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WO2005023198A2 - Compositions de modafinil - Google Patents

Compositions de modafinil Download PDF

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Publication number
WO2005023198A2
WO2005023198A2 PCT/US2004/029013 US2004029013W WO2005023198A2 WO 2005023198 A2 WO2005023198 A2 WO 2005023198A2 US 2004029013 W US2004029013 W US 2004029013W WO 2005023198 A2 WO2005023198 A2 WO 2005023198A2
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WO
WIPO (PCT)
Prior art keywords
crystal
acid
degrees
ray diffraction
diffraction pattern
Prior art date
Application number
PCT/US2004/029013
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English (en)
Other versions
WO2005023198A3 (fr
Inventor
Magali Bourghol Hickey
Matthew Peterson
Orn Almarsson
Mark Oliveira
Original Assignee
Cephalon, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US10/660,202 external-priority patent/US7927613B2/en
Application filed by Cephalon, Inc. filed Critical Cephalon, Inc.
Priority to CA2534664A priority Critical patent/CA2534664C/fr
Priority to US10/570,405 priority patent/US7566805B2/en
Priority to AU2004270238A priority patent/AU2004270238B2/en
Priority to JP2006525508A priority patent/JP4842819B2/ja
Priority to BRPI0413777-9A priority patent/BRPI0413777A/pt
Priority to NZ545133A priority patent/NZ545133A/en
Priority to CN2004800319825A priority patent/CN1874993B/zh
Priority to MXPA06002507A priority patent/MXPA06002507A/es
Priority to EP20040783308 priority patent/EP1670753A4/fr
Priority to KR1020067004425A priority patent/KR101184797B1/ko
Priority to CA002556106A priority patent/CA2556106A1/fr
Priority to JP2006552169A priority patent/JP4917441B2/ja
Priority to EP10001997A priority patent/EP2292213A1/fr
Priority to EP05712282A priority patent/EP1718607A4/fr
Priority to BRPI0507455-0A priority patent/BRPI0507455A/pt
Priority to CN2005800041104A priority patent/CN1980888B/zh
Priority to EA200601390A priority patent/EA009949B1/ru
Priority to US10/587,086 priority patent/US20090018202A1/en
Priority to AU2005212229A priority patent/AU2005212229B2/en
Priority to PCT/US2005/002782 priority patent/WO2005077894A1/fr
Publication of WO2005023198A2 publication Critical patent/WO2005023198A2/fr
Publication of WO2005023198A3 publication Critical patent/WO2005023198A3/fr
Priority to IL173575A priority patent/IL173575A0/en
Priority to NO20060669A priority patent/NO20060669L/no
Priority to IL176934A priority patent/IL176934A/en
Priority to NO20063957A priority patent/NO20063957L/no
Priority to IL199140A priority patent/IL199140A/en
Priority to US12/708,998 priority patent/US8338646B2/en
Priority to US13/706,835 priority patent/US8809586B2/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/126—Acids containing more than four carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/06—Oxalic acid
    • C07C55/07—Salts thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/08—Malonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/12—Glutaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/255—Tartaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/265—Citric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
    • C07C65/05—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring o-Hydroxy carboxylic acids
    • C07C65/10—Salicylic acid

Definitions

  • the present invention relates to API-containing compositions, pharmaceutical compositions comprising such APIs, and methods for preparing the same.
  • APIs Active pharmaceutical ingredients in pharmaceutical compositions can be prepared in a variety of different forms.
  • Such APIs can be prepared so as to have a variety of different chemical forms including chemical derivatives, solvates, hydrates, co-crystals, or salts.
  • Such APIs can also be prepared to have different physical forms.
  • the APIs may be amorphous, may have different crystalline polymorphs, or may exist in different solvation or hydration states.
  • crystalline polymorphs typically have different solubilities from one another, such that a more thermodynamically stable polymorph is less soluble than a less thermodynamically stable polymorph.
  • compositions can also differ in properties such as shelf-life, bioavailability, morphology, vapour pressure, density, colour, and compressibility. Accordingly, variation of the crystalline state of an API is one of many ways in which to modulate the physical properties thereof. It would be advantageous to have new forms of these APIs that have improved properties, in particular, as oral formulations. Specifically, it is desirable to identify improved forms of APIs that exhibit significantly improved properties including increased aqueous solubility and stability. Further, it is desirable to improve the processability, or preparation of pharmaceutical formulations. For example, needlelike crystal forms or habits of APIs can cause aggregation, even in compositions where the API is mixed with other substances, such that a non-uniform mixture is obtained.
  • Needle-like morphologies can also give rise to filtration problems (See e.g., Mirroidabi et al. J. Pharm. Sci. Vol. 93, No. 7, pp. 1692-1700, 2004). It is also desirable to increase the dissolution rate of API-containing pharmaceutical compositions in water, increase the bioavailability of orally-administered compositions, and provide a more rapid onset to therapeutic effect. It is also desirable to have a form of the API which, when administered to a subject, reaches a peak plasma level faster, has a longer lasting therapeutic plasma concentration, and higher overall exposure when compared to equivalent amounts of the API in its presently- known form. Modafinil, an API used to treat subjects with narcolepsy, is practically insoluble in water. Modafinil(CAS Registry Number: 68693-11-8) is represented by the structure (I):
  • the present invention provides a co-crystal of modafinil, wherein 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, organohahde, nitro, S-heterocyclic ring, thiophene, N-heterocycl
  • the invention further provides a pharmaceutical composition comprising a co- crystal of modafinil.
