafinil can form a co-crystal;
(C) grinding, heating, co-sublimation, co-melting, or in solution in contact with modafinil under crystallization conditions with a co-crystal former to form a solid phase; and (d) modafinil and co-crystal formation. A method for producing modafinil co-crystals comprising isolating a co-crystal comprising a body is provided.

In one aspect, the co-crystal former is ether, thioether, alcohol, thiol, aldehyde, ketone, thioketone, nitrate ester, phosphate ester, thiophosphate ester, ester, thioester, sulfate ester, carboxylic acid, phosphonic acid, phosphinic acid , Sulfonic acid, amide, primary amine, secondary amine, ammonia, tertiary amine, sp2 amine, thiocyanate, cyanamide, oxime, nitrile, diazo, organic halide, nitro, S-heterocycle, thiophene, N At least 1 selected from the group consisting of heterocycle, pyrrole, O-heterocycle, furan, epoxide, hydroxamic acid, imidazole or pyridine
Having functional groups.

  Embodiments of the present invention that can include, but are not limited to, co-crystals, polymorphs and solvates include racemic modafinil, enantiomerically pure modafinil (ie, R (-)-modafinil or S- ( +)-Modafinil), or concentrated modafinil (eg, between about 55 and about 99 percent ee). Similarly, co-crystal formers and solvent molecules (eg, in solvates) may also exist in racemic, enantiomerically pure, or concentrated form in embodiments of the invention.

In a further aspect, the present invention provides:
(A) providing modafinil;
(B) providing a co-crystal former compatible with the functional group of modafinil such that the co-crystal former and modafinil can form a co-crystal;
(C) grinding, heating, co-sublimation, co-melting, or in solution in contact with modafinil under crystallization conditions with a co-crystal former to form a solid phase; and (d) modafinil and co-crystal formation. Dissolution of modafinil in water, simulated gastric fluid (SGF) or simulated intestinal fluid (SIF) for use in a pharmaceutical composition or pharmaceutical comprising isolating a co-crystal comprising the body A method of increasing sex is provided.

In a further aspect, the present invention increases the water dissolution rate or the dissolution rate in simulated gastric fluid or simulated intestinal fluid or in a solvent or solvents,
(A) providing modafinil;
(B) providing a co-crystal former compatible with the functional group of modafinil such that the co-crystal former and modafinil can form a co-crystal;
(C) grinding, heating, co-sublimation, co-melting, or in solution in contact with modafinil under crystallization conditions with a co-crystal former to form a solid phase; and (d) modafinil and co-crystal formation. A method for modulating the solubility of modafinil comprising isolating a co-crystal comprising a body is provided.

In a further aspect, the present invention relates to increased AUC, reduced time to T _max , increased length of time that the concentration of modafinil is above 1/2 T _max , or C _max increases,
(A) providing modafinil;
(B) providing a co-crystal former compatible with the functional group of modafinil such that the co-crystal former and modafinil can form a co-crystal;
(C) grinding, heating, co-sublimation, co-melting, or in solution in contact with modafinil under crystallization conditions with a co-crystal former to form a solid phase; and (d) modafinil and co-crystal formation. A method of modulating the bioavailability of modafinil comprising isolating a co-crystal comprising the body is provided.

In a further aspect, the invention provides:
(A) providing modafinil;
(B) providing a co-crystal former compatible with the functional group of modafinil such that the co-crystal former and modafinil can form a co-crystal;
(C) grinding, heating, co-sublimation, co-melting, or in solution in contact with modafinil under crystallization conditions with a co-crystal former to form a solid phase; and (d) modafinil and co-crystal formation. A method for modulating the dose response of modafinil for use in a pharmaceutical composition or medicament comprising isolating a co-crystal comprising the body is provided.

In yet a further aspect, the present invention provides:
(A) providing modafinil;
(B) providing a co-crystal former compatible with the functional group of modafinil such that the co-crystal former and modafinil can form a co-crystal;
(C) grinding, heating, co-sublimation, co-melting, or in solution in contact with modafinil under crystallization conditions with a co-crystal former to form a solid phase; and (d) modafinil and co-crystal formation. A method is provided for improving the stability of modafinil (compared to a reference form, such as its free form), comprising isolating a co-crystal comprising the body.

In yet a further aspect, the present invention provides:
(A) providing modafinil;
(B) providing a co-crystal former compatible with the functional group of modafinil such that the co-crystal former and modafinil can form a co-crystal;
(C) grinding, heating, co-sublimation, co-melting, or in solution in contact with modafinil under crystallization conditions with a co-crystal former to form a solid phase; and (d) modafinil and co-crystal formation. A method for modifying modafinil polymorphs comprising isolating a co-crystal comprising a body is provided.

In yet a further aspect, the present invention thus provides:
(A) providing (i) modafinil and (ii) a co-crystal former compatible with the functional group of modafinil such that the co-crystal former and modafinil can form a co-crystal; and (b) modafinil and Each combination of co-crystal formers is
(I) grinding modafinil with a co-crystal former under crystallization conditions, heating, co-sublimation, co-melting, or in solution to form a solid phase; and (ii) modafinil and co-crystal formation. A method for screening a co-crystal compound comprising screening for a co-crystal of modafinil containing a co-crystal former by subjecting to a procedure comprising isolating the co-crystal comprising the body is provided. .

An alternative aspect is:
(A) providing (i) modafinil and (ii) a plurality of different co-crystal formers compatible with each functional group of modafinil such that each co-crystal former and modafinil can form a co-crystal; b) each combination of modafinil and a co-crystal former,
(I) grinding modafinil with a co-crystal former under crystallization conditions, heating, co-sublimation, co-melting, or in solution to form a solid phase; and (ii) modafinil and co-crystal formation. By applying a procedure comprising isolating a co-crystal comprising a body, the method is attracted to a method for screening a co-crystal compound comprising screening for a co-crystal of modafinil comprising a co-crystal former. .

  In a further aspect, the present invention provides a co-crystal composition, wherein the co-crystal comprises a co-crystal comprising modafinil and a co-crystal former. In further embodiments, the co-crystal has improved properties compared to the free form (including hydrates and solvates). In further embodiments, the improved property is: a group consisting of: increased solubility, increased dissolution, increased bioavailability, increased dose response, or other properties described herein. Selected from.

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

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

  In another aspect, the present invention provides a novel polymorph or co-crystal (Form VII) of racemic modafinil.

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

  Each of the methods of the present invention may comprise a further step (s) in which the modafinil co-crystals produced thereby are incorporated into the pharmaceutical composition.

  In another embodiment, the pharmaceutical composition comprises one or more modified release profiles of racemic modafinil, R-(−)-modafinil and S-(+)-modafinil. The modified release profile can include two or more maxima of plasma concentration, such as a dual release profile.

  The present invention further provides a pharmaceutical comprising a modafinil co-crystal and a method of making the same. Typically, the medicament further comprises one or more pharmaceutically acceptable carriers, diluents or excipients. The medicaments of the present invention are described in further detail below.

  Each of the methods of the present invention may comprise a further step (s) in which the modafinil co-crystals produced thereby are incorporated into the medicament.

In a further aspect of the invention, it is associated with narcolepsy, multiple sclerosis-related fatigue, infertility, eating disorders, attention deficit hyperactivity disorder (ADHD), Parkinson's disease, incontinence, sleep apnea or myopathy Provided is a method for treating a subject, preferably a human subject, suffering from excessive daytime sleepiness, wherein modafinil is an effective active pharmaceutical agent for the disorder. The method comprises administering to a subject a therapeutically effective amount of a co-crystal or solvate comprising modafinil or modafinil polymorph.
[Detailed Description of the Invention]
Modafinil structure contains one stereocenter and can therefore exist as a racemate, one of two pure isomers, or two isomer pairs in either ratio. The chemical name of racemic modafinil is (±) -2-[(diphenylmethyl) sulfinyl] acetamide. The racemic modafinil isomer pair is R-(-)-2-[(diphenylmethyl) sulfinyl] acetamide or R-(-)-modafinil, and S-(+)-2-[(diphenylmethyl) sulfinyl. Acetamide or S-(+)-modafinil.

As used herein and unless otherwise specified, the term “enantiomerically pure” encompasses compositions that are substantially enantiomerically pure, and, for example, Includes compositions with an enantiomeric excess of greater than or equal to about 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 percent. Enantiomeric excess is the percentage of enantiomer A minus the percentage of enantiomer B, ie the formula:
ee percent = 100 × ([R]-[S] / ([R] + [S]), where R is the mole of R-(−)-modafinil and S is S-(+)-modafinil. Is a mole,
Defined by

  As used herein, the term “modafinil” includes racemates, other mixtures of R- and S-isomers, and single enantiomers, but racemates, R— It may be specifically indicated as an isomer, S-isomer or a mixture of either R- and S-isomers.

  As used herein and unless otherwise specified, the term “racemic co-crystal” is a co-form consisting of an enantiomer, co-crystal former or equimolar mixture of both of modafinil. Refers to crystals. For example, a co-crystal comprising modafinil and a non-stereoisomeric co-crystal former is a “racemic co-crystal” only when an equimolar mixture of enantiomers of modafinil is present. Similarly, a co-crystal comprising modafinil and a stereoisomeric co-crystal former is “racemic co-crystal” only when an equimolar mixture of the enantiomer of the modafinil and the enantiomer of the co-crystal former is present. It is.

  As used herein and unless otherwise specified, the term “enantiomerically pure co-crystal” refers to a stereoisomeric enantiomeric excess of about 90 percent ee (enantiomeric Refers to a co-crystal composed of modafinil and a stereo- or non-stereoisomer co-crystal former which is greater than or equal to excess).

As used herein, the term “co-crystal” refers to characteristic physical features such as structure, melting point and heat of fusion, except where noted, the API may be liquid at room temperature. Means a crystalline substance composed of two or more unique solids at room temperature (22 ° C.). The co-crystal of the present invention comprises a co-crystal former that is hydrogen bonded to modafinil or a derivative thereof. The co-crystal former may be hydrogen bonded directly to modafinil or may be hydrogen bonded to additional molecules that are bound to modafinil. The additional molecule may be hydrogen bonded to modafinil or ionic bonded to modafinil. The additional molecule can also be a different API. Solvates of modafinil compounds further free of co-crystal formers are not co-crystals according to the present invention. A co-crystal, however, can include one or more solvate molecules in the crystal lattice. That is, a co-crystal solvate, or a co-crystal further comprising a solvent or a compound that is liquid at room temperature, is a co-crystal according to the present invention, but modafinil and one or more liquids (at room temperature). For the purposes of the present invention is not a co-crystal. Other molecular recognition modalities may also exist, including π stacking, guest-host complex formation and van der Waals interactions. Of the interactions listed above, hydrogen bonds are the key interactions in the formation of co-crystals, thereby forming a non-covalent bond between one hydrogen bond donor and the other hydrogen bond acceptor. Action (and the required interaction of the present invention). Hydrogen bonding can result in several different intermolecular configurations. For example, hydrogen bonding can result in the formation of dimer, linear or cyclic structures. These arrangements can further include extended (two-dimensional) hydrogen-bonded networks and isolated triplet elements. An alternative embodiment provides a co-crystal where the co-crystal former is a second API. In another embodiment, the co-crystal former is not an API.

  For the purposes of the present invention, the chemical and physical properties of modafinil in co-crystal form may be compared to a reference compound (which is a different form of modafinil). The reference compound may be in free form, or more specifically in free form, anhydrate or hydrate, or more specifically, for example, hemihydrate, monohydrate, dihydrate, trihydrate , Tetrahydrate, pentahydrate; or as a free form solvate. For example, the free form of modafinil reference compound co-crystallized with the co-crystal former can be the free form of modafinil. A reference compound may also be specified as crystalline or amorphous. A reference compound may also be designated as the known most stable polymorph of the specified form of the reference compound.

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

When modafinil and selected co-crystal formers form co-crystals, the resulting co-crystals are, among others: solubility, dissolution, bioavailability, stability, C _max , T _max , processability (compressible) It has been surprisingly found that it often results in improved properties of modafinil compared to the free form of modafinil, including longer lasting therapeutic plasma concentrations. For example, modafinil in co-crystal form is particularly advantageous due to the low solubility of modafinil in water. In addition, the properties of the co-crystal conferred on modafinil are also useful because modafinil bioavailability can be improved and the plasma and / or serum concentration of modafinil can be improved. This is particularly advantageous for orally administrable formulations. Further, modafinil dose response may be improved by increasing the maximum achievable response of modafinil and / or increasing efficacy, for example, by increasing biological activity per administered equivalent.

  Thus, in a first aspect, the present invention relates to modafinil and co-crystal formers such that modafinil and co-crystal formers can be co-crystallized from the solution phase under crystallization conditions or from the solid state, for example by grinding or heating. Pharmaceutical compositions comprising co-crystals of crystal formers are provided. In another aspect, ether, thioether, alcohol, thiol, aldehyde, ketone, thioketone, nitrate ester, phosphate ester, thiophosphate ester, ester, thioester, sulfate ester, carboxylic acid, phosphonic acid, phosphinic acid, sulfonic acid, amide , Primary amine, secondary amine, ammonia, tertiary amine, sp2 amine, thiocyanate, cyanamide, oxime, nitrile, diazo, organic halide, nitro, S-heterocycle, thiophene, N-heterocycle, pyrrole At least one functional group selected from the group consisting of, O-heterocycle, furan, epoxide, hydroxamic acid, imidazole and pyridine, or modafinil and co-crystal former co-crystallize from solution phase under crystallization conditions Officials in the tables of this specification that are possible Co-crystal former with a group.

  In another embodiment, the use of excess (1 molar equivalent or more for a 1: 1 cocrystal) cocrystal former can be used to drive the formation of stoichiometric cocrystals. For example, a co-crystal with a stoichiometry of 1: 1, 2: 1, or 1: 2 is a stoichiometric amount of a given co-crystal of 2, 3, 4, 5, 6, 7, 8, 9, It can be produced by adding a co-crystal former in an amount that is 10, 15, 20, 25, 50, 75, 100 times or more. Such excessive use of the co-crystal former to form the co-crystal can be used in solution or when the modafinil and the co-crystal former are ground to cause co-crystal formation.

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

In another embodiment of the present invention, the co-crystal comprises modafinil that forms a dimeric primary amide structure via a hydrogen bond with an R ² ₂ (8) motif. For example, J. et al. Bernstein, Polymorphism in Molecular Crystals , Oxford University Press, 2002, pp. 55-59, or M.I. C. Eter, Acct. Chem. Res. 1990, 23, 120, or M.M. C. Etter, J. Phys. Chem. 1991, 95, 4601. In such structures, the NH ₂ moiety can also participate in hydrogen bonding with a donor or acceptor moiety, eg, from a co-crystal former or an additional (third) molecule, and the C═O moiety is It may participate in hydrogen bonding with the co-crystal former or donor moiety from additional molecules. In a further embodiment, the dimeric primary amide structure (formed by two modafinil molecules) has 1, 2, 3 or 4 hydrogen bond donors (1, 2, 3 or 4 From the co-crystal former. In a further embodiment, the dimeric primary amide structure further comprises one or two hydrogen bond acceptors (from one or two co-crystal formers). In a further embodiment, the dimeric primary amide structure further comprises a hydrogen bond donor and acceptor combination. For example, the primary amide structure of the dimer has 1 hydrogen bond donor and 1 hydrogen bond acceptor, 1 hydrogen bond donor and 2 hydrogen bond acceptors, 2 hydrogen bonds It may further comprise a bond donor and one hydrogen bond acceptor, two hydrogen bond donors and two hydrogen bond acceptors, or three hydrogen bond donors and one hydrogen bond acceptor.

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

In one embodiment, the co-crystal former is selected from the co-crystal formers of Table I and Table II. In other embodiments, the co-crystal former of Table I is designated as a Class 1, Class 2 or Class 3 co-crystal former (see the column labeled “Class” in Table I). Table I lists multiple pK _a values for co-crystal former with a plurality of functionalities. Certain functional groups corresponding to certain of the _pK-a value that is readily apparent to those skilled in the art.

  In another embodiment, specific functional groups of the co-crystal former that interact with modafinil are specified (eg, the columns named “functionality” and “molecular structure” in Table I, and “co-crystal former” See the column in Table II, labeled “functional groups of”).

In another embodiment, the co-crystal comprises one or more co-crystal formers. For example, 2, 3, 4, 5 or more co-crystal formers can be incorporated into a co-crystal comprising modafinil. Two or more co-crystal formers and a co-crystal comprising an API are bonded together through hydrogen bonds. In one embodiment, the incorporated co-crystal former hydrogen bonds to the modafinil molecule. In another embodiment, the co-crystal former is hydrogen bonded to either the modafinil molecule or the incorporated co-crystal former.

  In each method of the present invention, modafinil needs to be contacted with a co-crystal former. This may require grinding the two solids together or melting one or both components and recrystallizing them. This may also require either solubilizing modafinil and adding a co-crystal former, or solubilizing the co-crystal former and adding modafinil. Crystallization conditions apply to modafinil and co-crystal formers. This may require changing the properties of the solution, such as pH or temperature, and may typically require concentration of the solute, typically by removing the solvent by drying the solution. Removal of the solvent results in a concentration of both modafinil and co-crystal former that increases over time to facilitate crystallization. For example, the co-crystal can be crystallized using evaporation, cooling or the addition of antisolvent. In another embodiment, a slurry comprising modafinil and a co-crystal former is used to form a co-crystal. Once a solid phase comprising any crystals is formed, it can be tested as described herein.

  The co-crystal obtained as a result of these process steps can be easily incorporated into a pharmaceutical composition (or medicament) by conventional methods. The pharmaceutical compositions and medicaments are generally discussed in more detail below and may further comprise a pharmaceutically acceptable diluent, excipient or carrier.

In a further aspect, the present invention provides:
(A) providing modafinil;
(B) providing a co-crystal former compatible with the functional group of modafinil such that the co-crystal former and modafinil can form a co-crystal;
(C) grinding, heating, co-sublimation, co-melting, or in solution in contact with modafinil under crystallization conditions with a co-crystal former to form a solid phase; and (d) modafinil and co-crystal formation. A method for producing modafinil co-crystals comprising isolating a co-crystal comprising a body is provided.

  In one aspect, the co-crystal former is ether, thioether, alcohol, thiol, aldehyde, ketone, thioketone, nitrate ester, phosphate ester, thiophosphate ester, ester, thioester, sulfate ester, carboxylic acid, phosphonic acid, phosphinic acid , Sulfonic acid, amide, primary amine, secondary amine, ammonia, tertiary amine, sp2 amine, thiocyanate, cyanamide, oxime, nitrile, diazo, organic halide, nitro, S-heterocycle, thiophene, N -Having at least one functional group selected from the group consisting of heterocycle, pyrrole, O-heterocycle, furan, epoxide, hydroxamic acid, imidazole or pyridine.

In a further aspect, the present invention provides:
(A) providing modafinil;
(B) providing a co-crystal former compatible with the functional group of modafinil such that the co-crystal former and modafinil can form a co-crystal;
(C) contacting modafinil with a co-crystal former under crystallization conditions, heating, co-sublimation, co-melting or in solution;
(D) isolating the co-crystal formed thereby; and (e) incorporating the co-crystal into a pharmaceutical composition or medicament, a method for producing the pharmaceutical composition or medicament. provide.

  In another embodiment, the method of forming a co-crystal includes the metastable form of modafinil, the co-crystal former, or both. Metastable forms can include, but are not limited to, polymorphs, solvates or hydrates of modafinil or co-crystal formers. While not being bound by theory, the incorporation of metastable forms can facilitate the formation of co-crystals through increasing thermodynamic driving forces.

  Assaying the solid phase for the presence of the co-crystal of modafinil and the co-crystal former can be performed by conventional methods known in the art. For example, it is convenient and customary to assess the presence of co-crystals using powder X-ray diffraction techniques. This can be influenced by comparing diffractograms of modafinil, crystal formers and putative co-crystals to establish whether a true co-crystal has been formed. Other techniques used in a similar manner include differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), infrared spectroscopy (IR) and Raman spectroscopy. Single crystal X-ray diffraction is particularly useful in identifying co-crystal structures.

In a further aspect, the present invention thus provides:
(A) providing (i) modafinil and (ii) a co-crystal former compatible with the functional group of modafinil such that the co-crystal former and modafinil can form a co-crystal; and (b) modafinil and Each combination of co-crystal formers is
(I) grinding modafinil with a co-crystal former under crystallization conditions, heating, co-sublimation, co-melting, or in solution to form a solid phase; and (ii) modafinil and co-crystal formation. A method for screening a co-crystal compound comprising screening for a co-crystal of modafinil containing a co-crystal former by subjecting to a procedure comprising isolating the co-crystal comprising the body is provided. .

An alternative aspect is:
(A) providing (i) modafinil, and (ii) a co-crystal former and a plurality of different co-crystal formers compatible with the functional group of modafinil such that modafinil can form a co-crystal; and (b ) Each combination of modafinil and a co-crystal former,
(I) grinding modafinil with a co-crystal former under crystallization conditions, heating, co-sublimation, co-melting, or in solution to form a solid phase; and (ii) modafinil and co-crystal formation. By applying a procedure comprising isolating a co-crystal comprising a body, the method is attracted to a method for screening a co-crystal compound comprising screening for a co-crystal of modafinil comprising a co-crystal former. .

  The present invention encompasses several co-crystals comprising modafinil and a carboxylic acid co-crystal former. Some examples include modafinil co-crystals comprising malonic acid, tartaric acid (L- and DL-), succinic acid, citric acid, fumaric acid, gentisic acid, oxalic acid and 1-hydroxy-2-naphthoic acid. To do. These examples represent mono, di and tricarboxylic acid co-crystal formers. Other acids, including but not limited to carboxylic acids, including but not limited to palmitic acid, orotic acid, and adipic acid may be used as co-crystal formers with modafinil. These co-crystal formers may contain 1, 2, 3 or more carboxylic acid functional groups. Co-crystal formers can also include non-carboxylic acid molecules that can include, but are not limited to, urea, saccharin and caffeine.

  In another embodiment, the co-crystal comprises modafinil and a carboxylic acid as a co-crystal former. In another embodiment, the carboxylic acid co-crystal former has 1, 2, 3 or more carboxylic acid functional groups.