  • the pharmaceutical composition further comprises one or more pharmaceutically-acceptable carriers, diluents or excipients.
  • Pharmaceutical compositions according to the invention are described in further detail below.
  • the present invention provides a process for the preparation of a co-crystal of modafinil, which comprises: (a) providing modafinil; (b) providing a co-crystal former compatible with a functional group of modafinil such that the co-crystal former and the modafinil can form a co-crystal; (c) grinding, heating, co-subliming, co-melting, or contacting in solution the modafinil with the co-crystal former under crystallization conditions, so as to form a solid phase; and (d) isolating co-crystals comprising modafinil and the co-crystal former.
  • the co-crystal former has at least one functional group selected from the group consisting of 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, organohahde, nitro, S-heterocyclic ring, thiophene, N-heterocyclic ring, pyrrole, O-heterocyclic ring, furan, epoxide, hydroxamic acid, imidazole, or pyridine.
  • ether thioether
  • alcohol thio
  • Embodiments of the present invention including, but not limited to, co- crystals, polymorphs, and solvates can comprise racemic modafinil, enantiomerically pure modafinil (i.e., R-(-)-modafinil or S-(+)-modafinil), or enriched modafinil (e.g., between about 55 and about 90 percent ee).
  • co-crystal formers and solvent molecules e.g., in a solvate
  • the present invention provides a process for increasing the solubility of modafinil in water, simulated gastric fluid (SGF), or simulated intestinal fluid (SIF) for use in a pharmaceutical composition or medicament, which process comprises: (a) providing modafinil; (b) providing a co-crystal former compatible with a functional group of modafinil such that the co-crystal former and the modafinil can form a co-crystal; (c) grinding, heating, co-subliming, co-melting, or contacting in solution the modafinil with the co-crystal former under crystallization conditions, so as to form a solid phase; and (d) isolating co-crystals comprising the modafinil and the co-crystal former.
  • SGF simulated gastric fluid
  • SIF simulated intestinal fluid
  • the present invention provides a process for modulating the dissolution of modafinil, whereby the aqueous dissolution rate or the dissolution rate in simulated gastric fluid or in simulated intestinal fluid, or in a solvent or plurality of solvents is increased, which process comprises: (a) providing modafinil; (b) providing a co-crystal former compatible with a functional group of modafinil such that the co-crystal former and the modafinil can form a co-crystal; (c) grinding, heating, co-subliming, co-melting, or contacting in solution the modafinil with the co-crystal former under crystallization conditions, so as to form a solid phase; and (d) isolating co-crystals comprising the modafinil and the co-crystal former.
  • the present invention provides a process for modulating the bioavailability of modafinil, whereby the AUC is increased, the time to T max is reduced, the length of time the concentration of modafinil is above X ⁇ T ma ⁇ is increased, or C max is increased, which process comprises: (a) providing modafinil; (b) providing a co-crystal former compatible with a functional group of modafinil such that the co-crystal former and the modafinil can form a co-crystal; (c) grinding, heating, co-subliming, co-melting, or contacting in solution the modafinil with the co-crystal former under crystallization conditions, so as to form a solid phase; and (d) isolating co-crystals comprising the modafinil and the co-crystal former.
  • the present invention provides a process for modulating the dose response of modafinil for use in a pharmaceutical composition or medicament, which process comprises: (a) providing modafinil; (b) providing a co-crystal former compatible with a functional group of modafinil such that the co-crystal former and the modafinil can form a co-crystal; (c) grinding, heating, co-subliming, co-melting, or contacting in solution the modafinil with the co-crystal former under crystallization conditions, so as to form a solid phase; and (d) isolating co-crystals comprising the modafinil and the co-crystal former.
  • the present invention provides a process for improving the stability of modafinil (as compared to a reference form such as its free form), which process comprises: (a) providing modafinil; (b) providing a co-crystal former compatible with a functional group of modafinil such that the co-crystal former and the modafinil can form a co-crystal; (c) grinding, heating, co-subliming, co-melting, or contacting in solution the modafinil with the co-crystal former under crystallization conditions, so as to form a solid phase; and (d) isolating co-crystals comprising the modafinil and the co-crystal former.
  • the present invention provides a process for modifying the morphology of modafinil, which process comprises: (a) providing modafinil; (b) providing a co-crystal former compatible with a functional group of modafinil such that the co-crystal former and the modafinil can form a co-crystal; (c) grinding, heating, co-subliming, co-melting, or contacting in solution the modafinil with the co-crystal former under crystallization conditions, so as to form a solid phase; and (d) isolating co-crystals comprising the modafinil and the co-crystal former.
  • the present invention therefore provides a process of screening for co-crystal compounds, which comprises: (a) providing (i) modafinil and (ii) a co-crystal former compatible with a functional group of modafinil such that the co-crystal former and the modafinil can form a co-crystal; and (b) screening for co-crystals of modafinil with a co-crystal former by subjecting each combination of modafinil and co-crystal former to a procedure comprising: (i) grinding, heating, co-subliming, co-melting, or contacting in solution the modafinil with the co-crystal former under crystallization conditions, so as to form a solid phase; and (ii) isolating co-crystals comprising the modafinil and the co- crystal former.