  Several co-crystals can represent one or more specific interactions between modafinil and a carboxylic acid co-crystal former. For example, a carboxylic acid functional group can interact with a primary amide and / or S═O functional group of modafinil via a hydrogen bond. In another embodiment, the carboxylic acid functionality from the co-crystal former interacts with the primary amide functionality or S═O functionality of modafinil via a hydrogen bond. In another embodiment, the carboxylic acid functionality from the co-crystal former interacts with the outer surface of the modafinil amide dimer via a hydrogen bond. In another embodiment, the carboxylic acid functionality from the co-crystal former interacts with the modafinil amide dimer and the S = O functionality via a hydrogen bond. In another embodiment, the carboxylic acid functionality from the co-crystal former interacts with the two amide dimers of modafinil via hydrogen bonds.

  Modafinil and several co-crystal formers of the present invention have one or more chiral centers and can exist in a variety of stereoisomeric configurations. As a result of these chiral centers, modafinil and several co-crystal formers of the present invention exist as racemates, mixtures of enantiomers and individual enantiomers, and mixtures of diastereomers and diastereomers . For example, all such racemates, enantiomers and diastereomers, including cis- and trans-isomers, R- and S-enantiomers, and (D)-and (L) -isomers are Within the scope of the invention. The co-crystals of the present invention can include isomers of either modafinil or co-crystal formers or both. Modafinil and co-crystal former isomers can include, but are not limited to, stereoisomers such as enantiomers and diastereomers. In one embodiment, the co-crystal may comprise racemic modafinil and / or a co-crystal former. In another embodiment, the co-crystal may comprise enantiomerically pure R- or S-modafinil and / or a co-crystal former. In another embodiment, the co-crystals of the present invention have about 1 percent, 2 percent, 3 percent, 4 percent, 5 percent, 10 percent, 15 percent, 20 percent, 25 percent, 30 percent, 35 percent, 40 percent, 45 percent. Percent, 50 percent, 55 percent, 60 percent, 65 percent, 70 percent, 75 percent, 80 percent, 85 percent, 90 percent, 95 percent, 96 percent, 97 percent, 98 percent, 99 percent, 99 percent or more or any Modafinil or co-crystal formers with an enantiomeric excess of intermediate values of Some non-limiting examples of stereoisomeric co-crystal formers include tartaric acid and malic acid. In another embodiment, the polymorph or solvate of the present invention is about 1 percent, 2 percent, 3 percent, 4 percent, 5 percent, 10 percent, 15 percent, 20 percent, 25 percent, 30 percent, 35 percent, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99% Modafinil with an enantiomeric excess of these or any intermediate values may be included.

“Concentrated” modafinil of the present invention is present in an amount greater than or equal to about 5, 6, 7, 8, 9 or 10 weight percent and less than or equal to about 90, 91, 92, 93, 94 or 95 weight percent. It comprises both R-(-)-and S-(+)-isomers of modafinil. For example, a composition comprising 67 weight percent R-(-)-modafinil and 33 weight percent S-(+)-modafinil is a concentrated modafinil composition. In one such example, the composition is not racemic or enantiomerically pure. The term “enriched R-(−)-modafinil” is used to describe a composition of modafinil comprising 50 percent or more R-(−)-modafinil and less than 50 percent S-(+)-modafinil. Can be used. Similarly, the term “enriched S-(+)-modafinil” describes a composition of modafinil comprising 50 percent or more S-(+)-modafinil and less than 50 percent R-(−)-modafinil. Can be used to

  The terms “R-(−)-modafinil” and “S-(+)-modafinil” describe enriched modafinil, enantiomerically pure modafinil, or substantially enantiomerically pure modafinil. But may also specifically exclude concentrated modafinil, enantiomerically pure modafinil, and / or substantially enantiomerically pure modafinil.

  Co-crystals, solvates and polymorphs comprising an enantiomerically pure and / or enantiomerically enriched component (eg modafinil or a co-crystal former) are the corresponding co-forms comprising a racemic component. It can produce chemical and / or physical properties that are regulated with respect to that of the crystal. For example, the modafinil: malonic acid co-crystal from Example 1 comprises racemic modafinil. Enantiomerically pure R-(-)-modafinil: malonic acid is included within the scope of the present invention. Similarly, enantiomerically pure S-(+)-modafinil: malonic acid is included within the scope of the present invention. A co-crystal comprising an enantiomerically pure component can give rise to, for example, modulation of activity, bioavailability or solubility with respect to the corresponding co-crystal comprising a racemic component. As an example, the co-crystal R-(−)-modafinil: malonic acid may have controlled properties compared to the racemic modafinil: malonic acid co-crystal.

  Modafinil polymorphs and solvates are also prepared using the racemic modafinil of the present invention, enantiomerically pure modafinil, or any mixture of R-(−)-and S-(+)-modafinil. Can do.

  In another aspect, the invention provides a pharmaceutical composition comprising a co-crystal comprising enantiomerically pure modafinil and / or a co-crystal former, wherein bioavailability is modulated with respect to the racemic co-crystal. Products or pharmaceuticals. In another embodiment, the invention provides a pharmaceutical composition or medicament comprising a co-crystal comprising enantiomerically pure modafinil and / or a co-crystal former, the activity of which is modulated with respect to the racemic co-crystal. Include. In another embodiment, the present invention provides a pharmaceutical composition or medicament comprising a co-crystal comprising enantiomerically pure modafinil and / or a co-crystal former, the solubility being modulated with respect to the racemic co-crystal. Is included.

In another embodiment, the pharmaceutical composition or medicament may be formulated to contain modafinil in co-crystal form as micronized or nano-sized particles. More specifically, another embodiment combines the processing of pure modafinil into a co-crystal form with a controlled particle size creation method for manipulation into pharmaceutical dosage forms. This embodiment combines the two processing stages into a single stage through techniques that can include, but are not limited to, grinding, alloying or sintering (ie, heating the powder mixture). The coupling of these steps may be difficult to isolate in some cases (eg, amorphous, chemically or physically unstable) and bulk drug required for the formulation must be isolated and stored. Overcoming the serious limitation of having to.
Modulation of solubility In a further aspect, the present invention provides:
(A) providing modafinil;
(B) providing a co-crystal former compatible with the functional group of modafinil such that the co-crystal former and modafinil can form a co-crystal;
(C) grinding, heating, co-sublimation, co-melting, or in solution in contact with modafinil under crystallization conditions with a co-crystal former to form a solid phase; and (d) modafinil and co-crystal formation. Dissolution of modafinil in water, simulated gastric fluid (SGF) or simulated intestinal fluid (SIF) for use in a pharmaceutical composition or medicament comprising isolating a co-crystal comprising the body A method of increasing sex is provided.

  In one embodiment, the solubility of modafinil is at least 1.1, 1.2, 1.3, 1.5, 2.0, 5.0, 10. in water soluble (mg / mL) free form. It is adjusted to be increased by 0, 20.0, 25.0, 50.0, 75.0 or 100.0 times or more. Modafinil solubility is determined by chromatography (eg HPLC) or spectroscopic measurement of the amount of modafinil in a saturated solution such as UV spectroscopy, IR spectroscopy, Raman spectroscopy, quantitative mass spectrometry or gas chromatography. It can be measured by any conventional means such as

In another embodiment, the composition or medicament comprising the co-crystals, solvates and polymorphs of the present invention is a free form of modafinil as found in provigil [PROVIGIL] ^(R) (Cephalon, Inc.) You can compare. (See US Reissue Patent RE37,516) For example, the bioavailability of a composition or medicament of the present invention may be compared to that of PROVIGIL. As an aspect of the present invention, solubility can be determined by creating a co-crystal of a reference form (eg, crystalline or amorphous free form, hydrate or solvate), 2, 3, 4, 5, 7, It can be increased by 10, 15, 20, 25, 50, 75 or 100 times. Further water solubility can be measured in simulated gastric fluid (SGF) or simulated intestinal fluid (SIF) rather than water. The SGF of the present invention (undiluted) combines 1 g / L Triton X-100 and 2 g / L NaCl in water and adjusts the pH with 20 mM HCl to give a solution with a final pH = 1.7 Create by. SIF is 0.68% potassium dihydrogen phosphate, 1% pancreatin and sodium hydroxide with a final solution pH of 7.5. The pH of the solvent used is 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2. 1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.5, 4, 4.5, 5, 5. 5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5 or 12, or any value in between It can also be specified as the pH.

Examples of embodiments are: a co-crystal composition with water solubility at 37 ° C. and a pH of 7.0 that is increased at least 5 times above the reference form, in SGF that is increased at least 5 times above the reference form Co-crystal compositions with solubility, including co-crystal compositions with solubility in SIF increased at least 5 times over the reference form.
Modulating Solubility In another aspect of the invention, the dissolution profile of modafinil is modulated, thereby increasing the water dissolution rate, or the dissolution rate in simulated gastric fluid or simulated intestinal fluid, or solvent or solvents. The dissolution rate is the rate at which the API solid dissolves in the dissolution medium. For APIs (eg steroids) whose absorption rate is faster than the dissolution rate, the rate-limiting step of the absorption process is often dissolution rate. Due to the limited residence time at the absorption site, APIs that are not dissolved before they are removed from the absorption site of the intestine are considered useless. Thus, the dissolution rate has a significant impact on the performance of the API (poorly soluble). Due to this factor, the dissolution rate of API in solid dosage forms is an important routine quality control parameter used in the API manufacturing process. The following equation is an approximation:
Dissolution rate = KS (C _s -C)
Where K is the dissolution rate constant, S is the surface area, C _s is the apparent solubility, and C is the concentration of API in the dissolution medium.

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

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

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

In a further aspect, the invention thereby increases the rate of water dissolution, or simulated gastric fluid or simulated intestinal fluid, or dissolution rate in a solvent or solvents,
(A) providing modafinil;
(B) providing a co-crystal former compatible with the functional group of modafinil such that the co-crystal former and modafinil can form a co-crystal;
(C) grinding, heating, co-sublimation, co-melting, or contacting in solution under crystallization conditions with modafinil to form a solid phase; and (d) modafinil and co-crystal formation. A method for modulating the dissolution of modafinil comprising isolating a co-crystal comprising a body is provided.

Examples of the above embodiments are: a co-crystal composition with a dissolution rate in aqueous solution at 37 ° C. and a pH of 7.0 that is increased at least 5 times above the reference form, increased at least 5 times above the reference form A co-crystal composition with a dissolution rate in SIF that is increased by at least 5-fold over the reference form.
Bioavailability Modulation The methods of the present invention are used to make pharmaceutical modafinil formulations with greater solubility, dissolution and bioavailability. Bioavailability can be improved through increasing AUC, shortened time to T _max (time to reach peak serum concentration), or increased C _max . The present invention may result in higher plasma concentrations of modafinil when compared to the free form (reference form).

AUC is the area under the plot of API plasma concentration (not logarithm of concentration) versus time after API administration. The area is determined by the “trapezoidal rule” for convenience. That is, the data points are connected by straight line segments, a vertical line is drawn from the horizontal axis to each data point, and the sum of the areas of the triangles and trapezoids so constructed is calculated. When the last measured concentration _{(C n,} at time _{t n)} is not 0, AUC from _{t n} to infinite time is estimated by _C n _{/ k el.}

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

In a further aspect, the present invention relates to whether the AUC is increased, the time to T _max is shortened, or the length of time that the concentration of modafinil is above 1/2 T _max is increased. Or C _max is increased,
(A) providing modafinil;
(B) providing a co-crystal former compatible with the functional group of modafinil such that the co-crystal former and modafinil can form a co-crystal;
(C) grinding, heating, co-sublimation, co-melting, or in solution in contact with modafinil under crystallization conditions with a co-crystal former to form a solid phase; and (d) modafinil and co-crystal formation. A method of modulating the bioavailability of modafinil comprising isolating a co-crystal comprising the body is provided.

Examples of embodiments of the above: co-crystal compositions with a time as compared to the reference form to T _max that is increased at least 5% with time of the reference form to T _max is increased above a minimum 10% co A crystalline composition, a co-crystalline composition with a time to T _max increased by at least 15% above the reference form, a co-crystalline composition with a time to T _max increased by at least 20% above the reference form, co-crystal compositions with a T _max that is increased the reference form than at least 25% co-crystal compositions with a T _max that is increased the reference form than at least 30% is increased to the reference form exceeds a minimum 35% that co-crystal compositions with a T _max, co-crystal compositions with a T _max that is increased the reference form than at least 40% greater than the reference form minimum 5% involves AUC that is increased by co-crystal compositions, see At least 1 form Co-crystal composition with AUC increased by% over, co-crystal composition with AUC increased by at least 15% over the reference form, co-crystal composition with AUC increased by at least 20% over the reference form , Co-crystal composition with AUC increased by at least 25% above the reference form, co-crystal composition with AUC increased by at least 30% above the reference form, increased by at least 35% above the reference form A co-crystal composition with an AUC that is increased by at least 40% over the reference form. Other examples are included where the reference form is a crystal, the reference form is amorphous, or the reference form is an amorphous crystal of modafinil.
Dose response modulation In a further aspect, the invention provides:
(A) providing modafinil;
(B) providing a co-crystal former compatible with the functional group of modafinil such that the co-crystal former and modafinil can form a co-crystal;
(C) grinding, heating, co-sublimation, co-melting, or in solution in contact with modafinil under crystallization conditions with a co-crystal former to form a solid phase; and (d) modafinil and co-crystal formation. A method for modulating the dose response of modafinil for use in a pharmaceutical composition or medicament comprising isolating a co-crystal comprising the body is provided.

  The dose response is the quantitative relationship between the magnitude of the response and the dose that induces the response and can be measured by conventional means known in the art. The curve for the effect (as a dependent variable) on the dose (as an independent variable) for the API-cell line is the “dose response curve”. Typically, a dose response curve is the measured response to an API plotted against a given API (mg / kg) dose. A dose response curve can also be an AUC curve for a given API dose.

In one aspect of the invention, the co-crystals of the invention have an increased dose response curve or a more linear dose response curve than the corresponding reference compound.
Increased stability In yet a further aspect, the present invention provides:
(A) providing modafinil;
(B) providing a co-crystal former compatible with the functional group of modafinil such that the co-crystal former and modafinil can form a co-crystal;
(C) grinding, heating, co-sublimation, co-melting, or contacting in solution under crystallization conditions with modafinil to form a solid phase; and (d) modafinil and co-crystal formation. A method is provided for improving the stability of modafinil (compared to a reference form, such as its free form) comprising isolating a co-crystal comprising the body.

In a preferred embodiment, the compositions of the present invention, including formulations comprising modafinil co-crystals, solvates and modafinil, are stable and suitable for pharmaceutical use. Preferably, modafinil or a formulation thereof of the present invention is stable such that less than 0.2% of any degradant is formed when stored at 30 ° C. for 2 years. The term degradation product refers herein to the product (s) of a single type of chemical reaction. For example, if a hydrolysis event occurs that cleaves a molecule into two products, it can be considered as a single degradation product for purposes of the present invention. More preferably, when stored at 40 ° C. for 2 years, any one degradation product of less than 0.2% is formed. Alternatively, when stored at 30 ° C for 3 months, 0.2% or 0.15%, or less than 0.1% of any one degradation product is formed, or at 40 ° C 3 When stored for months, 0.2% or 0.15%, or less than 0.1% of any one degradation product is formed. In addition, or alternatively, when stored at 60 ° C. for 4 weeks, any one degradation product of 0.2% or 0.15% or less than 0.1% is formed. Relative humidity (RH) may be specified as ambient RH, 75% RH, or any single integer RH between 1 and 99%. In another embodiment, a single dose of the invention comprises less than 0.5%, 0.2% or 0.1% degradation product upon administration to a subject.
In yet a further aspect, the present invention provides:
(A) providing modafinil;
(B) providing a co-crystal former compatible with the functional group of modafinil such that the co-crystal former and modafinil can form a co-crystal;
(C) grinding, heating, co-sublimation, co-melting, or in solution in contact with modafinil under crystallization conditions with a co-crystal former to form a solid phase; and (d) modafinil and co-crystal formation. A method of modifying the form of modafinil comprising isolating a co-crystal comprising a body is provided.

  In one embodiment, the co-crystal comprises or consists of modafinil and a co-crystal former, where the interaction between the two, for example hydrogen bonding, is the corresponding interaction of Table III with the amino group of modafinil Occurs with the group to be. In a further embodiment, the co-crystal comprises modafinil and a co-crystal former of Table I or II. In one aspect of the present invention, a co-crystal having a hydrogen bond acceptor on a first molecule and a hydrogen bond donor on a second molecule, wherein the first and second molecules are a co-crystal former and modafinil, respectively. Or modafinil and co-crystal former respectively) are included in the present invention.

  A co-crystal may contain more than one chemical entity within its co-crystal structure. For example, the co-crystal can further include solvent molecules, water molecules, salts, and the like. In addition, the co-crystal is an API and two or more co-crystal formers, a co-crystal former and two or more APIs, two or more APIs, or two or more co-crystals. A formed body may be included.

As defined herein, a ternary co-crystal is composed of three distinct chemicals in stoichiometric ratios, each of which is solid at room temperature (except that the API may be liquid at room temperature). A co-crystal comprising an entity. In particular, the ternary co-crystal comprises three distinct chemical entities such as API: co-crystal former (1): co-crystal former (2), where the ratio of components is limited Although not, 1: 1: 1, 2: 1: 1, 2: 1: 2, 2: 1: 0.5, 2: 2: 1 and the like can be mentioned. Ternary co-crystals are also not limited to API (1): API (2): co-crystal former, API (1): API (2): API (3), and co-crystal former ( 1): Co-crystal former (2): Other combinations of ingredients that can mention co-crystal former (3) may also be included.

  In another embodiment, the present invention relates to modafinil and: malonic acid, glycolic acid, fumaric acid, tartaric acid, citric acid, succinic acid, gentisic acid, oxalic acid, 1-hydroxy-2-naphthoic acid, orotic acid, glutaric acid A co-crystal comprising one co-crystal former selected from the group consisting of L-tartaric acid, palmitic acid, L-proline, salicylic acid, lauric acid, L-malic acid and maleic acid.

  In a further aspect, the present invention provides the following co-crystals: modafinil: malonic acid, modafinil: glycolic acid, modafinil: maleic acid, modafinil: L-tartaric acid, modafinil: citric acid, modafinil: succinic acid, modafinil: DL- Tartaric acid, modafinil: fumaric acid (form I), modafinil: fumaric acid (form II), modafinil: gentisic acid, modafinil: oxalic acid, modafinil: 1-hydroxy-2-naphthoic acid, R-(-)-modafinil: malon Acid, OLE_LINK1R-(-)-modafinil: OLE_LINK1 succinic acid, R-(-)-modafinil: citric acid, R-(-)-modafinil: DL-tartaric acid, R-(-)-modafinil: 1-hydroxy-2 -Naphthoic acid, R-(-)-modafinil: orotic acid, R- ( ) -Modafinil: glutaric acid, R-(-)-modafinil: L-tartaric acid, R-(-)-modafinil: palmitic acid, R-(-)-modafinil: L-proline, R-(-)-modafinil: Salicylic acid, R-(-)-modafinil: lauric acid, R-(-)-modafinil: L-malic acid and R-(-)-modafinil: gentisic acid are provided.

  In another aspect, the present invention provides a novel polymorph or co-crystal of racemic modafinil (Form VII).

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

  The pharmaceutically acceptable co-crystal can be administered by controlled release or delayed release means. Controlled release pharmaceutical products have a common goal of improving drug therapy over that achieved by their uncontrolled release counterparts. Ideally, the use of an optimally designed controlled release formulation in medical treatment is characterized by the minimal drug substance used to cure or control the condition with a minimum amount of time. Advantages of controlled-release formulations are: 1) prolonged drug activity; 2) reduced dosing frequency; 3) increased patient compliance; 4) less total drug usage; 5) reduced local or systemic side effects 6) Minimization of drug accumulation; 7) Reduction in blood concentration fluctuations; 8) Improvement in treatment efficacy; 9) Increase in drug activity or reduction in loss; and 10) Increase in the rate of control of the disease or condition. Is included. (Kim, Cherng-ju, Controlled Release Dosage Form Design, 2 Technological 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 lead to wide variation in the concentration of the drug in the patient's blood and other tissues. These variations can affect a number of parameters such as dosing frequency, onset of action, duration of effectiveness, maintenance of therapeutic blood levels, toxicity, side effects, and the like. Advantageously, controlled release formulations may be used to control the onset of drug action, duration of action, plasma concentration within the therapeutic concentration range and peak blood concentration. In particular, the potential that can result from both underdosing the drug (ie, below the minimum therapeutic concentration) using a controlled or sustained release dosage form or formulation and exceeding the toxic concentration of the drug It may be ensured that maximum efficacy of the drug is achieved while minimizing adverse effects and safety concerns.

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

A variety of known controlled or sustained release dosage forms, formulations and devices can be adapted for use in the co-crystals and compositions of the invention. Examples include, but are not limited to, U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; No. 5,674,533; No. 5,059; No. 595; No. 5,591,767; No. 5,120,548; No. 5,073,543 5,639,476; 5,354,556; 5,733,566; and 6,365,185 B1, each of which is hereby incorporated by reference. Can be mentioned. Using these dosage forms, for example, to provide the desired release profile in variable proportions, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems ^(OROS (R) (Alza Such as Corporation, Mountain View, Calif.), Multi-layer coatings, microparticles, liposomes or microspheres, or combinations thereof may be used to provide delayed or controlled release of one or more active ingredients . In addition, ion exchange materials can be used to produce immobilized adsorbed co-crystals and thus achieve controlled delivery of the drug. Examples of specific anion exchangers include, but are not limited can be given ^Duolite (R) A568 and ^{Duolite (R) A143 (Rohm &} Haas, PA, USA Spring House).

  One aspect of the present invention is a pharmaceutically acceptable co-crystal, or a solvate, hydrate, dehydrate thereof, wherein the pharmaceutical composition, medicament or dosage form is formulated for controlled release. , Anhydrous or amorphous forms, and unit dosage forms comprising one or more pharmaceutically acceptable excipients or diluents. Certain dosage forms utilize osmotic drug delivery devices.

Specific and one known osmotic drug delivery device ^OROS (R) (Alza Corporation, Mountain View, California) called. This technique can be readily adapted for delivery of the compounds and compositions of the invention. Various aspects of the technology are described in US Pat. Nos. 6,375,978 B1; 6,368,626 B1; 6,342,249 B1; 6,333,050 B2; 6,287,295 B1; 6,283,953 B1; 6,270,787 B1; 6,245,357 B1; and 6,132,420 (Each of which is incorporated herein by reference). Specific adaptations of OROS ^(R) that can be used to administer the compounds and compositions of the present invention include, but are not limited to, OROS ^(R
) Push-Pull ^TM, it can be mentioned delayed (Delayed) Push-Pull ^TM, multilayer (Multi-Layer) Push-Pull TM and Push-Stick ^TM device, all of which are known. For example, http: // www. alza. com. Compound and additional OROS ^(R) device which can be used to control oral delivery of the compositions of the present ^invention include ^{OROS (R)} -CT and L-OROS ^(R). Above; Delivery Times, vol. See also II, II (Alza Corporation).