  • An alternative embodiment is drawn to a process of screening for co-crystal compounds, which comprises: (a) providing (t) modafinil and (ii) a plurality of different co-crystal formers compatible with a functional group of modafinil such that each co- crystal former and the modafinil can form a co-crystal; and (b) screening for co-crystals of modafinil with co-crystal formers by subjecting each combination of modafinil and co-crystal former to a procedure comprising: (i) grinding, heating, co-subliming, co-melting, or contacting in solution the modafinil with the co-crystal former under crystallization conditions, so as to form a solid phase; and (ii) isolating co-crystals comprising the modafinil and the co- crystal former.
  • the present invention provides a co-crystal composition
  • a co-crystal composition comprising a co-crystal, wherein said co-crystal comprises modafinil and a co-crystal former.
  • the co-crystal has an improved property as compared to the free form (which includes hydrates and solvates).
  • the improved property is selected from the group consisting of: increased solubility, increased dissolution, increased bioavailability, increased dose response, or other property described herein.
  • the present invention provides a co-crystal comprising modafinil and a co-crystal former selected from the group consisting of: malonic acid, glycolic acid, fumaric acid, tartaric acid, citric acid, succinic acid, gentisic acid, oxalic acid, l-hydroxy-2-naphthoic acid, orotic acid, glutaric acid, L-tartaric acid, palmitic acid, L-proline, salicylic acid, lauric acid, L-malic acid, and maleic acid.
  • a co-crystal former selected from the group consisting of: malonic acid, glycolic acid, fumaric 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, L-malic acid, and maleic
  • the present invention provides the following co- crystals: modafmihmalonic acid, modafinihglycolic acid, modafinikmaleic acid, modafinikL-tartaric acid, modafinil :citric acid, modafinil: succinic acid, modafinihDL-tartaric acid, modafinihfumaric acid (Form I), modafinihfumaric acid (Form II), modafinil: gentisic acid, modafinihoxalic acid, modafinil: l-hydroxy-2- naphthoic acid, R-(-)-modafmil:malonic acid, R-(-)-modafinil: succinic acid, R-(-)- modafmikcitric acid, R-(-)-modafinil:DL-tartaric acid, R-(-)-modafinil:l-hydroxy-2- naphthoic acid, R-(-)-modafmil:or
  • the present invention provides a novel polymorph or co-crystal of racemic modafinil (form VII).
  • the present invention provides the following modafinil solvates: acetic acid, tetrahydrofuran, 1,4-dioxane, methanol, nitromethane, acetone, ⁇ -xylene, benzene, ethanol, benzyl alcohol, isopropanol, acetonitrile, and toluene.
  • the processes according to the present invention may each comprise a further step or steps in which the modafinil co-crystal produced thereby is incorporated into a pharmaceutical composition.
  • a pharmaceutical composition comprises a modified release profile of one or more of racemic modafinil, R-(-)-modafinil, and S-(+)- modafinil.
  • the modified release profile can comprise, for example, two or more maxima of plasma concentration, such as a dual-release profile.
  • the invention further provides a medicament comprising a co-crystal of modafinil and methods of making the same.
  • the medicament further comprises one or more pharmaceutically-acceptable carriers, diluents or excipients.
  • Medicaments according to the invention are described in further detail below.
  • the processes according to the present invention may each comprise a further step or steps in which the modafinil co-crystal produced thereby is incorporated into a medicament.
  • a method for treating a subject, preferably a human subject, suffering from excessive daytime sleepiness associated with narcolepsy, multiple sclerosis related fatigue, infertility, eating disorders, attention deficit hyperactivity disorder (ADHD), Parkinson's disease, incontinence, sleep apnea, or myopathies where modafinil is an effective active pharmaceutical for said disorder.
  • the method comprises administering to the subject a therapeutically-effective amount of a co-crystal or a solvate comprising modafinil, or a polymorph of modafinil.
  • Figure 1- PXRD diffractogram of a co-crystal comprising modafinil and malonic acid.
  • Figure 4A and 4B- Raman spectrum of a co-crystal comprising modafinil and malonic acid Figure 4A
  • Figure 4B Raman spectrum of a co-crystal comprising modafinil and malonic acid
  • Figure 4B Raman spectrum of a co-crystal comprising modafinil and malonic acid
  • Figure 4B Raman spectrum of a co-crystal comprising modafinil and malonic acid
  • Figure 5 A and 5B Infrared spectrum of a co-crystal comprising modafinil and malonic acid (Figure 5 A), and three Infrared spectra of modafinil (top spectrum), malonic acid (middle spectrum), and a co-crystal comprising modafinil and malonic acid (bottom spectrum) (Figure 5B).
  • Figure 7 Packing diagram for modafinihmalonic acid co-crystal.
  • Figure 10- PXRD diffractogram of a co-crystal comprising modafinil and L-tartaric acid.
  • Figure 11 A- PXRD diffractogram of a co-crystal comprising modafinil and citric acid.
  • Figure 1 IB- DSC thermogram of a co-crystal comprising modafinil and citric acid.
  • Figure 13 DSC thermogram of a co-crystal comprising modafinil and succinic acid.
  • Figure 14 Packing diagram of a co-crystal comprising modafinil and succinic acid.
  • Figure 15 PXRD diffractogram of a co-crystal comprising modafinil and DL-tartaric acid.