Conventional OROS ^(R) oral dosage forms, compressing the drug powder (e.g., a co-crystal) into a hard tablet, drill to form a semipermeable membrane coated tablets with a cellulose derivative, and thereafter the coating Create a hole with (for example, using a laser). Kim, Cherng-ju, Controlled Release Dosage Form Design, 231-238 (Technical Publishing, Lancaster, PA: 2000). The advantage of such dosage forms is that the rate of delivery of the drug 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 vehicle. However, because these advantages are provided by the formation of osmotic pressure within the dosage form after administration, conventional OROS ^(R) drug delivery device for delivering a drug with low water solubility effectively Cannot be used. 234 above. Because the co-crystals of the present invention can be much more soluble in water than modafinil itself, they are well suited for delivery to patients based on osmotic pressure. The present invention encompasses, however, integration into (pure modafinil eg free co-crystal former) and OROS ^(R) dosage form of mixtures of isomers and isomers conventional crystalline modafinil.

  One particular dosage form of the present invention is: a wall defining a cavity, the wall having an exit orifice formed or formable therein and at least a portion of the wall being semi-permeable; An inflatable layer disposed in a cavity away from the exit orifice and in liquid communication with the semipermeable portion of the wall; in a relationship adjacent to and in direct contact with the inflatable layer adjacent to the exit orifice A moisture-free or substantially moisture-free drug layer disposed in a cavity; and an inner surface of the wall and at least an outer surface of the drug layer disposed in the cavity Wherein the drug layer comprises a co-crystal, or a solvate, hydrate, dehydrate, anhydride or amorphous form thereof. See US Pat. No. 6,368,626, which is incorporated herein by reference in its entirety.

  Another specific dosage form of the present invention is: a wall defining a cavity, the wall having an exit orifice formed or formable therein and at least a portion of the wall being semi-permeable An inflatable layer disposed in a cavity away from the outlet orifice and in liquid communication with the semipermeable portion of the wall; a relationship adjacent to and in direct contact with the inflatable layer adjacent to the outlet orifice; A drug layer disposed in the cavity of the liquid; a formulation of the liquid active ingredient absorbed in the porous particles (the drug particle layer compressed without significant leaching of the liquid active ingredient formulation) The dosage form comprises a placebo layer between the exit orifice and the drug layer, optionally adapted to withstand a compressive force sufficient to form a Here, the formulation of the active ingredient is Crystal, or a solvate, hydrate, dehydrate, comprising an anhydrous form or amorphous. See US Pat. No. 6,342,249, which is hereby incorporated by reference in its entirety.

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

  In another embodiment, the pharmaceutical composition or medicament comprises one or more modified release profiles of racemic modafinil, R-(−)-modafinil and S-(+)-modafinil. . The modified release profile can include two or more maxima of plasma concentration, such as, for example, a dual release profile. Such a modified release profile may assist a patient treated with a composition or medicament of the present invention that experiences, for example, a loss of wakefulness in the afternoon. A second “explosion” or release of the API for a minimum of 2, 3, 4, 5 or 6 hours after administration can help overcome these effects. In another embodiment, a pharmaceutical composition or medicament comprising a small loading dose released immediately after administration, followed by a nearly zero order release profile over the following 2, 3, 4, 5 or 6 hours may be used. . In such compositions, peak plasma concentrations can be reached around noon.

In another embodiment, a pharmaceutical composition or medicament comprising a modified release profile of modafinil may comprise R-(-)-modafinil and S-(+)-modafinil, wherein R- ( -)-Modafinil provides an initial increase in plasma concentration (initial _{Cmax with} R-(-)-modafinil) and S-(+)-modafinil is a delayed increase in plasma concentration (S-(+) -Provides subsequent C _max ) with modafinil. The delayed increase in C _max due to S-(+)-modafinil can be 2, 3, 4, 5, 6 hours or more after the initial C _max due to R-(−)-modafinil. In another embodiment, _{C max} is approximately equal to the initial _{C max} was the delay. In another embodiment, the delayed C _max is greater than the initial C _max . In another embodiment, the delayed C _max is less than the initial C _max . In another embodiment, the delayed C _max is due to racemic modafinil instead of S-(+)-modafinil. In another embodiment, the delayed C _max is due to R-(-)-modafinil instead of S-(+)-modafinil. In another embodiment, the initial C _max is due to racemic modafinil instead of R-(−)-modafinil. In another embodiment, the initial C _max is due to S-(+)-modafinil instead of R-(−)-modafinil. In another aspect, the modified release profile has a plasma concentration of 3, 4, 5 or more “explosions”.

  In another embodiment, one or more of racemic modafinil, R-(-)-modafinil or S-(+)-modafinil is present in a co-crystal, solvate, free form or polymorphic form thereof A pharmaceutical composition or medicament comprising a modified release profile of modafinil.

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

  In another embodiment, a pharmaceutical composition or medicament comprising a modified release profile of modafinil is administered transdermally. Such transdermal (TD) delivery may avoid first pass metabolism. In addition, only a fraction of the daily dose is delivered through the skin to produce basal systemic levels, to which oral treatment is added to ensure wakefulness effects, “pills and patches. -And-patch) strategy may be employed.

  Excipients used in the pharmaceutical compositions and medicaments of the present invention can be solid, semi-solid, liquid or combinations thereof. Preferably the excipient is a solid. Compositions and medicaments of the invention containing excipients may be manufactured by known techniques of pharmacy comprising admixing excipients with APIs or therapeutic agents. When the pharmaceutical composition or medicament of the present invention contains a desired amount of API per dosage unit and is intended for oral administration, it may be, for example, a tablet, caplet, pill, hard or soft. Capsule, troche, cachet, dispersible powder, granule, suspension, elixir, dispersant, liquid form, or any other form reasonably adapted for such administration . When intended for parenteral administration, it can be in the form of, for example, a suspension or transdermal patch. If intended for rectal administration, it may be in the form of, for example, a suppository. Presently preferred are oral dosage forms, such as tablets or capsules, each being a separate dosage unit containing a predetermined amount of API.

  A non-limiting example of excipients that can be used to manufacture the pharmaceutical compositions or medicaments of the present invention follows.

The pharmaceutical compositions and medicaments of the present invention optionally comprise one or more pharmaceutically acceptable carriers or diluents as excipients. Suitable carriers or diluents include, but are not limited to, lactose, including anhydrous lactose and lactose monohydrate, either individually or in combination; directly compressible starch and Starch, including hydrolyzed starch (eg, Celtab ^™ and Emdex ^™ ); mannitol; sorbitol; xylitol; D-glucose (eg, Cerelose ^™ 2000) and D-glucose monohydrate; Dicalcium phosphate dihydrate; Sucrose-based diluent; Powdered sugar; Calcium sulfate monohydrate; Calcium sulfate dihydrate; Granular calcium lactate trihydrate; Dexrate; Inositol; Hydrolyzed cereal solids; amylo Food grade sources of crystalline cellulose, α- and amorphous cellulose (eg Rexcel J), cellulose including powdered cellulose, hydroxypropylcellulose (HPC) and hydroxypropylmethylcellulose (HPMC); calcium carbonate; Glycine; bentonite; block copolymer; polyvinylpyrrolidone; Such carriers or diluents, when present, constitute a total of about 5% to 99%, preferably about 10% to about 85%, and more preferably about 20% to about 80% of the total weight of the composition. . The carrier (s), diluent (s) selected preferably exhibit suitable flow characteristics, and compressibility if a tablet is desired.

Lactose, mannitol, dibasic sodium phosphate and crystalline cellulose, either individually or in combination, are preferred diluents (especially Avicel PH crystalline cellulose such as Avicel PH 101). These diluents are chemically compatible with the API. Extragranular crystalline cellulose (ie, crystalline cellulose is added to the granular composition) can be used to improve hardness (for tablets) and / or disintegration time. Lactose, especially lactose monohydrate, is particularly preferred. Lactose typically provides a composition with a suitable release rate, stability, flowability before compression and / or drying properties of the API at a relatively low diluent cost. It provides a dense support that aids densification during granulation (when wet granulation is used) and thus improves the flow and tablet properties of the blend.

The pharmaceutical compositions and medicaments of the present invention optionally comprise one or more pharmaceutically acceptable disintegrants, especially as excipients for tablet formulations. Suitable disintegrants include, but are not limited to, sodium starch glycolate (eg, PenWest Explotab ^™ ) and pregelatinized corn starch (eg, National Starch), either individually or in combination.
and Chemical Company of National ^[National] TM 1551, National ^[National] TM 1550 and Korokon ^[Colocorn] starch encompasses TM 1550), clays (e.g., Veegum of R.T.Vanderbilt ^[Veegum] TM HV), purified cellulose, Cellulose cellulose, methylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose, cellulose such as croscarmellose sodium (eg Ac-Di-Sol ^{™ from} FMC), alginate, crospovidone, and agar, guar, locust bean, karaya, pectin and Mention may be made of gums such as tragacanth gum.

  The disintegrant may be added at any suitable stage during the manufacture of the composition, especially before granulation or during the lubrication stage prior to compression. Such disintegrants, when present, total about 0.2% to about 30%, preferably about 0.2% to about 10%, and more preferably about 0.2% to about 30% of the total weight of the composition. Make up 5%.

  Croscarmellose sodium is a preferred disintegrant for disintegration of tablets or capsules and, when present, is preferably about 0.2% to about 10%, more preferably about 0% of the total weight of the composition. .2% to about 7%, and even more preferably about 0.2% to about 5%. Croscarmellose sodium provides excellent intragranular disintegration capability for the granulated pharmaceutical compositions and medicaments of the present invention.

The pharmaceutical compositions and medicaments of the present invention optionally comprise one or more pharmaceutically acceptable binders or adhesives, especially as excipients for tablet formulations. Such binders and adhesives preferably allow normal processing operations such as sizing, lubrication, compression and packaging but still allow the tablet to disintegrate and the composition to be absorbed upon ingestion Sufficient cohesive strength is imparted to the powder being compressed. Such binders can also prevent or inhibit crystallization or recrystallization of the API of the present invention once the salt is dissolved in solution. Suitable binders and adhesives include, but are not limited to, either individually or in combination, gum arabic; tragacanth; sucrose; gelatin; glucose; but not limited to pregelatinized starch (eg, National Starches such as ^TM 1511 and National ^TM 1500); celluloses which may include, but are not limited to, methylcellulose and carmellose sodium (eg Tylose ^™ ); alginic acid and alginic acid salts; aluminum silicate PEG; guar gum; polysaccharide acid; bentonite; povidone such as povidone K-15, K-30 and K29 / 32; polymethacrylate; HPMC; hydroxypropyl cellulose (E.g. Klucel of Aqualon ^{[Klucel] TM);} and ethylcellulose (e.g., Dow Chemical Company of Ethocel ^{[Ethocel] TM).} Such binders and / or adhesives, when present, total about 0.5% to about 25%, preferably about 0.75% to about 15% of the total weight of the pharmaceutical composition or medicament, and More preferably, it constitutes about 1% to about 10%.

  Many of the binders are polymers comprising amide, ester, ether, alcohol or ketone groups and are therefore preferably included in the pharmaceutical compositions and medicaments of the present invention. Polyvinyl pyrrolidone such as povidone K-30 is particularly preferred. Polymeric binders can have varying molecular weight, degree of crosslinking and polymer grade. The polymeric binder may also be a copolymer such as a block copolymer containing a mixture of ethylene oxide and propylene oxide units. Variations in the ratio of these units in a given polymer will affect properties and performance. Examples of block copolymers with varying composition of block units are Poloxamer 188 and Poloxamer 237 (BASF Corporation).

  The pharmaceutical compositions and medicaments of the present invention optionally comprise one or more pharmaceutically acceptable wetting agents as excipients. Such humectants are preferably selected to maintain the API in close association with water (conditions that would 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 alkyl phenyl ethers such as nonoxynol 9, nonoxynol 10 and octoxynol 9, poloxamers (polyoxyethylene and polyoxypropylene block copolymers), polyoxyethylene fatty acid glycerides and oils such as polyoxyethylene (8) caprylic acid / capric mono- and diglycerides (e.g. Raburasoru of Gattefosse ^{[Labrasol] TM),} polyoxyethylene (35) castor oil and polyoxyethylene (4 ) Hydrogenated castor oil; polyoxyethylene alkyl ethers such as polyoxyethylene (20) cetostearyl ether, polyoxyethylene fatty acid esters such as polyoxyethylene (40) stearate, polyoxyethylene sorbitan esters such as polysorbate 20 and polysorbate 80 (Eg Tween ^™ 80 from ICI), propylene glycol fatty acid esters such as propylene glycol laurate (eg Latteglycol ^{™ from} Gattefosse), sodium lauryl sulfate, fatty acids and their salts such as oleic acid, sodium oleate and olein Acid triethanolamine, glyceryl fatty acid ester such as glyceryl monostearate, sorbitan s Including Le, for example sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate and sorbitan monostearate, Tairokisaporu, and mixtures thereof. Such humectants, when present, total about 0.25% to about 15%, preferably about 0.4% to about 10%, and more preferably about 0% of the total weight of the pharmaceutical composition or medicament. .5% to about 5%.

  A wetting agent that is an anionic surfactant is preferred. Sodium lauryl sulfate is a particularly preferred wetting agent. Sodium lauryl sulfate, when present, is about 0.25% to about 7%, more preferably about 0.4% to about 4%, and even more preferably about 0% of the total weight of the pharmaceutical composition or medicament. .5% to about 2%.

The pharmaceutical compositions and medicaments of the present invention optionally contain one or more pharmaceutically acceptable lubricants (including anti-adhesive agents and / or glidants) as excipients. Comprising. Suitable lubricants include, but are not limited to, glyceryl behapate (eg, Gattefose Compritol ^™ 888), either individually or in combination; stearic acid and sodium magnesium stearate, calcium and sodium. Including salts thereof; hydrogenated vegetable oils (eg Abitec's Sterotex ^™ ); colloidal silica; talc; wax: boric acid; sodium benzoate; sodium acetate; sodium fumarate; for example Dow Chemical Company carbowax ^[Carbowax] TM 4000 and Carbowax ^[Carbowax] TM 6000 of); sodium oleate; lauryl sulfate sodium And lauryl magnesium sulfate. Such lubricants, when present, total about 0.1% to about 10%, preferably about 0.2% to about 8%, and more preferably about 0.1% of the total weight of the pharmaceutical composition or medicament. It constitutes 0.25% to about 5%.

  Magnesium stearate is a preferred lubricant used, for example, to reduce the friction between the device and the granulated mixture during compression of the tablet formulation.

  Suitable anti-adhesive agents can 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 the adhesion of the formulation to the device surface and also to reduce static in the blend. Talc, when present, is about 0.1% to about 10%, more preferably about 0.25% to about 5%, and even more preferably about 0.5% of the total weight of the pharmaceutical composition or drug. % To about 2%.

  Glidants may be used to facilitate the flow of the solid formulation powder. Suitable glidants include, but are not limited to, colloidal silicon dioxide, starch, talc, tricalcium phosphate, powdered cellulose and magnesium trisilicate. Colloidal silicon dioxide is particularly preferred.

  Other excipients such as colorants, flavors and sweeteners are known in the pharmaceutical art and can be used in the pharmaceutical compositions and medicaments of the present invention. The tablets can be coated, for example with an enteric coating, or uncoated. The composition of the present invention may further comprise, for example, a buffer.

  In some cases, one or more blowing agents may be used as a disintegrant 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 the disintegration of the dosage form, one or more blowing agents are preferably about 30% of the pharmaceutical composition or medicament. % To about 75%, and preferably about 45% to about 70%, for example about 60% by weight.

  According to one particularly preferred embodiment of the present invention, the blowing agent present in the solid dosage form in an amount less than effective to promote the disintegration of the dosage form is improved dispersion of the API in an aqueous medium. I will provide a. Without being bound by theory, it is believed that the foaming agent is effective in accelerating the dispersion of the API from the dosage form into the gastrointestinal tract, thereby further enhancing the rapid onset of absorption and therapeutic effects. When present in the pharmaceutical composition or medicament of the present invention so as to promote gastrointestinal dispersion but not enhance disintegration, the foaming agent is preferably about 1% to about 1% of the pharmaceutical composition or medicament. It is present in an amount of about 20%, more preferably about 2.5% to about 15%, and even more preferably about 5% to about 10% by weight.

A “foaming agent” as used herein is an agent comprising one or more compounds that act together or separately to generate gas upon contact with water. The gas generated is generally oxygen or most commonly carbon dioxide. Preferred blowing agents comprise acids and bases that react in the presence of water to produce 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 components of blowing agents useful in the present invention include carbonates (eg calcium carbonate), bicarbonates (eg sodium bicarbonate), sesquicarbonates and mixtures thereof. Calcium carbonate is the preferred base.

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

  In a preferred embodiment of the invention wherein the firing 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, and still More preferably from about 1:10 to about 10: 1. In a further preferred embodiment of the invention wherein the blowing agent comprises an acid and a base, the ratio of acid to base is approximately stoichiometric.

  Excipients that solubilize the metal salt of the API typically have both hydrophilic and hydrophobic regions, or preferably are amphiphilic or have amphiphilic regions. One type of amphiphilic or partially amphiphilic excipient comprises or is an amphiphilic polymer. One particular amphiphilic polymer is a polyalkylene glycol generally composed of ethylene glycol and / or propylene glycol subunits. Such polyalkylene glycols can be esterified at their ends with carboxylic acids, esters, anhydrides or other suitable moieties. Examples of such excipients include poloxamers (symmetric block copolymers of ethylene glycol and propylene glycol; eg poloxamer 237), polyalkylene glycolated esters of tocopherol (esters formed from di- or polyfunctional carboxylic acids; eg d- formed by α-tocopherol polyethylene glycol-1000 succinate), and macrogol glycerides (alcohol degradation of oils and esterification of polyalkylene glycols to produce mono, di, and triglycerides and mixtures of mono and diesters) For example, stearoyl macrogol-32 glycerides). Such pharmaceutical compositions and medicaments are advantageously administered orally.

  The pharmaceutical compositions and medicaments of the present invention comprise about 10% to about 50%, about 25% to about 50%, about 30% to about 45%, or about 30% to about 35% by weight API; % To about 50%, about 25% to about 50%, about 30% to about 45%, or about 30% to about 35% by weight of excipients that inhibit crystallization; 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 may be included. In one example, the weight ratio of API to excipient that inhibits crystallization is about 1: 1 to 1: 1.

  The solid dosage forms of the invention can be made by any suitable method that is not limited to the methods described herein.

  One specific method is as follows: (a) mixing the salt of the invention with one or more excipients to form an admixture; and (b) compressing or encapsulating the admixture. Each forming a tablet or capsule.

  In one preferred method, the solid dosage form comprises: (a) admixing a salt of the API of the invention with one or more excipients to form an admixture; (b) granulating the admixture. To form granules, and (c) tableting or encapsulating the blend to form tablets or capsules, respectively. Step (b) can be accomplished by any dry or wet granulation technique known in the art, but is preferably a dry granulation step. The salts of the present invention are advantageously granulated to form particles of about 1 micrometer to about 100 micrometers, about 5 micrometers to about 50 micrometers, or about 10 micrometers to about 25 micrometers. . One or more diluents, one or more disintegrants and one or more binders may preferably be added, for example in the mixing stage, and wetting agents are optionally added, for example in the granulation stage And one or more disintegrants are preferably added after granulation but before tableting or encapsulation. The lubricant is preferably added before tableting. Mixing and granulation can be performed independently under low or high shear forces. API content is uniform, easily disintegrates, flows with sufficient ease to ensure controlled weight fluctuations during capsule filling or tableting, and batches can be processed on selected equipment One method is preferably selected to form granules that are sufficiently dense in the bulk so that individual doses fit into the specified capsule or tablet form.

  In an alternative embodiment, the solid dosage form is made by a method that includes a spray drying step, wherein the API is one or more sprayable liquids, preferably aprotic (eg, non-aqueous or non-aqueous). Suspend in an alcoholic) sprayable liquid with one or more excipients and then rapidly spray dry over a stream of warm air.

  Granules or spray-dried powders resulting from any of the methods specifically described above can be compressed or molded to produce tablets, or encapsulated to produce capsules. Conventional tableting and encapsulation techniques known in the art may be used. If coated tablets are desired, conventional coating techniques are suitable.

  The excipient of the tablet composition of the present invention is preferably 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 in a standard disintegration assay. Or choose to provide a disintegration time of less.

In another aspect of the invention, a pharmaceutical composition or medicament comprising modafinil and an additional API may be manufactured. Modafinil and the additional API can be in the form of a co-crystal or can 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 to treat the same condition as modafinil. In such compositions comprising modafinil and caffeine, caffeine can give rapid release characteristics to the dissolution profile (small T _{max with} respect to modafinil), while modafinil has a therapeutic effect for several hours after administration. For example, the c _max of caffeine is 0.001, 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7 of that of modafinil. Or it may be 0.8 times. Combination therapy comprises administration in the same formulation of two or more APIs, or in two or more co-administered formulations. The APIs can be administered together at the same time or individually at specified intervals.

The use of modafinil is known in the art and includes narcolepsy, multiple sclerosis related malaise, infertility, eating disorders, attention deficit hyperactivity disorder (ADHD), Parkinson's disease, incontinence, sleep apnea or Includes treatment of myopathy. In another embodiment, any one or more of the modafinil compositions of the present invention may be used in one or more treatments of the above conditions. Dosage and administration of the modafinil composition of the invention can be determined using routine methods in the art, but can generally be between about 50 and about 700 mg / day.