  • Figure 16- PXRD diffractogram of a co-crystal comprising modafinil and fumaric acid (Form I).
  • Figure 17 Packing diagram of a co-crystal comprising modafinil and fumaric acid
  • Figure 19 PXRD diffractogram of a co-crystal comprising modafinil and gentisic acid.
  • Figure 20 PXRD diffractogram of a co-crystal comprising modafinil and oxalic acid.
  • Figure 23 DSC thermogram of a co-crystal comprising R-(-)-modafinil and malonic acid.
  • Figure 24- PXRD diffractogram of a co-crystal comprising R-(-)-modafinil and succinic acid.
  • Figure 25 DSC thermogram of a co-crystal comprising R-(-)-modafinil and succinic acid.
  • Figure 26 PXRD diffractogram of a co-crystal comprising R-(-)-modafmil and citric acid.
  • Figure 27 DSC thermogram of a co-crystal comprising R-(-)-modafinil and citric acid.
  • Figure 30- PXRD diffractogram of a co-crystal comprising R-(-)-modafinil and 1- hydroxy-2-naphthoic acid.
  • Figure 31 DSC thermogram of a co-crystal comprising R-(-)-modafinil and 1- hydroxy-2-naphthoic acid.
  • Figure 32 PXRD diffractogram of a co-crystal comprising R-(-)-modafinil and 1- hydroxy-2-naphthoic acid obtained from a high throughput experiment.
  • Figure 33 PXRD diffractogram of a co-crystal comprising R-(-)-modafinil and orotic acid.
  • Figure 34 DSC thermogram of a co-crystal comprising R-(-)-modafmil and orotic acid.
  • Figure 35 PXRD diffractogram of a solvate comprising modafinil and acetic acid.
  • Figure 36 TGA thermogram of a solvate comprising modafinil and acetic acid.
  • Figure 37 DSC thermogram of a solvate comprising modafinil and acetic acid.
  • Figure 38 Raman spectrum of a solvate comprising modafinil and acetic acid.
  • Figure 39 - PXRD diffractogram of a solvate comprising modafinil and tetrahydrofuran.
  • Figure 40 PXRD diffractogram of a solvate comprising modafinil and 1,4-dioxane.
  • Figure 41 PXRD diffractogram of a solvate comprising modafinil and methanol.
  • Figure 42 TGA thermogram of a solvate comprising modafinil and methanol.
  • Figure 43 DSC thermogram of a solvate comprising modafinil and methanol.
  • Figure 46 - PXRD diffractogram of a possible solvate comprising modafinil and acetone.
  • Figure 49 Stability plot of modafinihmalonic acid co-crystal over a 26 week period.
  • Figure 50 Closer view of stability plot of modafinihmalonic acid co-crystal over a 26 week period.
  • Figure 52 Dissolution profile of several formulations of modafinil free form and modafinihmalonic acid.
  • Figure 53 In Vitro dissolution profile of modafinihmalonic acid co-crystal in SGF and SIF.
  • Figure 54 In Vitro dissolution profile of modafinihmalonic acid co-crystal in HC1.
  • Figure 58 Packing diagram of acetone channel solvate of modafinil.
  • Figure 60 PXRD diffractogram of o-xylene solvate.
  • Figure 72 PXRD diffractogram of R-(-)-modafinil ethanol solvate.
  • Figure 73 TGA thermogram of R-(-)-modafinil ethanol solvate.
  • Figure 80 PXRD diffractogram of R-(-)-modafinil:citric acid co-crystal.
  • the structure of modafinil includes a stereocenter and, therefore, can exist as a racemate, one of two pure isomers, or any ratio of the two isomeric pairs.
  • the chemical name of racemic modafinil is ( ⁇ )-2-[(Diphenylmethyl) sulfinyl]acetamide.
  • the isomeric pairs of racemic modafinil are R-(-)-2-[(Diphenylmethyl) sulfinyl]acetamide or R-(-)-modafinil and S-(+)-2-[(Diphenylmethyl) sulfinyljacetamide or S-(+)-modafinil.
  • enantiomerically pure includes a composition which is substantially enantiomerically pure and includes, for example, a composition with greater than or equal to about 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 percent enantiomeric excess.
  • the term “modafinil” includes the racemate, other mixtures of R- and S-isomers, and single enantiomers, but may be specifically set forth as the racemate, R-isomer, S-isomer, or any mixture of both R- and S-isomers.
  • the term “racemic co-crystal” refers to a co-crystal which is comprised of an equimolar mixture of the enantiomers of modafinil, the co-crystal former, or both.
  • a co-crystal comprising modafinil and a non-stereoisomeric co-crystal former is a "racemic co-crystal" only when there is present an equimolar mixture of the modafinil enantiomers.
  • a co-crystal comprising modafinil and a stereoisomeric co-crystal former is a "racemic co-crystal" only when there is present an equimolar mixture of the modafinil enantiomers and of the co-crystal former enantiomers.
  • co-crystal refers to a co-crystal which is comprised of modafinil and a stereoisomeric or non-stereoisomeric co-crystal former where the enantiomeric excess of the stereoisomeric species is greater than or equal to about 90 percent ee (enantiomeric excess).
  • co-crystal as used herein means a crystalline material comprised of two or more unique solids at room temperature (22 degrees C), each containing distinctive physical characteristics, such as structure, melting point, and heats of fusion, with the exception that, if specifically stated, the API may be a liquid at room temperature.