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

General methods for co-crystal production a) High-throughput crystallization using the CrystalMax ^(R) platform CrystalMax ^(R) is a rapid polymorph of API and API candidates, salts and co-crystals. It comprises a series of automated integrated high-throughput robotic stations that can be generated, identified and characterized. Worksheet generation and combinatorial mixture design is performed using the patented design software Architect ^™ . Typically, an API or API candidate is dispensed from an organic solvent into a tube and dried under a stream of nitrogen. The salt and / or co-crystal former can also be dispensed and dried in the same manner. Water and organic solvents can be dispensed into tubes in combination using a multichannel dispenser. Each tube of the 96 tube array is then sealed within 15 seconds of the combined dispense to avoid solvent evaporation. The mixture is then heated to 70 ° C. for 2 hours and then supersaturated with a cooling ramp of 1 ° C./min to 5 ° C. Visual confirmation is then performed to detect crystals and / or solid material. Once a solid is identified in the tube, it is isolated by aspiration and drying. A Raman spectrum is then obtained on the solid and cluster classification of the spectral pattern is performed using patented software (Inquire ^™ ).
b) Crystallization from solution Co-crystals can be obtained by dissolving the separate components in a solvent and adding one to the other. In that case, the co-crystal may precipitate or crystallize upon slow evaporation of the solvent mixture. Co-crystals can also be obtained by dissolving the two components in the same solvent or mixture of solvents. Co-crystals can also be obtained by nucleating a binary saturated solution and nucleating with a pulverized mixture of co-crystals.
c) Crystallization from the melt (co-melt) Co-crystals can be obtained by melting the two components together (ie, co-melting) and causing recrystallization. In some cases, an anti-solvent may be added to facilitate crystallization.
d) Heat transfer microscopy Co-crystals can be obtained by melting a higher melting component on a glass slide and recrystallizing it. The second component is then melted and recrystallized. Co-crystals can occur as separated phases / bands between the eutectic bands of the two original components.
e) Mixing and / or grinding Co-crystals can be obtained by mixing or grinding the two components together in the solid state. For example, Example 12 describes the synthesis of modafinil: 1-hydroxy-2-naphthoic acid co-crystals obtained by milling with the addition of a small amount of a suitable solvent (wet milling). Similarly, Example 5 describes the synthesis of modafinil: citric acid monohydrate co-crystals obtained by milling both with and without the addition of a small amount of a suitable solvent. In one embodiment, the co-crystal is produced via pulverization or pulverization of modafinil with the co-crystal former (dry pulverization). In another embodiment, the co-crystal is produced via pulverization or pulverization of modafinil, the co-crystal former and a small amount of solvent (wet pulverization).

In another embodiment, the co-crystal is produced with or without the addition of a solvent. Solvents used in such a co-crystallization process are not limited, but acetone, methanol, ethanol, isopropyl alcohol, ethyl acetate, isopropyl acetate, nitromethane, dichloromethane, chloroform, toluene, propylene glycol, dimethyl sulfoxide (DMSO), dimethyl Mention may be made of other organic solvents including formamide (DMF), diethyl ether (ether), ethyl formate, hexane, acetonitrile, benzyl alcohol, water or alcohol.
f) Co-sublimation The co-crystal can be obtained by co-subliming the mixture in the same sample cell as an intimate mixture by either heating, mixing or placing the mixture of co-crystal formers under vacuum. it can. Co-crystals are individual sample cells in which the API and co-crystal former are connected to a single cold finger, each of which co-sublimates the two components on the cold finger to form the desired co-crystal. Can also be obtained by co-sublimation using a Knudsen device contained in a vacuum atmosphere (maintained at the same or different temperatures).
Analytical Methods Differential scanning calorimetry (DSC) analysis of the samples was performed using the Q1000 differential scanning calorimetry using Advantage for QW-Series, version 1.0.0.78, Thermal Advantage Release 2.0 (2001 TA Instruments-Water LLC). Performed using a meter (TA Instruments, Newcastle, Del.). In addition, the analysis software used was Universal Analysis 2000 for Windows 95/98/2000 / NT, version 3.1E; Build 3.1.0.40 (2001 TA Instruments-Water LLC).

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

  DSC analysis of the sample was performed by placing the modafinil sample in an aluminum pan with a corrugated pan lid. The starting temperature was typically 20 ° C. with a heating rate of 10 ° C./min and the end temperature was 200 ° C. All reported DSC transitions represent endothermic or exothermic transition temperatures at their respective peaks with an error of ± 2 ° C unless otherwise indicated.

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

For the TGA experiment, the purge gas used was dry nitrogen, the balance purge was 40 mL / min N ₂ , and the sample purge was 60 mL / min N ₂ .

  TGA was performed on the sample by placing the modafinil sample in an aluminum dish. The onset temperature was typically 20 ° C. with a heating rate of 10 ° C./min and the end temperature was 300 ° C.

  The powder X-ray diffraction (PXRD) pattern of the sample was obtained from D / Max Rapid, Contact (Rigaku / MSC, USA) using its control software RINT Rapid Control software, Rigaku Rapid / XRD, version 1.0.0 (1999 Rigaku). Woodlands, Texas). 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.). there were.

  For PXRD analysis, the acquisition parameters were as follows. That is, the X-ray source is Cu with K-rays at 1.5406 mm; the xy stage is manual; the collimator size is 0.3 mm; and the capillary (Charles Super Company, Natick, Mass., USA) has a diameter of 0 .3 mm; using reflection mode; power to the x-ray tube is 46 kV; current to the x-ray tube is 40 mA; ω axis is in the range of 0-5 ° at a rate of 1 ° / min. Vibrating; φ axis rotated at 360 ° angle at a rate of 2 ° / sec; 0.3 mm collimator; Collection time was 60 minutes; Temperature was room temperature; and no heater was used. Samples were presented to the X-ray source in a boron-rich glass capillary.

  In addition, the analysis parameters were as follows. That is, the integral 2θ range is 2-60 °; the integral χ range is 0-360 °; the number of χ segments is 1; the step size used is 0.02, and the integration utility. Was cyint; using normalization; dark count was 8; ω correction was 180; and χ and φ corrections were 0.

PXRD diffractograms were also acquired via a Bruker AXS D8 Discover X-ray diffractometer. This instrument is GADDS ^™ (all-region diffraction detector (General
Area Diffraction Detection System), Bruker AXS HI-STAR area detector at a distance of 15.05 cm by instrument calibration, copper X-ray source (Cu / K _α 1.54056 Angstrom), automated xyz stage, and 0 Equipped with a 5 mm collimator. The sample was compressed into pellet form and placed on an xyz stage. The diffractogram was acquired in reflection mode at 40 kV and 40 mA output settings under ambient conditions (25 ° C.) while the sample remained stationary. The exposure time was varied and specified for each sample. The resulting diffractogram is subjected to a spatial remapping procedure to reveal the geometric pincushion distortion of the area detector, then from -118.8 to -6.18 ° and 2θ2.1-37 along χ. Integration was performed using the normalization set for bottle normalization with a step size of 0.02 ° at °.

  Since the peak intensity may vary from sample to sample, for example due to crystalline impurities, the relative intensity of the peaks in the diffractogram is not necessarily a limitation of the PXRD pattern. Furthermore, the angle of each peak can vary by about ± 0.1 °, preferably ± 0.05. The majority of the entire pattern or pattern peak may also move from about ± 0.1 ° to about ± 0.2 ° due to instrument and operator calibration, setting differences and other variations. All reported PXRD peaks in the Figures, Examples and elsewhere in this specification are reported with a 2θ error of about ± 0.1 °.

For the PXRD data herein including tables and figures, each composition of the present invention has any one of the 2θ angle peaks, any 2, any 3, any 4, any 5, any 6, Any 7 or any 8 or more may be characterized. Any 1, 2, 3, 4, 5 or 6 DSC transitions can also be used to characterize the compositions of the present invention. Various combinations of PXRD peaks and DSC transitions can also be used to characterize the composition.

  Heat transfer (hot stage) microscopy was completed on a Zeiss Axioplan 2 microscope equipped with a Mettler Toledo FP90 controller. The thermal stage used was a Mettler Toledo FP82HT. All melting point measurements were completed by placing the sample on a microscope slide and covered with a cover glass. The initial temperature was set at 30 ° C. and the temperature was increased at a rate of 10 ° C./min. Melting was observed with a 5 × microscope objective.

HPLC method: (modified from Donovan et al. Therapeutic Drug Monitoring 25: 197-202.
Column: Astec Cyclobond I 2000 RSP 250 × 4.6 mm (part number 4111121)
Mobile phase A: 20 mM sodium phosphate, pH 3.0
B: 70:30 Mobile phase A: Acetonitrile Flow rate: 1.0 mL / min (about 1500 PSI)
Flow program: Gradient analysis time: 35 minutes Detection: UV at 225 nm
Injection volume: 10 microliters Column temperature: 30 ± 1 ° C
Standard dilution: 90:10 (v / v) mobile phase A: acetonitrile needle wash: acetonitrile purge solvent and seal wash: 90:10 (v / v) water: acetonitrile mobile phase preparation method:
1. Preparation of 1 M sodium phosphate: 120 g sodium phosphate is dissolved in water and made up to 1000 mL; filtered.
2. Preparation of mobile phase A (20 mM sodium phosphate, pH 3.0): For 1 liter, dilute 20 mL of 1 M sodium phosphate with water to 1000 mL; adjust pH to 3.0 with phosphoric acid.
3. Preparation of mobile phase B (70:30 (v / v) 20 mM sodium phosphate, pH 3.0: acetonitrile): For 1 liter, mix 700 mL of mobile phase A and 300 mL of acetonitrile.
Sample preparation:
1. Samples are dissolved in 90:10 (v / v) 20 mM sodium phosphate, pH 3.0: acetonitrile to an appropriate concentration of 20 micrograms / mL.
Raman acquisition The samples were either left in their treated glass vials or aliquots of the samples were transferred to glass slides. A glass vial or glass slide was placed in the appropriate position in the sample chamber. Measurements were made with an Almega ^™ dispersed Raman (Almega ^™ Dispersive) fitted with a 785 nm laser light source.
(Raman, Thermo-Nicolet, 5225 Verona Road, Madison, WI 53711-4495). The sample was manually brought into focus using the microscope portion of the apparatus with a 10 × power objective lens (unless otherwise indicated), thus directing the laser to the surface of the sample. Spectra were acquired using the parameters outlined in Table A. (Exposure time and number of exposures can vary; changes to parameters will be shown for each acquisition.)

IR acquisition IR spectra were obtained using Nexus ^™ 470 FT-IR, Thermo-Nicolet, 5225 Verona Road, Madison, WI 53711-4495, and control and analysis software: OMNIC, version 6.0a, (C) Thermo -Analyzed using Nicolet, 1995-2004.

  Co-crystal data are shown in Table IV and the figure.

Racemic modafinil: malonic acid co-crystal Malonic acid (114.9 mg, 1.104 mmol) was added to a solution containing racemic modafinil (150 mg, 0.549 mmol) in acetic acid (600 microliters). The mixture was then heated on a hot plate at 67 ° C. until all material was dissolved. The solution was then dried under a stream of nitrogen to yield a 1: 1 modafinil: malonic acid co-crystal as a colorless solid. The solid material was characterized using PXRD. The material was then further dried overnight under a stream of nitrogen to yield the same material with a slight excess of malonic acid. The colorless solid was characterized using PXRD (Bruker), DSC, TGA, IR and Raman spectroscopy. PXRD data for the modafinil: malonic acid (1: 1) co-crystal are listed in Table IV and the diffractogram is shown in FIG. 1 (data collected / received). DSC shows an endothermic transition at about 106 ° C. and the thermogram is shown in FIG. The TGA thermogram is shown in FIG. 4A and 4B show the Raman spectra of the modafinil: malonic acid co-crystal and the three Raman spectra of modafinil, malonic acid and the co-crystal, respectively. Figures 5A and 5B show the IR spectra of the modafinil: malonic acid co-crystal and three IR spectra of modafinil, malonic acid and the co-crystal, respectively. The modafinil: malonic acid co-crystals include, but are not limited to, 5.00, 9.17, 10.08, 16.81, 18.26, 19.43, 21.36, 21.94, 22. 1, any 2, any 3, any 4, any 5 or any of the peaks of FIG. Any 6 or more may be characterized.

Modafinil: malonic acid co-crystals were also prepared by grinding together the API and co-crystal former. Racemic modafinil (2.50 g, 0.009 mol) and malonic acid (1.01 g, 0.0097 mol) were mixed for 7 days in a large mortar and pestle (malonic acid was prepared on the first day). Slowly added over 7 days at a ratio of 1: 1.05, and increments added over the next 7 days, which resulted in a modafinil: malonic acid ratio of 1: 2. The mixture was milled for the first 45 minutes and 20 minutes each time more malonic acid was added. On the seventh day, the mixture of co-crystal and starting components was heated in a sealed 20 mL vial at 80 ° C. for about 35 minutes to help complete the co-crystal formation. The PXRD analysis (Bruker) of the resulting material is completed and shown in FIG. 6A (data received). The modafinil: malonic acid co-crystals include, but are not limited to, 5.08, 9.28, 16.81, 18.27, 19.45, 21.39, 21.99, 22.83, 23. Any one, any 2, any 3, any 4, any 5, or any 6 of the peaks in FIG. 6A that can mention 2θ of 50, 24.58, 25.12 and 28.49 ° C. It can be characterized by more than that. The DSC thermogram of the co-crystal is shown in FIG. 6B (endothermic transition at about 116 ° C.). Single crystal data of the modafinil: malonic acid co-crystal were obtained and reported below. FIG. 7 shows a packing diagram of modafinil: malonic acid.

Crystal data: C ₁₈ H ₁₉ NO ₆ S, M = 377.40, monoclinic C2 / c; a = 18.728 (8) angstrom, b = 5.480 (2) angstrom, c = 33.894 (13) Angstrom, α = 90 °, β = 91.864 (9) °, γ = 90 °, T = 100 (2) K, Z = 8, D _c = 1.442 Mg / m ³ , V = 3477 (2) Cubic Angstrom, λ = 0.10773 Angstrom, 6475 reflections measured, 3307 unique (R _int = 0.1567). Final residuals (final residuals) is, I> 2σ (I) for _{R 1 = 0.1598, wR 2 =} 0.3301, and for all 3307 data _{R 1 = 0.2544, wR 2 =} 0.3740 met It was.

  Other methods were also used to produce modafinil: malonic acid co-crystals. A third preparation was performed by placing modafinil (30 mg, 0.0001 mol) and excess malonic acid in a stainless steel vial. 20 microliters of acetone was added to the vial. The vial was then placed in a grinder (wig-l-bug, Bratt Technologies, 115V / 60 Hz) and the solid mixture was pulverized for 5 minutes. The resulting powder was then collected and characterized using PXRD and DSC. In yet another method of making the modafinil: malonic acid co-crystal, the third method above was completed without the addition of a solvent. All of the above methods using malonic acid were shown to yield identical co-crystals via PXRD and DSC analysis.

Racemic modafinil: glycolic acid co-crystal Racemic modafinil (1 mg, 0.0037 mmol) and glycolic acid (0.30 mg, 0.0037 mmol) were dissolved in acetone (400 microliters). The solution was evaporated to dryness and the resulting solid was characterized using PXRD (Rigaku). PXRD data for modafinil: glycolic acid co-crystals are listed in Table IV. See Figures 8A and 8B. FIG. 8A shows a PXRD diffractogram after background noise subtraction. FIG. 8B shows raw PXRD data as collected.

An alternative process for the modafinil: glycolic acid co-crystal was also completed. To a solution of modafinil (1 mg, 0.0037 mmol) dissolved in a mixture of acetone and methanol (3: 1, 100 microliters), glycolic acid (0.28 mg, 0.0037 mmol) dissolved in methanol (50 microliters) was added. Added. The solvent was then evaporated to dryness under a stream of nitrogen to give a mixture of the two starting components. Acetone (200 microliters) was then added to the mixture and it was heated to 70 ° C. and maintained at 70 ° C. for 2 hours. The sample was then cooled to 5 ° C. and maintained at that temperature for 1 day. After 1 day, the lid was removed from the vial and the solvent was evaporated to dryness to yield modafinil: glycolic acid co-crystal as a colorless solid. The modafinil: glycolic acid co-crystal was characterized by PXRD. The modafinil: glycolic acid co-crystals include, but are not limited to, 9.51, 14.91, 15.97, 19.01, 20.03, 21.59, 22.75, 25.03 and 25. Any one, any 2, any 3, any 4, any 5, or any 6 or more of the peaks of FIG. 8A that may mention 2θ of 71 ° may be characterized. The modafinil: glycolic acid co-crystals are similarly, but not limited to, 9.53, 14.93, 15.99, 19.05, 20.05, 21.61, 2.77 and 25.05. Any one, any 2, any 3, any 4, any 5, or any 6 or more of the peaks in FIG.

Racemic modafinil: maleic acid co-crystal Maleic acid (30.7 mg, 0.264 mmol) was added to a solution containing modafinil (150 mg, 0.549 mmol) in acetic acid (600 microliters). The mixture was then heated on a hot plate at 67 ° C. until all material was dissolved. The solution was then dried under a stream of nitrogen to yield a clear amorphous material. The amorphous material was stored at room temperature in a sealed vial. After 2 days, solid material began to form and was collected and characterized as modafinil: maleic acid co-crystal using PXRD (Rigaku) as shown in FIGS. 9A and 9B. FIG. 9A shows the PXRD diffractogram after background noise subtraction. FIG. 9B shows raw PXRD data. PXRD data for the modafinil: maleic acid co-crystals are listed in Table IV. The modafinil: maleic acid co-crystals include, but are not limited to, 4.69, 6.15, 9.61, 10.23, 15.65, 16.53, 17.19, 18.01, 19. Characterized by any one, any 2, any 3, any 4, any 5, or any 6 or more of the peaks of FIG. 9A that can include 97, 21.83 and 22.45 ° 2θ. It can be. The modafinil: maleic acid co-crystals are similarly, but not limited to, 4.69, 6.17, 9.63, 10.25, 15.67, 16.53, 17.21, 18.05. , 19.99, 21.85, and 22.47 ° 2θ, any one of the peaks in FIG. 9B, any 2, any 3, any 4, any 5, or any 6 or more Can be characterized.

Racemic modafinil: co-crystal of L-tartaric acid To a solution of racemic modafinil (10.12 mg, 0.037 mmol) in methanol (2 mL) was added L-tartaric acid (5.83 mg, 0.039 mmol). The solution was then allowed to evaporate at room temperature, yielding a clear viscous material. The material was further dried under flowing nitrogen for 2 days and then placed in a vial and capped. A small amount of colorless solid formed after 6 days. One day after the first solid was seen, approximately 60% of the remaining clear amorphous amount was converted to solid form. A sample of this material was analyzed by PXRD (Bruker) as shown in FIG. The modafinil: L-tartaric acid co-crystals include, but are not limited to, 6.10, 7.36, 9.38, 14.33, 16.93, 17.98, 18.81, 20.15, 20 Any one, any 2, any 3, any 4, any 5, or any 6 or more of the peaks in FIG. 10 that may include 2θ of .71, 22.49 and 25.04 °. Can be a feature.

Racemic modafinil: citric acid co-crystal Racemic modafinil (25.3 mg, 93 mmol) and citric acid monohydrate (26.8 mg, 128 mmol) were triturated together for 3 minutes. 1 mg of the resulting mixture was then dissolved in acetone (100 microliters) and heated to 70 ° C. and maintained at that temperature for 2 hours. The solution was then cooled to 5 ° C. and left at that temperature for 2 days. After 2 days the lid was removed from the vial and a drop of water was added. The solvent was then evaporated to yield modafinil: citric acid monohydrate co-crystal as a colorless solid. The modafinil: citric acid monohydrate co-crystal was characterized by PXRD (Rigaku) as shown in FIG. 11A (background subtracted). The modafinil: citric acid co-crystals include, but are not limited to, 5.29, 7.29, 9.31, 12.41, 13.29, 17.29, 17.97, 18.79, 21. Any one, any 2, any 3, any 4, any 5, or any 6 or more of the peaks in FIG. 11A that can mention 37 and 23.01 ° 2θ may be characterized.

  Other methods were also used to produce modafinil: citric acid monohydrate co-crystals. The second preparation was performed by placing modafinil (30 mg, 0.0001 mol) and excess citric acid monohydrate in a stainless steel vial. 20 microliters of acetone was added to the vial. The vial was then placed in a grinder (wig-l-bug, Bratt Technologies, 115V / 60 Hz) and the solid mixture was pulverized for 5 minutes. The resulting powder was then collected and characterized using PXRD and DSC. The DSC thermogram is shown in FIG. 11B. In yet another method of making the modafinil: citric acid monohydrate co-crystal, the second method above was completed without the addition of solvent. All of the above methods using citric acid monohydrate were shown to yield identical co-crystals via PXRD and DSC analysis.

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

An alternative process for the modafinil: succinic acid co-crystal was also completed. To a racemic modafinil (49.7 mg, 0.182 mmol) and succinic acid (21.6 mg, 0.182 mmol) in a round bottom flask was added methanol (1.5 mL). The mixture was then dissolved at 65 ° C. on a hot plate. Modafinil: succinic acid co-crystal core crystals from the above preparation were then added to the flask. The methanol was then evaporated using a rotary evaporator and a 65 ° C. hot water bath to yield the modafinil: succinic acid co-crystal as a colorless solid. The collected solid PXRD (Rigaku) confirms the synthesis of the modafinil: succinic acid co-crystal. The modafinil: succinic acid co-crystals include, but are not limited to, 5.45, 9.93, 15.85, 17.97, 18.73, 19.95, 21.33, 21.93, 23. Any one, any 2, any 3, any 4, any 5, or any 6 or more of the peaks of FIG. 12A that may mention 01 and 25.11 ° 2θ may be characterized. The modafinil: succinic acid co-crystals are similarly, but not limited to, 5.45, 9.93, 15.87, 17.99, 18.75, 19.95, 21.95, 23.03. And any one, any 2, any 3, any 4, any 5, or any 6 or more of the peaks in FIG. 12B that may mention 2θ of 25.07 °. Single crystal data of the modafinil: succinic acid co-crystal were obtained and reported below. FIG. 14 shows a packing diagram of the modafinil: succinic acid co-crystal.

Crystal data: C ₁₇ H ₁₈ NO ₄ S, triclinic P-1; a = 5.672 (4) angstrom, b = 8.719 (6) angstrom, c = 16.191 (11) angstrom, α = 93.807 (14) °, β = 96.471 (17) °, γ = 92.513 (13) °, T = 100 (2) K, Z = 2, D _c = 1.392 Mg / m ³ V = 792.8 (9) cubic angstrom, λ = 0.10773 angstrom, measured 2448 reflections, 1961 unique (R _int = 0.0740). The final residual, _R 1 = 0.1008 for _{I> 2σ (I), wR} 2 = 0.2283, and all the 1961 data _R 1 = _0.1593, was wR 2 = 0.2614.