  • the co-crystals of the present invention comprise a co-crystal former H- bonded to modafinil or a derivative thereof.
  • the co-crystal former may be H-bonded directly to modafinil or may be H-bonded to an additional molecule which is bound to modafinil.
  • the additional molecule may be H-bonded to modafinil or bound ionically to modafinil.
  • the additional molecule could also be a different API.
  • Solvates of modafinil compounds that do not further comprise a co-crystal former are not co- crystals according to the present invention.
  • the co-crystals may however, include one or more solvate molecules in the crystalline lattice.
  • a solvate of co-crystal, or a co-crystal further comprising a solvent or compound that is a liquid at room temperature is a co-crystal according to the present invention, but crystalline material comprised of only modafinil and one or more liquids (at room temperature) are not co-crystals for purposes of the present invention.
  • Other modes of molecular recognition may also be present including, pi-stacking, guest-host complexation and van der Waals interactions.
  • hydrogen-bonding is the dominant interaction in the formation of the co-crystal, (and a required interaction according to the present invention) whereby a non-covalent bond is formed between a hydrogen bond donor of one of the moieties and a hydrogen bond acceptor of the other.
  • Hydrogen bonding can result in several different intermolecular configurations. For example, hydrogen bonds can result in the formation of dimers, linear chains, or cyclic structures. These configurations can further include extended (two- dimensional) hydrogen bond networks and isolated triads.
  • An alternative embodiment provides for a co-crystal wherein the co-crystal former is a second API. In another embodiment, the co-crystal former is not an API.
  • the chemical and physical properties of modafinil in the form of a co-crystal may be compared to a reference compound that is modafinil in a different form.
  • the reference compound may be specified as a free form, or more specifically, an anhydrate or hydrate of a free form, or more specifically, for example, a hemihydrate, monohydrate, dihydrate, trihydrate, quadrahydrate, pentahydrate; or a solvate of a free form.
  • the reference compound for modafinil in free form co-crystallized with a co-crystal former can be modafinil in free form.
  • the reference compound may also be specified as crystalline or amorphous.
  • the reference compound may also be specified as the most stable polymorph known 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 modafinikco-crystal former are acceptable.
  • co-crystals with vacancies within the crystalline lattice are included in the present invention.
  • a co-crystal with less than or about 0.01, 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 percent vacancies within the crystalline lattice are included in the present invention.
  • the vacancies can be due to missing modafinil molecules or missing co-crystal former molecules from the crystalline lattice, or both. It has surprisingly been found that when modafinil and a selected co-crystal former are allowed to form co-crystals, the resulting co-crystals often give rise to improved properties of modafinil, as compared to modafinil in the free form, particularly with respect to: solubility, dissolution, bioavailability, stability, C max , Tmax, processability (including compressibility), longer lasting therapeutic plasma concentration, etc. For example, a co-crystal form of modafinil is particularly advantageous due to the low solubility of modafinil in water.
  • the co- crystal properties conferred upon modafinil are also useful because the bioavailability of modafinil can be improved and the plasma concentration and/or serum concentration of modafinil can be improved. This is particularly advantageous for orally-adrninistrable formulations.
  • the dose response of modafinil can be improved, for example by increasing the maximum attainable response and/or increasing the potency of modafinil by increasing the biological activity per dosing equivalent.
  • the present invention provides a pharmaceutical composition (or medicament) comprising a co-crystal of modafinil and a co-crystal former, such that the modafinil and the co-crystal former are capable of co- crystallizing from a solution phase under crystallization conditions or from the solid- state, for example, through grinding or heating.
  • the co-crystal former which has at least one functional group selected from the group consisting of 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, organohahde, nitro, S-heterocyclic ring, thiophene, N-heterocyclic ring, pyrrole, O- heterocyclic ring, furan, epoxide, hydroxamic acid, imidazole, and pyridine, or a functional group in a Table herein,
  • the use of an excess (more than 1 molar equivalent for a 1:1 co-crystal) of a co-crystal former can be used to drive the formation of stoichiometric co-crystals.
  • co-crystals with stoichiometries of 1:1, 2:1, or 1:2 can be produced by adding co-crystal former in an amount that is 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100 times or more than the stoichiometric amount for a given co-crystal.
  • Such an excessive use of a co-crystal former to form a co-crystal can be employed in solution or when grinding modafinil and a co-crystal former to cause co-crystal formation.
  • a modafinil co-crystal further comprises a co-crystal former which is hydrogen bonded via a preferred interaction between two or more functional groups.
  • modafinil and malonic acid co- crystallize through the interaction of a carboxylic acid functional group of the co- crystal former with sulfoxide and amide functional groups of modafinil.
  • the co-crystal comprises modafinil wherein the modafinil forms a dimeric primary amide structure via hydrogen bonds with an R 2 2 (8) motif. See e.g., J. Bernstein, Polymorphism in Molecular Crystals. Oxford University Press, 2002, pp. 55-59, or M. C Etter, Acct.
  • the NH 2 moiety can also participate in a hydrogen bond with a donor or an acceptor moiety from, for example, a co-crystal former or an additional (third) molecule
  • the dimeric primary amide structure (formed by two modafinil molecules) further comprises one, two, three, or four hydrogen bond donors (from one, two, three, or four co-crystal formers).
  • the dimeric primary amide structure further comprises one or two hydrogen bond acceptors (from one or two co-crystal formers).
  • the dimeric primary amide structure further comprises a combination of hydrogen bond donors and acceptors.
  • the dimeric primary amide structure can further comprise one hydrogen bond donor and one hydrogen bond acceptor, one hydrogen bond donor and two hydrogen bond acceptors, two hydrogen bond donors 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 where modafinil and the co-crystal former are bonded together through hydrogen bonds.
  • 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 specified as a Class 1, Class 2, or Class 3 co-crystal former (see column labeled "class" Table I). Table I lists multiple pK a values for co-crystal formers having multiple functionalities. It is readily apparent to one skilled in the art the particular functional group corresponding to a particular pK a value.
  • the particular functional group of a co-crystal former interacting with modafinil is specified (see for example Table I, columns labeled "Functionality” and "Molecular Structure” and the column of Table II labeled "Co- Crystal Former Functional Group”).
  • the co-crystal comprises more than one co-crystal former.
  • two, three, four, five, or more co-crystal formers can be incorporated in a co-crystal with modafinil.
  • Co-crystals which comprise two or more co-crystal formers and an API are bound together via hydrogen bonds.
  • incorporated co-crystal formers are hydrogen bonded to modafinil molecules.
  • co-crystal formers are hydrogen bonded to either the modafinil molecules or the incorporated co-crystal formers.
  • modafinil there is a need to contact modafinil with the co-crystal former. This may involve grinding the two solids together or melting one or both components and allowing them to recrystallize. This may also involve either solubilizing modafinil and adding the co-crystal former, or solubilizing the co-crystal former and adding modafinil. Crystallization conditions are applied to modafinil and the co-crystal former. This may entail altering a property of the solution, such as pH or temperature and may require concentration of the solute, usually by removal of the solvent, typically by drying the solution.
  • Solvent removal results in the concentration of both modafinil and the co-crystal former increasing over time so as to facilitate crystallization.
  • evaporation, cooling, or the addition of an antisolvent may be used to crystallize co-crystals.
  • a slurry comprising modafinil and a co-crystal former is used to form co-crystals. Once the solid phase comprising any crystals is formed, this may be tested as described herein.
  • the co-crystals obtained as a result of such process steps may be readily incorporated into a pharmaceutical composition (or medicament) by conventional means.
  • Pharmaceutical compositions and medicaments in general are discussed in further detail below and may further comprise a pharmaceutically-acceptable diluent, excipient or carrier.
  • the present invention provides a process for the preparation of a co-crystal of modafinil, which comprises: (a) providing modafinil; (b) providing a co-crystal former compatible with a functional group of modafinil such that the co-crystal former and the modafinil can form a co- crystal; (c) grinding, heating, co-subliming, co-melting, or contacting in solution the modafinil with the co-crystal former under crystallization conditions, so as to form a solid phase; and (d) isolating co-crystals comprising modafinil and the co-crystal former.
  • the co-crystal former has at least one functional group selected from the group consisting of 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, organohahde, nitro, S-heterocyclic ring, thiophene, N-heterocyclic ring, pyrrole, O-heterocyclic ring, furan, epoxide, hydroxamic acid, imidazole, or pyridine.
  • ether thioether
  • alcohol thio
  • the present invention provides a process for the production of a pharmaceutical composition or medicament, which process comprises: (a) providing modafinil; (b) providing a co-crystal former compatible with a functional group of modafinil such that the co-crystal former and the modafinil can form a co- crystal; (c) grinding, heating, co-subliming, co-melting, or contacting in solution the modafinil with the co-crystal former under crystallization conditions; (d) isolating co-crystals formed thereby; and (e) incorporating the co-crystals into a pharmaceutical composition or medicament.
  • a process for the formation of co-crystals includes a meta-stable form of modafinil, the co-crystal former, or both.
  • a meta-stable form can be for example, but not limited to, a polymorph, solvate, or hydrate of modafinil or the co-crystal former. While not bound by theory, the incorporation of a meta-stable form may facilitate co-crystal formation via increasing the thermodynamic driving force.
  • Assaying the solid phase for the presence of co-crystals of modafinil and the co-crystal former may be carried out by conventional methods known in the art. For example, it is convenient and routine to use powder X-ray diffraction techniques to assess the presence of co-crystals.
  • Other techniques used in an analogous fashion, include differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), infrared spectroscopy (IR), and Raman spectroscopy. Single crystal X-ray diffraction is especially useful in identifying co- crystal structures.
  • the present invention therefore provides a process of screening for co-crystal compounds, which comprises: (a) providing (/) modafinil and (ii) a co-crystal former compatible with a functional group of modafinil such that the co-crystal former and the modafinil can form a co-crystal; and (b) screening for co-crystals of the modafinil with the co-crystal former by subjecting each combination of modafinil and co-crystal former to a procedure comprising: (i) grinding, heating, co-subliming, co-melting, or contacting in solution the modafinil with the co-crystal former under crystallization conditions so as to form a solid phase; and (ii) isolating co-crystals comprising the modafinil and the co- crystal former.
  • An alternative embodiment is drawn to a process of screening for co-crystal compounds, which comprises: (a) providing (i) modafinil and (ii) a plurality of different co-crystal formers compatible with a functional group of modafinil such that the co-crystal former and the modafinil can form a co-crystal; and (b) screening for co-crystals of the modafinil with the co-crystal formers by subjecting each combination of the modafinil and the co-crystal formers to a procedure comprising: (i) grinding, heating, co-subliming, co-melting, or contacting in solution the modafinil with each co-crystal former under crystallization conditions so as to form a solid phase; and (ii) isolating co-crystals comprising the modafinil and the co- crystal former.