  A third method was also used to produce modafinil: succinic acid co-crystals. The method was performed by placing modafinil (30 mg, 0.0001 mol) and excess succinic acid in a stainless steel vial. 20 microliters of acetone was added to the vial. The vial was then placed in a grinder (wig-l-bug, Bratt Technologies, 115V / 60 Hz) and the solid mixture was pulverized for 5 minutes. The resulting powder was then collected and characterized using PXRD and DSC. All of the above methods using succinic acid have been shown to yield identical co-crystals via PXRD and DSC analysis.

Racemic modafinil: DL-tartaric acid co-crystal A suspension of racemic modafinil (162 mg; 0.591 mmol) and DL-tartaric acid (462 mg; 3.08 mmol) in acetone (10 mL) was heated to reflux for 1 minute. . Undissolved DL-tartaric acid was filtered off through a 0.2 micrometer PTFE filter while the suspension was still hot. The remaining solution was allowed to cool to room temperature and then to 0 ° for 1 hour. Large colorless crystals were observed after 1 hour. The mother liquor was decanted and the solids were air dried and characterized by PXRD (Rigaku) as shown in FIG. The modafinil: DL-tartaric acid co-crystals include, but are not limited to, 4.75, 9.53, 10.07, 15.83, 17.61, 19.37, 20.25, 21.53, 22 Any one, any 2, any 3, any 4, any 5, or any 6 of the peaks in FIG. 15 that can mention 2θ (as collected) of .55 and 23.75 ° It can be characterized by more than that.

Racemic modafinil: fumaric acid co-crystal (form I)
Racemic modafinil (30 mg, 0.0001 mol) and fumaric acid (2.3 mg, 0.0002 mol) were placed in a stainless steel vial. 20 microliters of acetone was added to the vial. The vial was then placed in a grinder (wig-l-bug, Bratt Technologies, 115V / 60 Hz) and the solid mixture was pulverized for 5 minutes. The resulting powder was then collected and characterized as modafinil: fumaric acid co-crystal (Form I) using PXRD (Rigaku) as shown in FIG. The co-crystal is a 2: 1 co-crystal comprising 2 moles of modafinil per mole of fumaric acid. The modafinil: fumaric acid co-crystal (Form I) is not limited to 5.45, 9.95, 10.91, 15.93, 18.03, 18.81, 19.93, 20. Any one, any two, any three, any of the peaks in FIG. 16 that can include 25, 21.37, 21.95, 23.09 and 25.01 ° 2θ (as collected) 4, any 5, or any 6 or more. Single crystal data of the modafinil: fumaric acid co-crystal (Form I) are obtained and reported below. FIG. 17 shows a packing diagram of the modafinil: fumaric acid co-crystal (Form I).

Crystal _{data: C 17 H 17 NO 4 S} , M = 331.38, triclinic P-1; a = 5.7000 ( 15) Å, b = 8.735 (2) Å, c = 16.204 (4) Angstrom, α = 93.972 (6) °, β = 97.024 (6) °, γ = 93.119 (7) °, T = 100 (2) K, Z = 2, D _c = 1.381 Mg / m ³ , V = 797.2 (4) cubic angstrom, λ = 0.10773 angstrom, 4047 reflections measured, 2615 unique (R _int = 0.0475). The final residual, _R 1 = 0.0784 for _{I> 2σ (I), wR} 2 = 0.1584, and for all 2615 data _R 1 = _0.1154, was wR 2 = 0.1821.

Racemic modafinil: fumaric acid co-crystal (form II)
Racemic modafinil (30 mg, 0.0001 mol) and fumaric acid (1.2 mg, 0.0001 mol) were placed in a stainless steel vial. 20 microliters of acetone was added to the vial. The vial was then placed in a grinder (wig-l-bug, Bratt Technologies, 115V / 60 Hz) and the solid mixture was pulverized for 5 minutes. The resulting powder was then collected and characterized as modafinil: fumaric acid co-crystal (Form II) using PXRD (Rigaku) as shown in FIG. The modafinil: fumaric acid co-crystal (form II) is not limited to 6.47, 8.57, 9.99, 13.89, 14.53, 16.45, 17.13, 17. Any one, any, or two of the peaks in FIG. 18 that can include 51, 18.39, 20.05, 20.79, 25.93 and 27.95 ° 2θ (as collected) 3, any 4, any 5, or any 6 or more.

Racemic modafinil: gentisic acid co-crystal Racemic modafinil (30 mg, 0.0001 mol) and gentisic acid (1.5 mg, 0.0001 mol) were placed in a stainless steel vial. 20 microliters of acetone was added to the vial. The vial was then placed in a grinder (wig-l-bug, Bratt Technologies, 115V / 60 Hz) and the solid mixture was pulverized for 5 minutes. The resulting powder was then collected and characterized using PXRD (Rigaku) as shown in FIG. The modafinil: gentisic acid co-crystals include, but are not limited to, 6.96, 12.92, 14.76, 17.40, 18.26, 20.10, 20.94, 23.46 and 24. Characterized by any one, any 2, any 3, any 4, any 5, or any 6 or more of the peaks in FIG. 19 that can include 36 ° 2θ (where collected) obtain.

Racemic Modafinil: Oxalic Acid Co-Crystal One process for preparing modafinil: oxalic acid co-crystal is described as racemic modafinil (30 mg, 0.0001 mol) and oxalic acid (1-2 mg, 0.0001-0.0002 mol). Was performed in stainless steel vials. 20 microliters of acetone was added to the vial. The vial was then placed in a grinder (wig-l-bug, Bratt Technologies, 115V / 60 Hz) and the solid mixture was pulverized for 5 minutes. The resulting powder was then collected and characterized using PXRD (Bruker) as shown in FIG. In another process for preparing the modafinil: oxalic acid co-crystal, the above process was completed without the addition of solvent. Both methods were shown to yield identical co-crystals via PXRD analysis. The modafinil: oxalic acid co-crystals include, but are not limited to, 5.98, 13.68, 14.80, 17.54, 19.68, 21.12, 21.86 and 28.90 ° 2θ. Any one, any 2, any 3, any 4, any 5, or any 6 or more of the peaks of FIG. 20 that can be cited (as collected) can be characterized.

Racemic modafinil: co-crystal of 1-hydroxy-2-naphthoic acid Racemic modafinil (30 mg, 0.0001 mol) and 1-hydroxy-2-naphthoic acid (21 mg, 0.0001 mol) were placed in a stainless steel vial. It was. 20 microliters of acetone was added to the vial. The vial was then placed in a grinder (wig-l-bug, Bratt Technologies, 115V / 60 Hz) and the solid mixture was pulverized for 5 minutes. The resulting powder was then collected and characterized using PXRD (Bruker) as shown in FIG. Modafinil: 1-hydroxy-2-naphthoic acid co-crystals include, but are not limited to, 5.72, 7.10, 11.48, 14.16, 15.66, 17.92, 19.18, 20 Any one of the peaks in FIG. 21, 21, 21.94, 24.38 and 26.86 ° 2θ (as collected) It may be characterized by any 4, any 5 or any 6 or more. The PXRD peaks at 10.05 and 26.36 ° 2θ can be from excess co-crystal formers.

R-(-)-modafinil: malonic acid co-crystal R-(-)-modafinil: malonic acid co-crystal is R-(-)-modafinil (29.7 mg, 0.109 mmol, 82 percent R-isomer). ) With malonic acid (11.9 mg, 0.114 mmol). The ground mixture was then heated to 80 ° C. for 10 minutes. The powder was analyzed by PXRD (Bruker) and DSC as shown in FIGS. 22 and 23, respectively. The PXRD pattern confirms that a co-crystal has been made and shows many similarities to the PXRD pattern of the racemic modafinil: malonic acid co-crystal. Co-crystals of R-(−)-modafinil: malonic acid are not limited, but 5.04, 9.26, 16.73, 18.23, 19.37, 21.90, 22.74, 24. Any one, any 2, any 3, any 4, any 5, or any 6 of the peaks in FIG. 22 that can include 2θ (data collected) of .44 and 25.67 °. Or more than that. DSC showed a melting range of 111.5-114.7 ° C. with a heat of fusion of 112.9 J / g.

R-(-)-modafinil: succinic acid co-crystal R-(-)-modafinil: succinic acid co-crystal is R-(-)-modafinil (30.9 mg, 0.113 mmol, 82.2 percent R- Isomer) was prepared by grinding with succinic acid (14.8 mg, 0.125 mmol). The ground mixture was then heated to 145 ° C. for 5 minutes. The powder was analyzed by PXRD (Bruker) and DSC as shown in FIGS. 24 and 25, respectively. The PXRD pattern confirms that a co-crystal was made and shows many similarities to the PXRD pattern of the racemic modafinil: succinic acid co-crystal made from solution. R-(-)-modafinil: Succinic acid co-crystals include, but are not limited to, 5.36, 9.83, 15.80, 17.88, 18.70, 19.87, 21.21, 21. Any one, any two, any three, any four, any five or any six of the peaks in FIG. 24 that can mention .85 and 25.96 ° 2θ (data collected). Or more than that. DSC showed a melting range of 143.3-145.2 ° C. with a heat of fusion of 140.7 J / g.

R-(-)-modafinil: citric acid co-crystal R-(-)-modafinil: citric acid co-crystal is R-(-)-modafinil (30.0 mg, 0.110 mmol, 82.2 percent R- Isomer) was prepared by grinding with citric acid monohydrate (27.1 mg, 0.129 mmol). The powder was analyzed by PXRD (Bruker) and DSC as shown in FIGS. 26 and 27, respectively. The PXRD pattern confirms that a co-crystal has been made and shows many similarities to the PXRD pattern of the racemic modafinil: citric acid co-crystal. R-(-)-modafinil: co-crystals of citric acid include, but are not limited to, 5.18, 7.23, 9.23, 12.32, 13.23, 17.25, 17.92, 18 Any one, any two, any three, any four of the peaks in FIG. 26 that can include 2θ (data collected) of .76, 20.25, 21.30, and 23.71 °. Any 5 or any 6 or more. DSC showed a melting range of 83.5-89.0 ° C. with a heat of fusion of 39.8 J / g.

Co-crystal of R-(-)-modafinil: DL-tartaric acid Co-crystal of R-(-)-modafinil: DL-tartaric acid was found from a high-throughput crystallization experiment from dichloromethane. The vial contained a 1: 2 mixture of R-(−)-modafinil (over 98 percent R-isomer) and DL-tartaric acid. The co-crystal was also found from a 1: 1 mixture of R-(−)-modafinil (over 98 percent R-isomer) and DL-tartaric acid in nitromethane. Solid material was collected and characterized using PXRD (Bruker) and DSC as shown in FIGS. 28 and 29, respectively. Co-crystals of R-(−)-modafinil: DL-tartaric acid include, but are not limited to, 4.67, 15.41, 17.97, 19.46, 20.50, 22.91 and 24.63 °. 2θ (where collected) can be characterized by any 1, any 2, any 3, any 4, any 5, or any 6 or more of the peaks of FIG. Endothermic transitions were present at about 107, 152 and 187 ° C.

R-(-)-modafinil: co-crystal of 1-hydroxy-2-naphthoic acid R (-)-modafinil (98.6 mg; 0.361 mmol, 98 percent or more R-isomer) and 1-hydroxy-2-naphtho To a solid mixture of acid (71.2 mg; 0.378 mmol) was added o-xylene (4.5 mL). The mixture was heated to reflux for less than 1 minute when both solids dissolved. The solution was then slowly cooled to room temperature where the solid crystallized. The solid was collected via filtration and air dried. The powder was characterized using PXRD (Bruker) as shown in FIG. The same material was made from benzene, toluene and acetone using the above procedure. Co-crystals of R-(-)-modafinil: 1-hydroxy-2-naphthoic acid include, but are not limited to, 5.27, 8.85, 10.60, 12.11, 14.47, 17.80. , 18.80, 21.20, 23.03 and 25.61 ° 2θ (where collected) any one of the peaks in FIG. 30, any 2, any 3, any 4, any 5 or any 6 or more may be characterized.

The co-crystal of R-(-)-modafinil: 1-hydroxy-2-naphthoic acid can also be obtained from R-(-)-modafinil (over 98 percent R-isomer) and 1-hydroxy-2-naphthoic acid in nitromethane. Also obtained from high-throughput crystallization experiments from vials containing a 1: 1 mixture of Solid material was collected and characterized using DSC and PXRD (Bruker) as shown in FIGS. 31 and 32, respectively. Co-crystals of R-(-)-modafinil: 1-hydroxy-2-naphthoic acid include, but are not limited to, 5.34, 8.99, 10.68, 12.15, 14.51, 21.28. , 23.14 and 24.50 ° 2θ (as collected) any one of the peaks in FIG. 32, any 2, any 3, any 4, any 5, or any It can be characterized by 6 or more. DSC shows an endothermic transition at about 118 and 179 ° C.

R-(-)-modafinil: orotic acid co-crystal R-(-)-modafinil: orotic acid co-crystal was prepared in acetone (100 microliters) with R-(-)-modafinil (1 mg, 0.0036 mmol, Obtained from high throughput crystallization experiments from vials containing> 98 percent R-isomer) and orotic acid (1.14 mg, 0.0073 mmol). The resulting solid material was characterized using PXRD (Bruker) and DSC as shown in FIGS. 33 and 34, respectively. The R-(−)-modafinil: orotic acid co-crystals include, but are not limited to, 9.77, 17.85, 20.52, 20.95, 24.03 and 26.80 ° 2θ (collected). 33 can be characterized by any one, any 2, any 3, any 4, any 5, or any 6 or more of the peaks of FIG. The PXRD peaks at 14.61 and 28.60 may correspond to an excess of co-crystal former. Endothermic transitions were present at about 116, 130 and 169 ° C.

Racemic modafinil acetic acid solvate To racemic modafinil (12.9 mg, 0.047 mmol) was added acetic acid (40 microliters). The mixture was heated at 50 ° C. to completely dissolve the solid. The solution was allowed to cool to room temperature and left overnight, which did not produce a precipitate. The solution was then evaporated under flowing nitrogen until a precipitate was observed. The resulting solid was further dried under flowing nitrogen. The product characterization was achieved via PXRD (Rigaku), TGA, DSC and Raman spectroscopy as shown in FIGS. 35-38, respectively. An alternative process for the modafinil acetic acid solvate was also completed. A sample of modafinil acetic acid solvate is dissolved by dissolving racemic modafinil (12.9 mg, 0.047 mmol) in acetic acid (40 microliters) and incubating at 65 ° C. for 30 minutes, followed by 25 Prepared by cooling to 0 ° C. and incubating overnight. The sample was then evaporated to approximately 1/3 volume. Rapid nucleation and crystal growth was observed after centrifugation of the sample. An additional 20 microliters of acetic acid was then added. The sample was heated at 50 ° C. until partial dissolution of the crystals was observed. The sample was then cooled to room temperature for 1 hour in an attempt to induce crystal growth and then to 5 ° C. for 3 hours. The sample was then dried under nitrogen gas. A rapid appearance of crystals was observed. Modafinil acetic acid solvates include, but are not limited to, 6.17, 9.63, 15.69, 17.97, 19.99 and 21.83 ° 2θ (data collected). Any one, any 2, any 3, any 4, any 5, or any 6 or more of the peaks of FIG. 35 can be characterized.

Racemic Modafinil Tetrahydrofuran Solvate Modafinil tetrahydrofuran (THF) solvate was prepared by placing racemic modafinil (10.4 mg, 0.038 mmol) in tetrahydrofuran (1 mL). The powder did not dissolve completely in THF and was converted to long fine needles overnight, which were collected and analyzed by PXRD (Rigaku) as shown in FIG. Modafinil tetrahydrofuran solvates include, but are not limited to, 6.97, 9.79, 10.97, 16.19, 19.03, 19.71, 20.59, 22.25 and 25.13 °. Can be characterized by any one, any 2, any 3, any 4, any 5, or any 6 or more of the peaks of FIG. .

Racemic modafinil 1,4-dioxane solvate To racemic modafinil (11.6 mg, 0.042 mmol) was added 1,4-dioxane (1 mL). The mixture was then left overnight and converted into long fine needles that were collected and analyzed by PXRD (Rigaku) as shown in FIG. Modafinil 1,4-dioxane solvates include, but are not limited to, 6.93, 9.85, 10.97, 16.19, 18.97, 19.61, 20.33, 20.65 and Any one, any 2, any 3, any 4, any 5, or any 6 or more of the peaks in FIG. 40 that can include 22.07 ° 2θ (data collected) Can be characterized. The PXRD pattern also contains some spikes that were the result of equipment malfunction and could not be removed.

Racemic Modafinil Methanol Solvate Modafinil methanol solvate is obtained by evaporating 2 mL of a 30 mg / mL racemic modafinil solution in methanol overnight under flowing nitrogen. The methanol solvate was characterized by PXRD (Rigaku), TGA and DSC as shown in FIGS. 41, 42 and 43, respectively. Modafinil methanol solvates include, but are not limited to, 6.15, 9.89, 12.25, 15.69, 17.97, 20.07, 2,
Any one, any 2, any 3, any 4, any 5, or any of the peaks in FIG. 41 that may include 1.85 and 22.73 ° 2θ (data collected) It can be characterized by 6 or more.

Racemic modafinil nitromethane solvate To racemic modafinil (12.9 mg, 0.047 mmol) was added nitromethane (1 mL). The mixture that did not completely dissolve was left overnight and converted to large rectangular crystals. The solid was collected and analyzed by PXRD (Rigaku) as shown in FIG. Modafinil nitromethane solvates include, but are not limited to, 6.17, 9.77, 15.89, 18.11, 20.07, 22.17, 22.91, 25.31 and 25.83 °. 44 can be characterized by any one, any 2, any 3, any 4, any 5, or any 6 or more of the peaks of FIG. .

Racemic modafinil acetone solvate A solution containing racemic modafinil (300 mg, 0.001 mol) and glutaric acid (150 mg, 0.001 mol) in acetone (3 mL) was used to dissolve all solid material. Heated until it boiled. Once the solid dissolved, the solution was placed on an aluminum block at 5 ° C. Crystals began to form at the bottom of the vial after 15 minutes standing at 5 ° C. The solution was then decanted and single crystals were collected and analyzed using PXRD (Rigaku) as shown in FIG. The crystals were determined to be an acetone solvate of modafinil. The acetone solvates of modafinil include, but are not limited to, 6.11, 9.53, 15.81, 18.11, 20.03, 21.63, 22.45, 25.23, 25.65, Any one, any two, any three, any four, any five of the peaks in FIG. 45 that can include 28.85, 30.23, and 32.93 degrees 2θ (as collected). Or any 6 or more may be characterized. The acetone solvate can also be obtained according to the above procedure using several other co-crystal formers including adipic acid, lactobionic acid, maleic acid and glycolic acid.

  Racemic modafinil (1 mg, 0.0037 mmol) and mandelic acid (0.55 mg, 0.0037 mmol) were dissolved in acetone (400 microliters). The solution was evaporated to dryness and the resulting solid was characterized using PXRD (Rigaku) as shown in FIG. The resulting solid is a mixture of modafinil acetone solvate and another product. The form can include, but is not limited to, 6.11, 9.53, 15.77, 18.03, 20.01 and 21.61 ° 2θ (with background removed). Any one, any 2, any 3, any 4, any 5, or any 6 or more of the peaks may be characterized. Other peaks including 6.75, 10.31, 14.77, and 23.27 appear to correspond to modafinil polymorphs.

Racemic modafinil (1 mg, 0.0037 mmol) and fumaric acid (0.42 mg, 0.0037 mmol) were dissolved in 1,2-dichloroethane (400 microliters). The solution was evaporated to dryness and the resulting solid was characterized using PXRD (Rigaku) as shown in FIG. The resulting solid can be a solvate of modafinil. The morphology includes, but is not limited to, 5.87, 8.95, 12.49, 13.99, 18.19, 19.99, 21.57 and 25.01 ° 2θ (background removed) 47) can be characterized by any 1, any 2, any 3, any 4, any 5, or any 6 or more of the peaks of FIG.

New Form of Racemic Modafinil Racemic modafinil was dispensed from a stock solution containing 50 mg modafinil in 20 mL 15: 5 acetone / methanol mixture. The solution was then evaporated to dryness under a stream of nitrogen. Benzoic acid was dispensed from the acetone solution and the mixture was evaporated again to dryness. 200 microliters of isopropyl alcohol or methanol was then added and the vial was capped. After standing at room temperature for 1 day, the lid was removed and the solvent was evaporated. PXRD (Rigaku) was performed on the samples as shown in FIG. A new form of racemic modafinil that appears to be polymorphic or co-crystalline is referred to as Form VII. Form VII includes, but is not limited to 5.47, 9.99, 15.73, 17.85, 18.77, 20.05, 21.23, 22.05, 24.15 and 25.13 ° 48 can be characterized by any one, any 2, any 3, any 4, any 5, or any 6 or more of the peaks in FIG. .

Racemic Modafinil: Malonic Acid Co-Crystal Pharmacokinetic Study in Dogs Racemic modafinil: malonic acid teaching crystals (from Example 1) were administered to dogs in a pharmacokinetic study. Modafinil: malonic acid co-crystal particles with a median particle size of about 16 micrometers were administered in the study. As a reference, micronized modafinil with a median particle size of about 2 micrometers was also administered in the study. The AUC of the modafinil: malonic acid co-crystal was determined to be 40-60 percent greater than that of pure modafinil. Such higher bioavailability specifically illustrates the modulation of important pharmacokinetic parameters according to one aspect of the present invention. The accumulation of important pharmacokinetic parameters measured during animal studies is included in Table V.

Stability of racemic modafinil: malonic acid co-crystal in solid state The stability of racemic modafinil: malonic acid co-crystal was measured at various temperatures and relative humidity over several weeks. Degradation was not found to occur at 20 or 40 ° C. At 60 ° C., about 0.14 percent degradation per day was determined based on a simple exponential model. At 8O 0 C, about 8 percent degradation per day was measured.

Modafinil: malonic acid co-crystal stability was also measured at various temperatures and relative humidity over a period of 26 weeks. FIGS. 49 and 50 are stored at various conditions including: 25 ° C., 60% RH; 40 ° C., 75 percent RH; 40 ° C., ambient RH; 60 ° C., ambient RH; 80 ° C., ambient RH; The impurity area% as measured through HPLC versus time (weeks) of the sample was shown. These data indicate that the compound is stable when stored at or below 40 ° C. for a minimum of 26 weeks. FIG. 51 compares PXRD patterns of early and 26 week old samples of modafinil: malonic acid co-crystals for several temperatures and RH levels.

Racemic modafinil: malonic acid co-crystal formulation The racemic modafinil: malonic acid co-crystal formulation was completed using lactose. One of the two mixtures, modafinil and lactose, and the modafinil: malonic acid co-crystal and a second one of lactose were ground together in a mortar and pestle. The mixture targeted a 1: 1 weight ratio of modafinil to lactose. In the modafinil and lactose mixture, 901.2 mg modafinil and 901.6 mg lactose were ground together. In a modafinil: malonic acid co-crystal and lactose mixture, 1221.6 mg of co-crystal and 871.4 mg of lactose were ground together. The resulting powder was analyzed by PXRD and DSC. The PXRD pattern and DSC thermogram of the mixture showed virtually no change when compared to both individual components. The DSC of the co-crystal mixture showed only a co-crystal melting peak at 113.6 ° C. with a heat of fusion of 75.9 J / g. This heat of fusion is 59.5% of that found for the co-crystal alone (127.5 J / g). This result is consistent with a 58.4% weight ratio of the co-crystal in the mixture. The DSC of the modafinil and lactose mixture had a melting point of 165.7 ° C. This is slightly lower than the measured melting point of modafinil (168.7 ° C.). The heat of fusion (59.3 J / g) of the mixture is 46.9% of that of modafinil alone (126.6 J / g), which is consistent with an estimate of 50%.

In vitro dissolution of both modafinil: malonic acid co-crystal and pure modafinil was tested in capsules. Both gelatin and hydroxypropyl methylcellulose (HPMC) capsules were used in the dissolution test. Capsules were formulated with and without lactose. All formulations were crushed with a mortar and pestle prior to transport into capsules. Capsule dissolution was tested in 0.01 M HCl (see FIG. 52).
Use sieved and ground material in gelatin capsules in 0.01N HCl:
A 38 micrometer sieve was passed through the modafinil and modafinil: malonic acid co-crystals. In gelatin capsules (size 0, B & B Pharmaceuticals, Lot No. 15-01202), 200.0 mg sieved modafinil, 280.4 mg sieved modafinil: malonic acid co-crystal, 200.2 mg ground modafinil, or 280.3 mg of ground modafinil: malonic acid co-crystal was loaded. The dissolution test was performed in a Vankel VK 7000 Benchsaver dissolution test apparatus with a VK750D heater / circulator set at 37 ° C. At 0 minutes, the capsule was dropped into a container containing 900 mL of 0.01 M HCl and stirred with a paddle.

Absorbance readings were measured using a Cary 50 spectrophotometer (wavelength set at 260 nm) at the following time points: 0, 5, 10, 15, 20, 25, 30, 40, 50 and 60 minutes. . Absorbance values were compared to those of standards and the modafinil concentration of the solution was calculated.
Use ground material in gelatin or HPMC capsules with and without lactose in 0.01N HCl:
Modafinil and modafinil: malonic acid co-crystals were mixed with an equivalent amount of lactose (Spectrum, Lot QV0460) for approximately 5 minutes. Gelatin capsules (size 0, B & B Pharmaceuticals, lot number 15-01202), 400.2 mg modafinil and lactose (approximately 200 mg modafinil) or 560.1 mg modafinil: malonic acid co-crystal and lactose (approximately 200 mg modafinil) Filled. HPMC capsules (size 0, Shionogi, lot number A312A6) with 399.9 mg modafinil and lactose, 560.9 mg modafinil: malonic acid co-crystal and lactose, 199.9 mg modafinil, or 280.5 mg modafinil: malon The acid co-crystal was filled. Dissolution tests were performed as described above.

In Vitro Dissolution FIG. 53 shows in vitro dissolution data for micronized racemic modafinil: malonic acid co-crystallized and micronized modafinil in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). Both samples were mixed with lactose and filled into HPMC capsules. The co-crystal released modafinil in solution in both SGF and SIF more rapidly than the free form of modafinil released. FIG. 54 compares dissolution of HPMC capsules filled with modafinil: malonic acid co-crystals mixed with lactose and dissolution of PROVIGIL tablets. FIG. 55 shows a dynamic vapor sorption (DVS) isothermal plot of the modafinil: malonic acid co-crystal. This plot shows no appreciable water adsorption up to a minimum of 40 percent RH at 26 ° C.

In vivo studies Pharmacokinetic studies were completed in dogs using both racemic modafinil: malonic acid and PROVIGIL tablets (200 mg) formulated with lactose. Seven capsules were loaded with modafinil: malonic acid co-crystal and lactose to 476.24 ± 2 mg (each containing 200 mg modafinil). FIG. 56 shows that the co-crystal formulation has increased C _max and increased bioavailability. Several important pharmacokinetic parameters are described in Table VI. In Table VI, “C _max ” is the maximum plasma concentration, “AUC (inf)” is the extrapolated area under the curve, and “t _1/2 ” is the plasma concentration starting with administration at the C _max level Is the amount of time to decrease to half of the time, “T _max ” is the time from administration to maximum plasma concentration, “CL” is the disappearance rate of modafinil, and “F%” is biological It is the availability percentage.

R-(-)-modafinil: gentisic acid co-crystal R-(-)-modafinil (50 mg, 0.183 mmol,> 98 percent R-isomer) and gentisic acid (28.2 mg, 0.183 mmol) in stainless steel Placed in steel vial. Ten microliters of acetone was added to the vial. The vial was then placed in a grinder (wig-l-bug, Bratt Technologies, 115V / 60 Hz) and the solid mixture was pulverized for 5 minutes. The resulting powder was then collected and characterized using PXRD (Rigaku) as shown in FIG. Co-crystals of R-(-)-modafinil: gentisic acid are not limited, but 7.07, 9.07, 12.31, 13.03, 14.09, 18.93, 19.83.
And any of the peaks in FIG. 57 that can cite and 21.27 ° 2θ (as collected), or any 2, any 3, any 4, any 5, or any 6 or more Can be characterized. The other PXRD peaks at 7.51, 16.03, 17.63, 18.39, 23.57, 26.93 and 28.85 ° correspond to excess co-crystal formers.

Racemic modafinil channel solvate
A modafinil channel solvate was unexpectedly discovered. The channel solvate was dissolved on a hot plate at 60 ° C. with racemic modafinil (97.9 mg, 0.358 mmol) and 1-hydroxy-2-naphthoic acid (68.8 mg) in acetone (3.15 mL). , 0.366 mmol). The solution was then evaporated hot under flowing nitrogen to a total volume of 1.6 mL. Once cooled, crushed racemic modafinil: 1-hydroxy-2-naphthoic acid co-crystal nuclei were placed in the solution. Single crystals were obtained and characterized using single x-ray analysis. Single crystal x-ray parameters: P2 (1) / n, a = 12.737 (3) angstrom, b = 5.5945 (11) angstrom, c = 22.392 (5) angstrom, α = 90 °, β = 104.140 (4) °, γ = 90 °, V = 1547.3 (5) cubic angstroms, Z = 2. 58 and 59 show the packing diagrams of the modafinil acetone channel solvate. The packing diagram shows acetone with various positions within the channel structure. The ethyl acetate channel solvate was also prepared according to the above method using ethyl acetate instead of acetone.

Racemic modafinil o-xylene hemisolvate
The semi-solvate of o-xylene is racemic modafinil (49.6 mg, 0.181 mmol) and 1-hydroxy-2-naphthoic acid (68.3 mg, 0.363 mmol) in o-xylene (4.5 mL). ) To form a 1: 2 solution. The mixture was heated on a hot plate with swirling until all solids were dissolved. The solution was then allowed to crystallize in a sealed vial. The resulting powder was collected on a centrifuge filter and analyzed by PXRD (Bruker) as shown in FIG. Raman spectroscopy (FIG. 61), TGA (FIG. 62) and DSC (FIG. 63) were also used to analyze and characterize the hemisolvate. The o-xylene solvates include, but are not limited to 5.31, 6.53, 6.96, 10.68, 14.20, 17.64, 19.93, 25.69 and 26.79. Any one, any 2, any 3, any 4, any 5, or any 6 or more of the peaks of FIG. The o-xylene solvate includes, but is not limited to, any one or two of the peaks in FIG. 61 (center spectrum) which can include 1641, 1407, 1379, 1211, 1024 and 721 cm ⁻¹ . , Any 3, any 4, any 5 or any 6 or more.

Benzene hemisolvate of racemic modafinil The racemic modafinil (50.6 mg, 0.181 mmol) and 1-hydroxy-2-naphthoic acid (70. Formed by preparing a 1: 2 solution of 1 mg, 0.373 mmol). The mixture was heated on a hot plate with swirling until all solids were dissolved. The solution was then allowed to crystallize in a sealed vial. The resulting powder was collected on a centrifuge filter and analyzed by PXRD (Bruker) as shown in FIG. Raman spectroscopy (FIG. 65), TGA (FIG. 66) and DSC (FIG. 67) were also used to analyze and characterize the hemisolvate. The benzene solvate is not limited to 5.82, 6.09, 8.1.
The figure which can mention 2 (theta) of 1, 10.28, 12.06, 13.28, 14.73, 17.03, 19.11, 19.93, 21.23, 25.38, and 26.43 degrees. Any one of the 64 peaks, any 2, any 3, any 4, any 5, or any 6 or more may be characterized. The benzene solvate includes, but is not limited to, any one of the peaks in FIG. 65 (center spectrum) which can include 1637, 1600, 1409, 1380, 1214, 1025, 998 and 721 cm ⁻¹ . 2, any 3, any 4, any 5, or any 6 or more.

Racemic modafinil toluene hemisolvate Toluene hemisolvate was prepared in toluene (1 mL) with racemic modafinil (37.3 mg, 0.136 mmol) and 1-hydroxy-2-naphthoic acid (51.3 mg, Formed by making a 1: 2 solution of 0.273 mmol). The mixture was heated on a hot plate with swirling until all solids were dissolved. The solution was then allowed to crystallize in a sealed vial. The resulting powder was collected on a centrifuge filter and analyzed by PXRD (Bruker) as shown in FIG. Raman spectroscopy (Figure 69), TGA (Figure 70) and DSC (Figure 71) were also used to analyze and characterize the hemisolvate. The toluene solvates include, but are not limited to, 5.30, 5.96, 10.65, 12.90, 14.51, 17.60 and 18.15 ° 2θ. Any one, any 2, any 3, any 4, any 5, or any 6 or more of the peaks may be characterized. The toluene solvate includes, but is not limited to, any one of the peaks in FIG. 69 (center spectrum) which can include 1640, 1581, 1408, 1380, 1209, 1024, 1001 and 722 cm ⁻¹ . 2, any 3, any 4, any 5, or any 6 or more.

Pharmacokinetics of isomers of modafinil A canine pharmacokinetic study (N = 6) with a single intravenous dose of R-(-)-modafinil was completed. The purity of R-(-)-modafinil in the administered formulation was about 80 percent. This formulation was also compared to a racemic modafinil formulation administered by intravenous route in a cross-design to the same dog. Results are reported in Table VII. In Table VII, “C _max ” is the maximum plasma concentration, “AUC (inf)” is the extrapolated area under the curve, and “t _1/2 ” is the plasma concentration starting with administration at the C _max level. The amount of time to decrease by half, “V _d ” is the distribution volume, and “CL” is the disappearance rate of modafinil.

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

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

  These results lead to differences in the formation of inactive sulfone metabolites and thus significant differences in the metabolism of both isomers of modafinil resulting in greater exposure to API when administered as R-(-)-modafinil. To suggest. The different profiles observed between the intravenous and oral routes show that sulfone metabolite formation is mainly catalyzed by cytochrome CYP3A4 present at both intestinal and liver levels, and CYP3A4 versus S-(+)-modafinil. Can be explained by the fact that its affinity for R-(-)-modafinil is higher (stereoselective metabolism). This can lead to faster metabolite formation with S-(+)-modafinil, which can reduce exposure to the API.

Ethanol solvate of R-(−)-modafinil R-(−)-modafinil (100 mg, 0.366 mmol, 85.4 percent R-isomer) and racemic modafinil (40 mg, 0) in ethanol (3 mL). .146 mmol) was prepared. The mixture was heated to reflux to dissolve the entire solid and then cooled to room temperature (25 ° C.). After stopping at room temperature for 15 minutes, the solution was placed at 5 ° C. overnight. A solid precipitate was observed after 1 day and was collected, dried and characterized using PXRD and TGA (Figures 72 and 73). The solid was determined to be the ethanol solvate of R-(−)-modafinil.

  Ethanol solvates of R-(−)-modafinil include, but are not limited to, 6.13, 9.59, 15.69, 17.97, 20.05, 21.55, 22.35, 25. 72, 29.07 ° 2θ (Rigaku PXRD, data collected) any one of the peaks in FIG. 72, any 2, any 3, any 4, any 5, or any Or 6 or more.

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

Benzyl alcohol solvate of R-(−)-modafinil R-(−)-modafinil (100 mg, 0.366 mmol) was triturated with benzyl alcohol (40 microliters) for 5 minutes. The finely ground powder was then analyzed by PXRD, DSC and TGA (FIGS. 74, 75 and 76). The powder was determined to be the benzyl alcohol solvate of R-(−)-modafinil.

  The benzyl alcohol solvate of R-(−)-modafinil is not limited to 5.77, 7.76, 10.48, 15.78, 17.80, 18.57, 21.53, 22 Any one of the peaks in FIG. 74, which can include .97 and 27.73 ° 2θ (Bruker PXRD, data collected), or any 5, or any 5 or Any 6 or more may be characterized.

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

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

Isopropanol solvate of R-(−)-modafinil R-(−)-modafinil was slurried in isopropanol overnight. The liquid was filtered through a centrifugal filter and then dried under flowing nitrogen gas at 5 ° C. The resulting solid was analyzed via PXRD.

  Isopropanol solvates of R-(−)-modafinil include, but are not limited to, 5.76, 7.77, 10.49, 15.79, 18.58, 21.53, 25.76 and 27. Any one, any 2, any 3, any 4, any 5, or any 6 or any of the peaks in FIG. 77 that can include 74 ° 2θ (Bruker PXRD, data collected) The above can be characterized.

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

  Acetonitrile solvates of R-(−)-modafinil include, but are not limited to, 5.29, 6.17, 8.16, 10.19, 11.19 and 21.86 ° 2θ (Bruker PXRD, The data can be characterized as any one, any 2, any 3, any 4, any 5, any 6 or more of the peaks in FIG.

R-(-)-modafinil: co-crystal of glutaric acid R-(-)-modafinil (20-30 mg, over 98 percent R-isomer) and glutaric acid (15-20 mg) in the presence of a drop of benzyl alcohol Milled together below.

The resulting solid is characterized by PXRD (see FIG. 79) and may contain co-crystals. The R-(−)-modafinil: glutaric acid co-crystal is not limited to 4.30, 8.67, 9.78, 17.99, 18.92, 19.74, 20.50, Any one of the peaks in FIG. 79 that can include 21.36, 22.25, 23.87, 27.16, 29.24 and 32.46 ° 2θ (Bruker PXRD, data collected). Any 2, any 3, any 4, any 5, or any 6 or more.

  Wet milling was also used with acetone and water, both of which resulted in the formation of co-crystals.

R-(-)-modafinil: citric acid co-crystal R-(-)-modafinil (20-30 mg,> 98 percent R-isomer) and citric acid monohydrate (15-20 mg) were added in a drop. Milled together in the presence of benzyl alcohol.

  The resulting solid is characterized by PXRD (see FIG. 80) and may contain co-crystals. The R-(−)-modafinil: citric acid co-crystals include, but are not limited to, 5.23, 7.06, 9.10, 12.43, 13.18, 14.37, 17.34, Peaks in FIG. 80 that can include 17.95, 20.85, 21.39, 22.03, 22.96, 23.54, and 24.93 ° 2θ (Bruker PXRD, data collected). Any one, any 2, any 3, any 4, any 5, or any 6 or more may be characterized.

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

R-(-)-modafinil: co-crystal of L-tartaric acid R-(-)-modafinil (20-30 mg, over 98 percent R-isomer) and L-tartaric acid (15-20 mg) were added to a drop of benzyl alcohol. In the presence of.

  The resulting solid is characterized by PXRD (see FIG. 81) and may contain co-crystals. The co-crystal of R-(-)-modafinil: L-tartaric acid is not limited, but 4.56, 10.33, 14.45, 17.29, 19.91, 21.13, 23.10. , 24.10 and 26.76 ° 2θ (Bruker PXRD, data collected) any one of the peaks in FIG. 81, any 2, any 3, any 4, any 5 or any 6 or more may be characterized.

  Wet milling was also used with acetone and water, both of which resulted in the formation of co-crystals.

R-(-)-modafinil: oxalic acid co-crystal R-(-)-modafinil (20-30 mg, over 98 percent R-isomer) and oxalic acid (15-20 mg) in the presence of a drop of benzyl alcohol Milled together below.

The resulting solid is characterized by PXRD (see FIGS. 82A and 82B) and may contain one or more co-crystals. Co-crystals of R-(-)-modafinil: oxalic acid (Form I) are not limited to 5.99, 14.73, 16.59, 17.38, 18.64, 25.66 and 28 .85 ° 2θ (Bruker
PXRD, data collected) can be characterized by any one, any 2, any 3, any 4, any 5, or any 6 or more of the peaks in FIG. 82A. Co-crystals of R-(−)-modafinil: oxalic acid (form II) are not limited to 5.66, 14.76, 17.20, 17.63, 19.60, 24.90 and 28. Any one, any 2, any 3, any 4, any 5, or any 6 of the peaks in FIG. 82B that may include .84 ° 2θ (Bruker PXRD, data collected) or It can be characterized by more than that.

  Wet milling was also used with acetone and water, both of which resulted in the formation of co-crystals.

R-(-)-modafinil: palmitic acid co-crystal R-(-)-modafinil (20-30 mg, over 98 percent R-isomer) and palmitic acid (15-20 mg) in the presence of a drop of benzyl alcohol Milled together below.

  The resulting solid is characterized by PXRD (see FIG. 83) and may contain co-crystals. The R-(−)-modafinil: palmitic acid co-crystal is not limited to 3.80, 6.55, 7.66, 10.24, 11.49, 19.48, 21.09, Any one, any two, any three of the peaks in FIG. 83 that can include 21.74, 22.20, 22.97, and 23.99 ° 2θ (Bruker PXRD, data collected). , Any 4, any 5 or any 6 or more.

R-(-)-modafinil: co-crystal of L-proline R-(-)-modafinil (20-30 mg,> 98 percent R-isomer) and L-proline (15-20 mg) were added to a drop of benzyl alcohol. In the presence of.

  The resulting solid is characterized by PXRD (see FIG. 84) and may contain co-crystals. The R-(-)-modafinil: L-proline co-crystal is not limited to 6.52, 8.53, 10.25, 14.69, 19.06, 19.71, 20.75. Any one of the peaks in FIG. 84, which can include 22.29, 22.75, 25.08 and 26.27 ° 2θ (Bruker PXRD, data collected), either 3, any 4, any 5, or any 6 or more.

  Wet milling was also used with acetone and methanol, both of which resulted in the formation of co-crystals.

R-(-)-modafinil: salicylic acid co-crystal R-(-)-modafinil (20-30 mg,> 98 percent R-isomer) and salicylic acid (15-20 mg) in the presence of a drop of benzyl alcohol Crushed together.

The resulting solid is characterized by PXRD (see FIG. 85) and may contain co-crystals. The R-(-)-modafinil: salicylic acid co-crystals are not limited to 8.92, 10.85, 12.18, 14.04, 17.07, 17.59.
, 18.81, 21.24, 23.32, 25.22 and 28.59 ° 2θ (Bruker PXRD, data collected) any one of the peaks in FIG. 2, any 3, any 4, any 5, or any 6 or more.

R-(-)-modafinil: co-crystal of lauric acid R-(-)-modafinil (20-30 mg, over 98 percent R-isomer) and lauric acid (15-20 mg) in the presence of a drop of benzyl alcohol Milled together below.

  The resulting solid is characterized by PXRD (see FIG. 86) and may contain co-crystals. The R-(-)-modafinil: lauric acid co-crystals are not limited to 3.12, 6.55, 10.24, 13.97, 16.40, 17.62, 19.02, Any one or two of the peaks in FIG. 86 that can list 20.05 (Bruker PXRD, data collected) at 20.05, 21.38, 22.24, 23.81 and 25.96 °. , Any 3, any 4, any 5 or any 6 or more.

  Wet milling was also used with acetone and methanol, both of which resulted in the formation of co-crystals.

R-(-)-modafinil: co-crystal of L-malic acid R-(-)-modafinil (20-30 mg, over 98 percent R-isomer) and L-malic acid (15-20 mg) were added in a drop. Milled together in the presence of acetone.

  The resulting solid is characterized by PXRD (see FIG. 87) and may contain co-crystals. The R-(-)-modafinil: L-malic acid co-crystals are not limited, but 4.62, 9.32, 10.32, 15.83, 16.71, 17.38, 19. Any one of the peaks in FIG. 87, which can include 30, 19.93, 21.48, 23.07, 24.26 and 27.25 ° 2θ (Bruker PXRD, data collected) 2, any 3, any 4, any 5, or any 6 or more.

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

Production of benzhydrylthioacetic acid from bromodiphenylmethane (one-pot procedure)
To a solution of thiourea (30.4 g, 0.399 mol) in water (200 mL) was added bromodiphenylmethane (98.8 g, 0.399 mol) at 42 ° C. 10 of the mixture
Heated slowly to reflux for minutes. The reaction mixture was then cooled to 50 ° C. and 5N NaOH (200 mL) was then added. The reaction mixture was then heated to reflux (101-102 ° C.) for 30 minutes and then cooled to 60 ° C. To this reaction mixture was slowly added a solution of chloroacetic acid (53.4 g, 0.565 mol) and NaOH (22.2 g) in water (150 mL) over 45 minutes. The reaction mixture was stirred for another 30 minutes. The reaction was then cooled to room temperature and washed with t-butyl methyl ether (200 ml) to remove any non-carboxylic acid impurities. The aqueous layer was acidified (pH 2.0) using concentrated HCl (50 mL). The resulting precipitate was filtered, washed with water (2 × 200 mL) and heptane (200 mL) and air dried to yield benzhydrylthioacetic acid (116.8 g, 100%) as a colorless solid. (See U.S. Pat. No. 4,066,686)

Preparation of benzhydrylthioacetic acid from benzhydrol using trifluoroacetic acid in dichloromethane To a solution of benzhydrol (90 g, 0.488 mol) and trifluoroacetic acid (90 mL) in dichloromethane (300 mL), dichloromethane (60 mL The thioglycolic acid (40 g, 0.488 mol) in) was added dropwise over 20 minutes. The reaction was complete in 1 hour. The solvent was removed in vacuo to yield a crude solid that was dried overnight under high vacuum. The solid was treated with 2N NaOH (1.0 L) and washed with t-butyl methyl ether (200 ml) to remove non-carboxylic acid impurities. The aqueous solution was then acidified with concentrated HCl and the resulting precipitate was collected, washed with water and dried to give benzhydrylthioacetic acid (128.5 g) as a colorless solid.