  • the present invention includes several co-crystals comprising modafinil and a carboxylic acid co-crystal former.
  • modafinil co-crystals comprising malonic acid, tartaric acid (L- and DL-), succinic acid, citric acid, fumaric acid, gentisic acid, oxalic acid, and l-hydroxy-2-na ⁇ hthoic acid.
  • L- and DL- lactylic acid co-crystal formers
  • Other acids, including carboxylic acids may be used as co-crystal formers with modafinil including, but not limited to, palmitic acid, orotic acid, and adipic acid etc.
  • co-crystal formers may comprise one, two, three, or more carboxylic acid functional groups.
  • Co-crystal formers can also include non-carboxylic acid molecules such as, but not limited to, urea, saccharin, and caffeine.
  • a co-crystal comprises modafinil and a carboxylic acid as a co-crystal former.
  • the carboxylic acid co-crystal former has one, two, three, or more carboxylic acid functional groups.
  • co-crystals may exhibit one or more particular interactions between modafinil and a carboxylic acid co-crystal former.
  • a carboxylic acid functional group from the co-crystal former interacts with the periphery of the amide dimer of modafinil via a hydrogen bond.
  • a carboxylic acid functional group from the co-crystal former interacts with two amide dimers of modafinil via a hydrogen bond.
  • Modafinil and some co-crystal formers of the present invention have one or more chiral centers and may exist in a variety of stereoisomeric configurations. As a consequence of these chiral centers, modafinil and several co-crystal formers of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers.
  • Co-crystals of the present invention can include isomeric forms of either modafinil or the co-crystal former or both. Isomeric forms of modafinil and co-crystal formers include, but are not limited to, stereoisomers such as enantiomers and diastereomers.
  • a co-crystal can comprise racemic modafinil and/or a co-crystal former.
  • a co-crystal can comprise enantiomerically pure R- or S-modafinil and/or a co-crystal former.
  • a co-crystal of the present invention can comprise modafinil or a co- crystal former with an enantiomeric excess of 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, 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, greater than 99 percent, or any intermediate value.
  • stereoisomeric co-crystal formers include tartaric acid and malic acid.
  • a polymorph or a solvate of the present invention can comprise modafinil with an enantiomeric excess of 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, 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, greater than 99 percent, or any intermediate value.
  • Enriched modafinil comprises both the R-(-)- and S-(+)-isomers of modafinil in amounts greater than or equal to about 5, 6, 7, 8, 9, or 10 percent by weight and less than or equal to about 90, 91, 92, 93, 94, or 95 percent by weight.
  • a composition comprising 67 percent by weight R-(-)-modafinil and 33 percent by weight S-(+)-modaf ⁇ nil is an enriched modafinil composition.
  • the composition is neither racemic nor enantiomerically pure.
  • enriched R-(-)-modafinil may be used to describe a composition of modafinil with greater than 50 percent R-(-)-modafinil and less than 50 percent S-(+)-modafinil.
  • enriched S-(+)-modafinil may be used to describe a composition of modafinil with greater than 50 percent S-(+)- modafmil and less than 50 percent R-(-)-modafinil.
  • R-(-)-modafinil and "S-(+)-modafinil” can be used to describe enriched modafinil, enantiomerically pure modafinil, or substantially enantiomerically pure modafinil, but may also specifically exclude enriched modafinil, enantiomerically pure modafinil, and/or substantially enantiomerically pure modafinil.
  • Co-crystals, solvates, and polymorphs comprising enantiomerically pure and/or enantiomerically enriched components can give rise to chemical and/or physical properties which are modulated with respect to those of the corresponding co-crystal comprising a racemic component.
  • the modafinihmalonic acid co-crystal from Example 1 comprises racemic modafinil.
  • Enantiomerically pure R-(-)-modafmil:malonic acid is included in the scope of the invention.
  • enantiomerically pure S-(+)-modafinil:malonic acid is included in the scope of the invention.
  • a co-crystal comprising an enantiomerically pure component can give rise to a modulation of, for example, activity, bioavailability, or solubility, with respect to the corresponding co-crystal comprising a racemic component.
  • the co-crystal R-(-)-modafinil:malonic acid can have modulated properties as compared to the racemic modafinihmalonic acid co- crystal.
  • Polymorphs and solvates of modafinil can also be prepared with racemic modafinil, enantiomerically pure modafinil, or with any mixture of R-(-)- and S-(+)- modafmil according to the present invention.
  • the present invention includes a pharmaceutical composition or medicament comprising a co-crystal with enantiomerically pure modafinil and/or co-crystal former wherein the bioavailability is modulated with respect to the racemic co-crystal.
  • the present invention includes a pharmaceutical composition or medicament comprising a co-crystal with enantiomerically pure modafinil and/or co-crystal former wherein the activity is modulated with respect to the racemic co-crystal.
  • the present invention includes a pharmaceutical composition or medicament comprising a co- crystal with enantiomerically pure modafinil and/or co-crystal former wherein the solubility is modulated with respect to the racemic co-crystal.