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

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

Resolution of benzhydrylsulfinylacetic acid using S-(−)-α-methylbenzylamine Solution of (±) -benzhydrylsulfinylacetic acid (62.4 g, 0.227 mol) in water (300 mL) at 80 ° C. To was added S-(−)-α-methylbenzylamine (30 mL, 0.236 mol) and stirred at reflux (101-102 ° C.) for 10 minutes. The solution was slowly cooled to 40 ° C. and the resulting precipitate was filtered, washed with water and dried to give a colorless solid (71.4 g). The salt was recrystallized in water (500 ml) to give another colorless solid (53.5 g). The salt was then suspended in water (200 mL), acidified with concentrated HCl (50 mL) and stirred for 10 minutes. The resulting suspension was filtered and washed with water to yield R-(−)-benzhydrylsulfinyl acetic acid (21.5 g) as a colorless solid. The chiral purity as determined by HPLC was> 99.9% ee. (See U.S. Pat. No. 4,927,855)

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

Preparation of racemic modafinil via activation using N, N-carbonyldiimidazole (CDI) Suspension of (±) -benzhydrylsulfinyl acetic acid (10.0 g, 0.036 mol) in tetrahydrofuran (100 mL) N, N-carbonyldiimidazole (7.1 g, 0.043 mol) was added to the solution to give a clear solution. The solution was stirred for 10 minutes and a precipitate formed upon CO ₂ evolution. NH ₃ gas was then bubbled through the reaction mixture for 10 minutes to raise the reaction temperature from 16 to 33 ° C. The reaction mixture was then diluted with water and extracted with ethyl acetate (3 × 50 mL). The organic layers were combined, washed with water, brine and dried over Na ₂ SO ₄ . The organic layer was then concentrated in vacuo to yield crude modafinil (11.5 g). Recrystallization from 60% aqueous methanol yielded pure modafinil (6.0 g) as a colorless solid.

Synthesis of (±) -modafinil from benzhydrol A solution of benzhydrol (30 g, 0.162 mol) and trifluoroacetic acid (15 mL) in dichloromethane (120 mL) was added to methyl thioglycolate (30 mL) in dichloromethane (30 mL). 0.178 mol) of solution was added dropwise over 20 minutes. The reaction was stirred at room temperature for 1 hour and saturated NaHCO ₃ solution was added slowly. The organic layer was separated and concentrated in vacuo to yield crude benzhydryl thioacetate (38.2 g, 89%).

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

Racemic modafinil was obtained from the oxidation of benzhydrylthioacetamide using H ₂ O ₂ following the same method used for the oxidation of benzhydrylthioacetic acid in the preparation of R-(−)-modafinil.

PXRD diffractogram of co-crystal comprising modafinil and malonic acid. DSC thermogram of a co-crystal comprising modafinil and malonic acid. TGA thermogram of a co-crystal comprising modafinil and malonic acid. Of the Raman spectrum of the co-crystal comprising modafinil and malonic acid (FIG. 4A) and of the co-crystal comprising modafinil and malonic acid (upper spectrum), modafinil (lower spectrum), malonic acid (middle spectrum) and Three Raman spectra (Figure 4B). Infrared spectrum of co-crystal comprising modafinil and malonic acid (FIG. 5A), and modafinil (upper spectrum), malonic acid (middle spectrum) and co-crystal comprising modafinil and malonic acid (lower spectrum) Of three infrared spectra (FIG. 5B). PXRD diffractogram of co-crystal comprising modafinil and malonic acid. DSC thermogram of a co-crystal (from milling) comprising modafinil and malonic acid. Modafinil: packing diagram of malonic acid co-crystal. PXRD diffractogram of co-crystals comprising modafinil and glycolic acid, with background removed and collected, respectively. PXRD diffractogram of co-crystal comprising modafinil and maleic acid, with background removed and collected, respectively. PXRD diffractogram of co-crystal comprising modafinil and L-tartaric acid. PXRD diffractogram of co-crystal comprising modafinil and citric acid. DSC thermogram of a co-crystal comprising modafinil and citric acid. PXRD diffractogram of co-crystals comprising modafinil and succinic acid, with background removed and collected, respectively. DSC thermogram of a co-crystal comprising modafinil and succinic acid. Fig. 3 is a packing diagram of a co-crystal comprising modafinil and succinic acid. PXRD diffractogram of co-crystal comprising modafinil and DL-tartaric acid. PXRD diffractogram of co-crystal (form I) comprising modafinil and fumaric acid. FIG. 4 is a packing diagram of a co-crystal (form I) comprising modafinil and fumaric acid. PXRD diffractogram of co-crystal (form II) comprising modafinil and fumaric acid. PXRD diffractogram of co-crystal comprising modafinil and gentisic acid. PXRD diffractogram of co-crystal comprising modafinil and oxalic acid. PXRD diffractogram of co-crystal comprising modafinil and 1-hydroxy-2-naphthoic acid. PXRD diffractogram of a co-crystal comprising R (−)-modafinil and malonic acid. DSC thermogram of a co-crystal comprising R-(-)-modafinil and malonic acid. PXRD diffractogram of a co-crystal comprising R-(−)-modafinil and succinic acid. DSC thermogram of a co-crystal comprising R-(-)-modafinil and succinic acid. PXRD diffractogram of a co-crystal comprising R (−)-modafinil and citric acid. DSC thermogram of a co-crystal comprising R-(-)-modafinil and citric acid. PXRD diffractogram of a co-crystal comprising R-(−)-modafinil and DL-tartaric acid. DSC thermogram of a co-crystal comprising R-(-)-modafinil and DL-tartaric acid. PXRD diffractogram of co-crystal comprising R-(−)-modafinil and 1-hydroxy-2-naphthoic acid. DSC thermogram of a co-crystal comprising R-(-)-modafinil and 1-hydroxy-2-naphthoic acid. PXRD diffractogram of a co-crystal comprising R-(−)-modafinil and 1-hydroxy-2-naphthoic acid obtained from a high throughput experiment. PXRD diffractogram of a co-crystal comprising R-(−)-modafinil and orotic acid. DSC thermogram of a co-crystal comprising R-(-)-modafinil and orotic acid. PXRD diffractogram of a solvate comprising modafinil and acetic acid. TGA thermogram of a solvate comprising modafinil and acetic acid. DSC thermogram of a solvate comprising modafinil and acetic acid. Raman spectrum of a solvate comprising modafinil and acetic acid. PXRD diffractogram of a solvate comprising modafinil and tetrahydrofuran. PXRD diffractogram of a solvate comprising modafinil and 1,4-dioxane. PXRD diffractogram of a solvate comprising modafinil and methanol. TGA thermogram of a solvate comprising modafinil and methanol. DSC thermogram of a solvate comprising modafinil and methanol. PXRD diffractogram of a solvate comprising modafinil and nitromethane. PXRD diffractogram of a solvate comprising modafinil and acetone. PXRD diffractogram of a possible solvate comprising modafinil and acetone. PXRD diffractogram of a possible solvate comprising modafinil and 1,2-dichloroethane. PXRD diffractogram of modafinil polymorph (form VII). Modafinil: malonic acid co-crystal stability plot over 26 weeks. Expanded view of the stability plot of the modafinil: malonic acid co-crystal over 26 weeks. Comparison of PXRD diffractograms of modafinil: malonic acid co-crystals after enduring several environmental conditions. Free form of modafinil and modafinil: dissolution profiles of several formulations of malonic acid. Modafinil: malonic acid co-crystal in vitro dissolution profile in SGF and SIF. Modafinil: Malonic acid co-crystal in vitro dissolution profile in HCl. Modafinil: DVS plot of malonic acid co-crystal. Modafinil: malonic acid co-crystal pharmacokinetics in dogs. PXRD diffractogram of a co-crystal comprising R-(-)-modafinil and gentisic acid. Packing diagram of modafinil acetone channel solvate. Additional packing diagram of acetone channel solvate of modafinil. PXRD diffractogram of o-xylene solvate. Raman spectrum (middle spectrum) of o-xylene solvate. TGA thermogram of o-xylene solvate. DSC thermogram of o-xylene solvate. PXRD diffractogram of benzene solvate. Raman spectrum of benzene solvate (middle spectrum). TGA thermogram of benzene solvate. DSC thermogram of benzene solvate. PXRD diffractogram of toluene solvate. Raman spectrum (middle spectrum) of toluene solvate. TGA thermogram of toluene solvate. DSC thermogram of toluene solvate. PXRD diffractogram of ethanol solvate of R-(−)-modafinil. TGA thermogram of ethanol solvate of R-(−)-modafinil. PXRD diffractogram of benzyl alcohol solvate of R-(−)-modafinil. DSC thermogram of benzyl alcohol solvate of R-(−)-modafinil. TGA thermogram of benzyl alcohol solvate of R-(−)-modafinil. PXRD diffractogram of isopropanol solvate of R-(-)-modafinil. PXRD diffractogram of acetonitrile solvate of R-(−)-modafinil. PXRD diffractogram of R-(-)-modafinil: glutaric acid co-crystal. PXRD diffractogram of R-(-)-modafinil: citric acid co-crystal. PXRD diffractogram of R-(-)-modafinil: L-tartaric acid co-crystal. PXRD diffractogram of R-(-)-modafinil: oxalic acid co-crystal. PXRD diffractogram of R-(-)-modafinil: palmitic acid co-crystal. PXRD diffractogram of R-(-)-modafinil: L-proline co-crystal. PXRD diffractogram of R-(-)-modafinil: salicylic acid co-crystal. PXRD diffractogram of R-(-)-modafinil: lauric acid co-crystal. PXRD diffractogram of R-(-)-modafinil: L-malic acid co-crystal.

Claims (36)

  Modafinil and: malonic acid, tartaric acid, citric acid, succinic acid, gentisic acid, oxalic acid, l-hydroxy-2-naphthoic acid, orotic acid, glutaric acid, L-tartaric acid, palmitic acid, L-proline, salicylic acid, lauric acid A co-crystal comprising a compound forming a co-crystal selected from the group consisting of acid, L-malic acid and maleic acid. (A) the co-crystal is characterized by a powder X-ray diffraction pattern comprising a peak represented by a 2θ angle;
(I) whether the co-crystal is a modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises peaks of 5.08, 9.28 and 16.81 °;
(Ii) the co-crystal is a modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises peaks at 16.81, 18.27 and 19.45 °;
(Iii) whether the co-crystal is a modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises peaks of 9.28, 19.45 and 22.83 °;
(Iv) the co-crystal is a modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises peaks of 5.08 and 9.28 °;
(V) whether the co-crystal is a modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises peaks at 16.81 and 19.45 °;
(Vi) whether the co-crystal is a modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises peaks at 18.27 and 22.83 °;
(Vii) whether the co-crystal is a modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises a 5.08 ° peak;
(Viii) the co-crystal is a modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises a 9.28 ° peak; or (ix) the co-crystal is a modafinil: malonic acid co-crystal. A crystal and the X-ray diffraction pattern comprises a peak at 16.81 °;
(B) the co-crystal is characterized by a DSC thermogram, the co-crystal is a modafinil: malonic acid co-crystal, and the DSC thermogram comprises an endothermic transition at about 116 ° C .; or (c) The crystal is characterized by a Raman spectrum comprising a peak represented by cm ⁻¹ ;
(I) whether the co-crystal is modafinil: malonic acid co-crystal and the Raman spectrum comprises peaks of 1004, 633 and 265;
(Ii) whether the co-crystal is a modafinil: malonic acid co-crystal and the Raman spectrum comprises 1032, 1601 and 767 peaks;
(Iii) whether the co-crystal is a modafinil: malonic acid co-crystal and the Raman spectrum comprises 1004 and 633 peaks;
(Iv) the co-crystal is modafinil: malonic acid co-crystal and the Raman spectrum comprises peaks 1183 and 767; or (v) the co-crystal is modafinil: malonic acid co-crystal And the Raman spectrum comprises 1601 and 718 peaks,
The co-crystal of claim 1. (A) the co-crystal is characterized by a powder X-ray diffraction pattern comprising a peak represented by a 2θ angle;
(I) whether the co-crystal is modafinil: maleic acid co-crystal and the X-ray diffraction pattern comprises peaks at 4.69, 6.15 and 9.61 °;
(Ii) the co-crystal is a modafinil: maleic acid co-crystal and the X-ray diffraction pattern comprises peaks at 10.23, 19.97 and 21.83 °;
(Iii) the co-crystal is modafinil: maleic acid co-crystal and the X-ray diffraction pattern comprises peaks at 4.69, 10.23 and 21.83 °;
(Iv) the co-crystal is a modafinil: maleic acid co-crystal and the X-ray diffraction pattern comprises peaks at 4.69 and 19.97 °;
(V) whether the co-crystal is a modafinil: maleic acid co-crystal and the X-ray diffraction pattern comprises peaks at 6.15 and 9.61 °;
(Vi) whether the co-crystal is a modafinil: maleic acid co-crystal and the X-ray diffraction pattern comprises peaks at 4.69 and 6.15 °;
(Vii) whether the co-crystal is a modafinil: maleic acid co-crystal and the X-ray diffraction pattern comprises a peak at 4.69 °;
(Viii) the co-crystal is a modafinil: maleic acid co-crystal and the X-ray diffraction pattern comprises a 9.61 ° peak; or (x) the co-crystal is a modafinil: maleic acid co-crystal. And the X-ray diffraction pattern comprises a 19.97 ° peak; or (b) the co-crystal is characterized by DSC thermogram, and the co-crystal is modafinil: maleic acid co-crystal And the DSC thermogram comprises an endothermic transition at about 168 ° C.,
The co-crystal of claim 1. The co-crystal is characterized by a powder X-ray diffraction pattern comprising a peak represented by a 2θ angle;
(A) whether the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks of 6.10, 14.33 and 20.71 °;
(B) whether the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks of 16.93, 20.15 and 22.49 °;
(C) whether the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 16.93, 20.71 and 29.72 °;
(D) whether the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 6.10 and 20.15 °;
(E) whether the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 14.33 and 20.71 °;
(F) whether the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises 7.36 and 25.04 ° peaks;
(G) whether the co-crystal is a modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises a 6.10 ° peak;
(H) the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises a peak at 16.93 °; or (i) the co-crystal is modafinil: L-tartaric acid. And the X-ray diffraction pattern comprises a peak at 20.71 °,
The co-crystal of claim 1. The co-crystal is characterized by a powder X-ray diffraction pattern comprising a peak represented by a 2θ angle;
(A) whether the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises peaks of 5.29, 7.29 and 9.31 °;
(B) whether the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises peaks at 12.41, 13.29 and 14.61 °;
(C) whether the co-crystal is a modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises 17.29, 17.97 and 21.37 ° peaks;
(D) whether the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises peaks of 5.29 and 17.29 °;
(E) whether the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises 7.29 and 9.31 ° peaks;
(F) whether the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises peaks at 12.41 and 21.37 °;
(G) whether the co-crystal is a modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises a 5.29 ° peak;
(H) the co-crystal is a modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises a 7.29 ° peak; or (i) the co-crystal is a modafinil: citric acid co-crystal. A crystal and the X-ray diffraction pattern comprises a 12.41 ° peak,
The co-crystal of claim 1. (A) the co-crystal is characterized by a powder X-ray diffraction pattern comprising a peak represented by a 2θ angle;
(I) the co-crystal is modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises 5.45, 9.93 and 17.99 ° peaks;
(Ii) the co-crystal is a modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises 19.95, 21.95 and 25.07 ° peaks;
(Iii) the co-crystal is modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises 5.45, 17.99 and 21.35 ° peaks;
(Iv) whether the co-crystal is modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises 5.45 and 9.93 ° peaks;
(V) whether the co-crystal is a modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises 17.99 and 21.95 ° peaks;
(Vi) the co-crystal is a modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises 9.93 and 19.95 ° peaks;
(Vii) whether the co-crystal is a modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises a 5.45 ° peak;
(Viii) the co-crystal is a modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises a 9.93 ° peak; or (xi) the co-crystal is a modafinil: succinic acid co-crystal. And the X-ray diffraction pattern comprises a peak at 17.99 °; or (b) the co-crystal is characterized by DSC thermogram and the co-crystal is modafinil: succinic acid co-crystal And the DSC thermogram comprises an endothermic transition at about 149 ° C.,
The co-crystal of claim 1. The co-crystal is characterized by a powder X-ray diffraction pattern comprising a peak represented by a 2θ angle;
(A) whether the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises 4.75, 9.53 and 15.83 ° peaks;
(B) whether the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 17.61, 20.25 and 22.55 °;
(C) whether the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks of 10.07, 17.61 and 21.53 °;
(D) whether the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises 4.75 and 15.83 ° peaks;
(E) whether the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises 9.53 and 17.61 ° peaks;
(F) whether the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises 21.53 and 22.55 ° peaks;
(G) whether the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises a peak at 4.75 °;
(H) the co-crystal is a modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises a 9.53 ° peak; or (i) the co-crystal is modafinil: DL-tartaric acid. And the X-ray diffraction pattern comprises a 15.83 ° peak,
The co-crystal of claim 1. A co-crystal characterized by a powder X-ray diffraction pattern comprising a peak represented by a 2θ angle;
(A) whether the co-crystal is modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises 5.45, 9.95 and 18.03 ° peaks;
(B) whether the co-crystal is a modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 15.93, 18.81 and 21.95 °;
(C) whether the co-crystal is a modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 9.95, 19.93 and 23.09 °;
(D) whether the co-crystal is modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises 5.45 and 9.95 ° peaks;
(E) whether the co-crystal is modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises 5.45 and 18.03 ° peaks;
(F) whether the co-crystal is modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 15.93 and 21.95 °;
(G) whether the co-crystal is a modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises a 5.45 ° peak;
(H) whether the co-crystal is a modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises a 9.95 ° peak;
(I) the co-crystal is a modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises a peak at 18.03 °;
Co-crystal.   9. The co-crystal of claim 8, wherein the co-crystal is modafinil: fumaric acid Form I. A co-crystal characterized by a powder X-ray diffraction pattern comprising a peak represented by a 2θ angle; (a) the co-crystal is a modafinil: fumaric acid co-crystal and the X-ray diffraction pattern is Comprise peaks at 6.47, 8.57 and 9.99 °;
(B) whether the co-crystal is modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises peaks of 13.89, 14.53 and 20.79 °;
(C) whether the co-crystal is a modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 16.45, 18.39 and 20.05 °;
(D) whether the co-crystal is a modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises 6.47 and 20.79 ° peaks;
(E) whether the co-crystal is a modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises peaks of 9.99 and 14.53 °;
(F) whether the co-crystal is a modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises 13.89 and 20.05 ° peaks;
(G) whether the co-crystal is a modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises a 6.47 ° peak;
(H) the co-crystal is a modafinil: fumaric acid co-crystal and the X-ray diffraction pattern comprises a peak at 13.89 °; or (i) the co-crystal is a modafinil: fumaric acid co-crystal. A crystal and the X-ray diffraction pattern comprises a peak at 20.79 °,
Co-crystal.   11. The co-crystal of claim 10, wherein the co-crystal is modafinil: fumaric acid Form II. The co-crystal is characterized by a powder X-ray diffraction pattern comprising a peak represented by a 2θ angle;
(A) whether the co-crystal is modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises peaks of 6.96, 12.92 and 14.76 °;
(B) whether the co-crystal is a modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises peaks at 14.76, 18.26 and 20.10 °;
(C) the co-crystal is a modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises peaks of 6.96, 17.40 and 20.94 °;
(D) whether the co-crystal is modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises peaks of 6.96 and 14.76 °;
(E) whether the co-crystal is modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises peaks at 12.92 and 17.40 °;
(F) whether the co-crystal is modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises peaks of 6.96 and 18.26 °;
(G) whether the co-crystal is a modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises a 6.96 ° peak;
(H) the co-crystal is a modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises a peak at 14.76 °; or (i) the co-crystal is a modafinil: gentisic acid co-crystal. A crystal and the X-ray diffraction pattern comprises a peak at 18.26 °,
The co-crystal of claim 1. The co-crystal is characterized by a powder X-ray diffraction pattern comprising a peak represented by a 2θ angle;
(A) whether the co-crystal is modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises peaks of 5.98, 17.54 and 19.68 °;
(B) whether the co-crystal is modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises peaks at 13.68, 14.80 and 21.12 °;
(C) whether the co-crystal is modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises peaks at 17.54, 19.68 and 21.86 °;
(D) the co-crystal is a modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises 5.98 and 19.68 ° peaks;
(E) whether the co-crystal is modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises 13.68 and 14.80 ° peaks;
(F) the co-crystal is a modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises 5.98 and 17.54 ° peaks;
(G) whether the co-crystal is a modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises a 5.98 ° peak;
(H) the co-crystal is a modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises a 19.68 ° peak; or (i) the co-crystal is a modafinil: oxalic acid co-crystal. A crystal and the X-ray diffraction pattern comprises a peak at 17.54 °,
The co-crystal of claim 1. The co-crystal is characterized by a powder X-ray diffraction pattern comprising a peak represented by a 2θ angle;
(A) whether the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises peaks of 5.72, 7.10 and 14.16 °;
(B) whether the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises peaks at 11.48, 15.66 and 20.26 °;
(C) whether the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises peaks of 5.72, 7.10 and 20.26 °;
(D) whether the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.72 and 7.10 °;
(E) whether the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises peaks at 14.16 and 20.26 °;
(F) whether the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.72 and 14.16 °;
(G) whether the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises a peak at 5.72 °;
(H) the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises a peak at 7.10 °; or (i) the co-crystal is Modafinil: 1-hydroxy-2-naphthoic acid co-crystal, and the X-ray diffraction pattern comprises a peak at 14.16 °,
The co-crystal of claim 1. (A) the co-crystal is characterized by a powder X-ray diffraction pattern comprising a peak represented by a 2θ angle;
(I) whether the co-crystal is a modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises peaks of 5.04, 9.26 and 16.73 °;
(Ii) the co-crystal is a modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises peaks at 18.23, 19.37 and 22.74 °;
(Iii) the co-crystal is a modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises 5.04, 16.73 and 19.37 ° peaks;
(Iv) the co-crystal is a modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises 5.04 and 9.26 ° peaks;
(V) the co-crystal is a modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises peaks at 16.73 and 19.37 °;
(Vi) the co-crystal is a modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises 9.26 and 18.23 ° peaks;
(Vii) whether the co-crystal is a modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises a 5.04 ° peak;
(Viii) the co-crystal is a modafinil: malonic acid co-crystal and the X-ray diffraction pattern comprises a 9.26 ° peak; or (ix) the co-crystal is a modafinil: malonic acid co-crystal. And the X-ray diffraction pattern comprises a peak at 19.37 °; or (b) the co-crystal is characterized by a DSC thermogram and the co-crystal is a modafinil: malon co-crystal And the DSC thermogram comprises an endothermic transition at about 115 ° C.,
The co-crystal of claim 1.   The co-crystal of claim 15, wherein the modafinil is R-(-)-modafinil. (A) the co-crystal is characterized by a powder X-ray diffraction pattern comprising a peak represented by a 2θ angle;
(I) the co-crystal is modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.36, 9.83 and 17.88 °;
(Ii) the co-crystal is modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises peaks at 15.80, 19.87 and 21.85 °;
(Iii) the co-crystal is a modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.36, 9.83 and 21.85 °;
(Iv) the co-crystal is modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises 5.36 and 9.83 ° peaks;
(V) whether the co-crystal is modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises 17.88 and 19.87 ° peaks;
(Vi) the co-crystal is modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises 9.83 and 15.80 ° peaks;
(Vii) whether the co-crystal is modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises a peak at 5.36 °;
(Viii) the co-crystal is a modafinil: succinic acid co-crystal and the X-ray diffraction pattern comprises a 9.83 ° peak; or (ix) the co-crystal is a modafinil: succinic acid co-crystal. And the X-ray diffraction pattern comprises a peak at 17.88 °; or (b) the co-crystal is characterized by DSC thermogram, and the co-crystal is modafinil: succinic acid co-crystal And the DSC thermogram comprises an endothermic transition at about 145 ° C.
The co-crystal of claim 1.   The co-crystal of claim 17, wherein the modafinil is R-(-)-modafinil. (A) the co-crystal is characterized by a powder X-ray diffraction pattern comprising a peak represented by a 2θ angle;
(I) whether the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.18, 7.23 and 9.23 °;
(Ii) the co-crystal is a modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises peaks at 12.32, 13.23 and 17.25 °;
(Iii) the co-crystal is a modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises 9.23, 17.92 and 21.30 ° peaks;
(Iv) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises 5.18 and 9.23 ° peaks;
(V) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises 7.23 and 13.23 ° peaks;
(Vi) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises 17.25 and 17.92 ° peaks;
(Vii) whether the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises a peak at 5.18 °;
(Viii) the co-crystal is a modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises a peak at 7.23 °; or (ix) the co-crystal is a modafinil: citric acid co-crystal. And the X-ray diffraction pattern comprises a peak at 9.23 °; or (b) the co-crystal is characterized by DSC thermogram and the co-crystal is modafinil: succinic acid co-crystal And the DSC thermogram comprises an endothermic transition at about 89 ° C.
The co-crystal of claim 1.   20. A co-crystal according to claim 19, wherein modafinil is R-(-)-modafinil. The co-crystal is characterized by a powder X-ray diffraction pattern comprising a peak represented by a 2θ angle;
(A) whether the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises 5.27, 8.85 and 10.60 ° peaks;
(B) whether the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises peaks at 10.60, 14.47 and 21.20 °;
(C) whether the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises peaks of 5.27, 14.47 and 23.03 °;
(D) whether the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises 5.27 and 8.85 ° peaks;
(E) whether the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises peaks at 10.60 and 23.03 °;
(F) whether the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises peaks at 14.47 and 21.20 °;
(G) whether the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises a peak at 5.27 °;
(H) the co-crystal is modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises a peak at 8.85 °; or (i) the co-crystal is Modafinil: 1-hydroxy-2-naphthoic acid co-crystal and the X-ray diffraction pattern comprises a peak at 14.47 °,
The co-crystal of claim 1.   The co-crystal of claim 21, wherein the modafinil is R-(-)-modafinil. The co-crystal is characterized by a powder X-ray diffraction pattern comprising a peak represented by a 2θ angle;
(A) whether the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks of 4.67, 15.41 and 19.46 °;
(B) whether the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks of 17.97, 19.46 and 22.91 °;
(C) whether the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks of 4.67, 22.91 and 24.63 °;
(D) whether the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises 4.67 and 19.46 ° peaks;
(E) whether the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks of 17.97 and 22.91 °;
(F) whether the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 15.41 and 24.63 °;
(G) whether the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises a peak at 4.67 °;
(H) the co-crystal is modafinil: DL-tartaric acid co-crystal and the X-ray diffraction pattern comprises a peak at 19.46 °; or (i) the co-crystal is modafinil: DL-tartaric acid. And the X-ray diffraction pattern comprises a peak at 22.91 °,
The co-crystal of claim 1.   24. The co-crystal of claim 23, wherein modafinil is R-(-)-modafinil. The co-crystal is characterized by a powder X-ray diffraction pattern comprising a peak represented by a 2θ angle;
(A) whether the co-crystal is a modafinil: orotic acid co-crystal and the X-ray diffraction pattern comprises peaks at 9.77, 17.85 and 20.52 °;
(B) whether the co-crystal is a modafinil: orotic acid co-crystal and the X-ray diffraction pattern comprises peaks of 17.85, 24.03 and 26.80 °;
(C) whether the co-crystal is modafinil: orotic acid co-crystal and the X-ray diffraction pattern comprises 9.77, 20.52 and 24.03 ° peaks;
(D) whether the co-crystal is a modafinil: orotic acid co-crystal and the X-ray diffraction pattern comprises 9.77 and 17.85 ° peaks;
(E) whether the co-crystal is a modafinil: orotic acid co-crystal and the X-ray diffraction pattern comprises peaks at 17.85 and 24.03 °;
(F) the co-crystal is a modafinil: orotic acid co-crystal and the X-ray diffraction pattern comprises 9.77 and 26.80 ° peaks;
(G) whether the co-crystal is a modafinil: orotic acid co-crystal and the X-ray diffraction pattern comprises a peak at 9.77 °;
(H) the co-crystal is a modafinil: orotic acid co-crystal and the X-ray diffraction pattern comprises a 17.85 ° peak; or (i) the co-crystal is a modafinil: orotic acid co-crystal. A crystal and the X-ray diffraction pattern comprises a peak at 24.03 °,
The co-crystal of claim 1.   26. The co-crystal of claim 25, wherein modafinil is R-(-)-modafinil. The co-crystal is characterized by a powder X-ray diffraction pattern comprising a peak represented by a 2θ angle;
(A) the co-crystal is a modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises 7.07, 9.07 and 12.31 ° peaks;
(B) whether the co-crystal is modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises peaks of 9.07, 18.39 and 21.27 °;
(C) whether the co-crystal is a modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises peaks at 17.63, 23.57 and 26.93 °;
(D) whether the co-crystal is a modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises 9.07 and 16.03 ° peaks;
(E) whether the co-crystal is a modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises peaks at 7.51 and 21.27 °;
(F) whether the co-crystal is a modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises 7.07 and 7.51 ° peaks;
(G) whether the co-crystal is modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises a peak at 9.07 °;
(H) whether the co-crystal is a modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises a 7.07 ° peak;
(I) whether the co-crystal is modafinil: gentisic acid co-crystal and the X-ray diffraction pattern comprises a peak of 16.03 °;
(J) The co-crystal is modafinil: gentisic acid co-crystal, and the X-ray diffraction pattern has peaks of 7.07, 9.07, 16.03, 18.39, 21.27, and 23.57 °. Or (k) the co-crystal is modafinil: gentisic acid co-crystal and the X-ray diffraction pattern is 7.51, 12.31, 14.09, 16.03, 17.63 And comprising a peak at 23.57 °,
The co-crystal of claim 1. The co-crystal is characterized by a powder X-ray diffraction pattern comprising a peak represented by a 2θ angle;
(A) whether the co-crystal is a modafinil: glutaric acid co-crystal and the X-ray diffraction pattern comprises 9.78, 18.92 and 21.36 ° peaks;
(B) whether the co-crystal is modafinil: glutaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 20.50, 22.25 and 23.87 °;
(C) whether the co-crystal is modafinil: glutaric acid co-crystal and the X-ray diffraction pattern comprises 8.67, 19.74 and 27.16 ° peaks;
(D) whether the co-crystal is a modafinil: glutaric acid co-crystal and the X-ray diffraction pattern comprises 8.67 and 18.92 ° peaks;
(E) whether the co-crystal is a modafinil: glutaric acid co-crystal and the X-ray diffraction pattern comprises 9.78 and 20.50 ° peaks;
(F) whether the co-crystal is modafinil: glutaric acid co-crystal and the X-ray diffraction pattern comprises 21.36 and 23.87 ° peaks;
(G) whether the co-crystal is modafinil: glutaric acid co-crystal and the X-ray diffraction pattern comprises a peak at 23.87 °;
(H) whether the co-crystal is modafinil: glutaric acid co-crystal and the X-ray diffraction pattern comprises a peak at 8.67 °;
(I) whether the co-crystal is modafinil: glutaric acid co-crystal and the X-ray diffraction pattern comprises a 9.78 ° peak;
(J) The co-crystal is a modafinil: glutaric acid co-crystal and the X-ray diffraction pattern comprises peaks of 8.67, 9.78, 18.92, 20.50 and 23.87 °. Or (k) the co-crystal is a modafinil: glutaric acid co-crystal and the X-ray diffraction pattern has peaks of 18.92, 20.50, 21.36, 22.25 and 23.87 °. Comprising
The co-crystal of claim 1. The co-crystal is characterized by a powder X-ray diffraction pattern comprising a peak represented by a 2θ angle;
(A) whether the co-crystal is a modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises 7.06, 9.10 and 17.95 ° peaks;
(B) whether the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises peaks at 12.43, 13.18 and 20.85 °;
(C) the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises 5.23, 7.06 and 9.10 ° peaks;
(D) whether the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises peaks at 5.23 and 12.43 °;
(E) whether the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises peaks at 9.10 and 17.95 °;
(F) whether the co-crystal is a modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises peaks at 9.10 and 12.43 °;
(G) whether the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises a 7.06 ° peak;
(H) whether the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises a peak at 9.10 °;
(I) whether the co-crystal is modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises a peak at 17.95 °;
(J) The co-crystal is a modafinil: citric acid co-crystal and the X-ray diffraction pattern comprises peaks of 7.06, 12.43, 13.18, 17.95 and 20.85 °. Or (k) the co-crystal is a modafinil: citric acid co-crystal and the X-ray diffraction pattern has peaks of 7.06, 9.10, 17.95, 21.39 and 22.96 °. Comprising
The co-crystal of claim 1. The co-crystal is characterized by a powder X-ray diffraction pattern comprising a peak represented by a 2θ angle;
(A) whether the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 4.56, 10.33 and 17.29 °;
(B) whether the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks of 17.29, 19.91 and 21.13 °;
(C) whether the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 4.56, 14.45 and 19.91 °;
(D) whether the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises peaks at 4.56 and 10.33 °;
(E) whether the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises 17.29 and 19.91 ° peaks;
(F) whether the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises 19.91 and 21.13 ° peaks;
(G) whether the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises a peak at 4.56 °;
(H) whether the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises a peak at 10.33 °;
(I) the co-crystal is modafinil: L-tartaric acid co-crystal and the X-ray diffraction pattern comprises a 19.91 ° peak; or (j) the co-crystal is modafinil: L-tartaric acid. And the X-ray diffraction pattern comprises peaks at 4.56, 10.33, 17.29, 19.91 and 21.13 °,
The co-crystal of claim 1. The co-crystal is characterized by a powder X-ray diffraction pattern comprising a peak represented by a 2θ angle;
(A) whether the co-crystal is modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises peaks of 5.99, 14.73 and 17.38 °;
(B) whether the co-crystal is a modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises 17.38, 18.64 and 28.85 ° peaks;
(C) whether the co-crystal is modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises peaks at 14.73, 18.64 and 25.66 °;
(D) whether the co-crystal is a modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises peaks of 5.99 and 14.73 °;
(E) whether the co-crystal is modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises 17.38 and 18.64 ° peaks;
(F) whether the co-crystal is modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises peaks of 5.99 and 28.85 °;
(G) whether the co-crystal is a modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises a peak at 5.99 °;
(H) whether the co-crystal is a modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises a peak at 14.73 °;
(I) the co-crystal is a modafinil: oxalic acid co-crystal and the X-ray diffraction pattern comprises a 28.85 ° peak; or (j) the co-crystal is a modafinil: oxalic acid co-crystal. The crystal and the X-ray diffraction pattern comprises peaks of 5.99, 14.73, 17.38, 18.64 and 28.85 °,
The co-crystal of claim 1. The co-crystal is characterized by a powder X-ray diffraction pattern comprising a peak represented by a 2θ angle;
(A) whether the co-crystal is a modafinil: palmitic acid co-crystal and the X-ray diffraction pattern comprises peaks of 3.80, 6.55 and 7.66 °;
(B) whether the co-crystal is modafinil: palmitic acid co-crystal and the X-ray diffraction pattern comprises peaks of 10.24, 19.48 and 21.09 °;
(C) whether the co-crystal is modafinil: palmitic acid co-crystal and the X-ray diffraction pattern comprises 3.80, 19.48 and 23.99 ° peaks;
(D) whether the co-crystal is modafinil: palmitic acid co-crystal and the X-ray diffraction pattern comprises 3.80 and 6.55 ° peaks;
(E) whether the co-crystal is a modafinil: palmitic acid co-crystal and the X-ray diffraction pattern comprises 6.55 and 7.66 ° peaks;
(F) whether the co-crystal is a modafinil: palmitic acid co-crystal and the X-ray diffraction pattern comprises peaks at 19.48 and 23.99 °;
(G) whether the co-crystal is modafinil: palmitic acid co-crystal and the X-ray diffraction pattern comprises a peak at 3.80 °;
(H) whether the co-crystal is a modafinil: palmitic acid co-crystal and the X-ray diffraction pattern comprises a 6.55 ° peak;
(I) whether the co-crystal is modafinil: palmitic acid co-crystal and the X-ray diffraction pattern comprises a peak at 7.66 °;
(J) the co-crystal is a modafinil: palmitic acid co-crystal and the X-ray diffraction pattern comprises peaks at 3.80, 7.66, 10.24 and 19.48 °; k) The co-crystal is a modafinil: palmitic acid co-crystal and the X-ray diffraction pattern has peaks of 3.80, 6.55, 7.66, 10.24, 19.48 and 23.99 °. Comprising
The co-crystal of claim 1. The co-crystal is characterized by a powder X-ray diffraction pattern comprising a peak represented by a 2θ angle;
(A) the co-crystal is modafinil: L-proline co-crystal and the X-ray diffraction pattern comprises 6.52, 8.53 and 10.25 ° peaks;
(B) whether the co-crystal is modafinil: L-proline co-crystal and the X-ray diffraction pattern comprises peaks of 19.06, 22.75 and 25.08 °;
(C) the co-crystal is modafinil: L-proline co-crystal and the X-ray diffraction pattern comprises 6.52, 10.25 and 19.06 ° peaks;
(D) whether the co-crystal is modafinil: L-proline co-crystal and the X-ray diffraction pattern comprises 6.52 and 8.53 ° peaks;
(E) whether the co-crystal is modafinil: L-proline co-crystal and the X-ray diffraction pattern comprises 6.52 and 10.25 ° peaks;
(F) whether the co-crystal is modafinil: L-proline co-crystal and the X-ray diffraction pattern comprises peaks of 19.06 and 22.29 °;
(G) whether the co-crystal is modafinil: L-proline co-crystal and the X-ray diffraction pattern comprises a peak at 6.52 °;
(H) whether the co-crystal is modafinil: L-proline co-crystal and the X-ray diffraction pattern comprises a peak at 8.53 °;
(I) whether the co-crystal is modafinil: L-proline co-crystal and the X-ray diffraction pattern comprises a peak at 19.06 °;
(J) The co-crystal is a modafinil: L-proline co-crystal and the X-ray diffraction pattern includes peaks of 6.52, 10.25, 19.06, 22.75 and 25.08 °. Or (k) the co-crystal is modafinil: L-proline co-crystal and the X-ray diffraction pattern is 8.53, 10.25, 19.06, 22.29 and 25.08 °. Comprising a peak,
The co-crystal of claim 1. The co-crystal is characterized by a powder X-ray diffraction pattern comprising a peak represented by a 2θ angle;
(A) whether the co-crystal is a modafinil: salicylic acid co-crystal and the X-ray diffraction pattern comprises peaks of 8.92, 10.85 and 17.07 °;
(B) whether the co-crystal is a modafinil: salicylic acid co-crystal and the X-ray diffraction pattern comprises peaks at 12.18, 21.24 and 23.32 °;
(C) the co-crystal is modafinil: salicylic acid co-crystal and the X-ray diffraction pattern comprises 8.92, 18.81 and 25.22 ° peaks;
(D) whether the co-crystal is a modafinil: salicylic acid co-crystal and the X-ray diffraction pattern comprises 8.92 and 10.85 ° peaks;
(E) whether the co-crystal is a modafinil: salicylic acid co-crystal and the X-ray diffraction pattern comprises peaks of 17.07 and 21.24 °;
(F) whether the co-crystal is modafinil: salicylic acid co-crystal and the X-ray diffraction pattern comprises peaks at 23.32 and 25.22 °;
(G) whether the co-crystal is modafinil: salicylic acid co-crystal and the X-ray diffraction pattern comprises a peak at 8.92 °;
(H) whether the co-crystal is a modafinil: salicylic acid co-crystal and the X-ray diffraction pattern comprises a peak at 10.85 °;
(I) whether the co-crystal is modafinil: salicylic acid co-crystal and the X-ray diffraction pattern comprises a peak at 21.24 °;
(J) whether the co-crystal is a modafinil: salicylic acid co-crystal and the X-ray diffraction pattern comprises peaks of 8.92, 12.18, 17.07, 21.24 and 23.32 ° Or (k) the co-crystal is a modafinil: salicylic acid co-crystal and the X-ray diffraction pattern comprises peaks of 10.85, 14.04, 21.24 and 23.32 °,
The co-crystal of claim 1. The co-crystal is characterized by a powder X-ray diffraction pattern comprising a peak represented by a 2θ angle;
(A) whether the co-crystal is modafinil: lauric acid co-crystal and the X-ray diffraction pattern comprises peaks of 3.12, 6.55 and 10.24 °;
(B) whether the co-crystal is a modafinil: lauric acid co-crystal and the X-ray diffraction pattern comprises peaks at 6.55, 13.97 and 17.62 °;
(C) whether the co-crystal is modafinil: lauric acid co-crystal and the X-ray diffraction pattern comprises peaks of 3.12, 21.38 and 23.81 °;
(D) whether the co-crystal is a modafinil: lauric acid co-crystal and the X-ray diffraction pattern comprises peaks at 3.12 and 6.55 °;
(E) whether the co-crystal is modafinil: lauric acid co-crystal and the X-ray diffraction pattern comprises 10.24 and 17.62 ° peaks;
(F) whether the co-crystal is a modafinil: lauric acid co-crystal and the X-ray diffraction pattern comprises 21.38 and 23.81 ° peaks;
(G) whether the co-crystal is a modafinil: lauric acid co-crystal and the X-ray diffraction pattern comprises a peak at 3.12 °;
(H) whether the co-crystal is modafinil: lauric acid co-crystal and the X-ray diffraction pattern comprises a peak at 6.55 °;
(I) whether the co-crystal is modafinil: lauric acid co-crystal and the X-ray diffraction pattern comprises a peak at 21.38 °;
(J) The co-crystal is a modafinil: lauric acid co-crystal and the X-ray diffraction pattern comprises peaks of 3.12, 10.24, 16.40, 19.02 and 21.38 °. Or (k) the co-crystal is a modafinil: lauric acid co-crystal and the X-ray diffraction pattern has peaks of 3.12, 6.55, 10.24, 21.38 and 23.81 °. Comprising
The co-crystal of claim 1. The co-crystal is characterized by a powder X-ray diffraction pattern comprising a peak represented by a 2θ angle;
(A) whether the co-crystal is a modafinil: L-malic acid co-crystal and the X-ray diffraction pattern comprises peaks of 4.62, 9.32 and 19.30 °;
(B) whether the co-crystal is modafinil: L-malic acid co-crystal and the X-ray diffraction pattern comprises 9.32, 10.32 and 21.48 ° peaks;
(C) whether the co-crystal is modafinil: L-malic acid co-crystal and the X-ray diffraction pattern comprises peaks at 19.30, 21.48 and 24.26 °;
(D) the co-crystal is modafinil: L-malic acid co-crystal and the X-ray diffraction pattern comprises 4.62 and 9.32 ° peaks;
(E) whether the co-crystal is modafinil: L-malic acid co-crystal and the X-ray diffraction pattern comprises 9.32 and 10.32 ° peaks;
(F) whether the co-crystal is modafinil: L-malic acid co-crystal and the X-ray diffraction pattern comprises 19.30 and 21.48 ° peaks;
(G) whether the co-crystal is modafinil: L-malic acid co-crystal and the X-ray diffraction pattern comprises a peak at 4.62 °;
(H) whether the co-crystal is a modafinil: L-malic acid co-crystal and the X-ray diffraction pattern comprises a peak at 9.32 °;
(I) whether the co-crystal is modafinil: L-malic acid co-crystal and the X-ray diffraction pattern comprises a peak at 19.30 °;
(J) The co-crystal is a modafinil: L-malic acid co-crystal, and the X-ray diffraction pattern includes peaks of 4.62, 15.83, 17.38, 19.30, and 21.48 °. Or (k) the co-crystal is modafinil: L-malic acid co-crystal and the X-ray diffraction pattern is 9.32, 10.32, 17.38, 19.30, 21.48. And a peak at 24.26 °,
The co-crystal of claim 1.