  • a pharmaceutical composition or medicament can be formulated to contain modafinil in co-crystal form as micronized or nano-sized particles. More specifically, another embodiment couples the processing of pure modafinil to a co-crystal form with the process of making a controlled particle size for manipulation into a pharmaceutical dosage form. This embodiment combines two processing steps into a single step via techniques such as, but not limited to, grinding, alloying, or sintering (i.e., heating a powder mix). The coupling of these processes overcomes a serious limitation of having to isolate and store the bulk drug that is required for a formulation, which in some cases can be difficult to isolate (e.g., amorphous, chemically or physically unstable).
  • the present invention provides a process for increasing the solubility of modafinil in water, simulated gastric fluid (SGF), or simulated intestinal fluid (SIF) for use in a pharmaceutical composition or medicament, which process comprises: (a) providing modafinil; (b) providing a co-crystal former compatible with a functional group of modafinil such that the co-crystal former and the modafinil can form a co-crystal; (c) grinding, heating, co-subliming, co-melting, or contacting in solution the modafinil with the co-crystal former under crystallization conditions, so as to form a solid phase; and (d) isolating co-crystals comprising the modafinil and the co-crystal former.
  • the solubility of modafinil is modulated such that the aqueous solubility (mg/mL) is increased by at least 1.1, 1.2, 1.3, 1.5, 2.0, 5.0, 10.0, 20.0, 25.0, 50.0, 75.0, or 100.0 times or more than the free form.
  • Solubility of modafinil may be measured by any conventional means such as chromatography (e.g., HPLC) or spectroscopic determination of the amount of modafinil in a saturated solution, such as UV-spectroscopy, IR-spectroscopy, Raman spectroscopy, quantitative mass spectroscopy, or gas chromatography.
  • compositions or medicaments including co- crystals, solvates, and polymorphs of the present invention can be compared with free form modafinil as found in PRO VIGIL® (Cephalon, Inc.).
  • PRO VIGIL® Cerphalon, Inc.
  • solubility can be increased 2, 3, 4, 5, 7, 10, 15, 20, 25, 50, 75, or 100 times by making a co-crystal of the reference form (e.g., crystalline or amorphous free form, hydrate or solvate).
  • aqueous solubility can be measured in simulated gastric fluid (SGF) or simulated intestinal fluid (SIF) rather than water.
  • SIF is 0.68% monobasic potassium phosphate, 1% pancreatin, and sodium hydroxide where the pH of the final solution is 7.5.
  • the pH of the solvent used may also be specified as 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or 12, or any pH in between successive values.
  • Examples of embodiments includes: co-crystal compositions with an aqueous solubility, at 37 degrees C and a pH of 7.0, that is increased at least 5 fold over the reference form, co-crystal compositions with a solubility in SGF that is increased at least 5 fold over the reference form, co-crystal compositions with a solubility in SIF that is increased at least 5 fold over the reference form.
  • Dissolution Modulation in another aspect of the present invention, the dissolution profile of modafinil is modulated whereby the aqueous dissolution rate or the dissolution rate in simulated gastric fluid or in simulated intestinal fluid, or in a solvent or plurality of solvents is increased.
  • Dissolution rate is the rate at which API solids dissolve in a dissolution medium.
  • the rate-limiting step in the absorption process is often the dissolution rate. Because of a limited residence time at the absorption site, APIs that are not dissolved before they are removed from intestinal absorption site are considered useless. Therefore, the rate of dissolution has a major impact on the performance of APIs that are poorly soluble. Because of this factor, the dissolution rate of APIs 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)
  • K dissolution rate constant
  • S is the surface area
  • C s is the apparent solubility
  • C is the concentration of API in the dissolution medium.
  • C 3 -C is approximately equal to C s
  • the dissolution rate of modafinil may be measured by conventional means known in the art.
  • the increase in the dissolution rate of a co-crystal, as compared to the reference form (e.g., free form) may be specified, such as by 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100%, or by 2, 3, 4, 5 ,6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, 400, 500, 1000, 10,000, or 100,000 fold greater than the reference form (e.g., free form) in the same solution.
  • Conditions under which the dissolution rate is measured are the same as discussed above.
  • the increase in dissolution may be further specified by the time the composition remains supersaturated before reaching equilibrium solubility.
  • the present invention provides a process for modulating the dissolution of modafinil, whereby the aqueous dissolution rate or the dissolution rate in simulated gastric fluid or in simulated intestinal fluid, or in a solvent or plurality of solvents is increased, which process comprises: (a) providing modafinil; (b) providing a co-crystal former compatible with a functional group of modafinil such that the co-crystal former and the modafinil can form a co-crystal; (c) grinding, heating, co-subliming, co-melting, or contacting in solution the modafinil with the co-crystal former under crystallization conditions, so as to form a solid phase; and (d) isolating co-crystals comprising the modafinil and the co-crystal former.
  • Examples of above embodiments include: co-crystal compositions with a dissolution rate in aqueous solution, at 37 degrees C and a pH of 7.0, that is increased at least 5 fold over the reference form, co-crystal compositions with a dissolution rate in SGF that is increased at least 5 fold over the reference form, co-crystal compositions with a dissolution rate in SIF that is increased at least 5 fold over the reference form.
  • Bioavailability Modulation The methods of the present invention are used to make a pharmaceutical modafinil formulation with greater solubility, dissolution, and bioavailability. Bioavailability can be improved via an increase in AUC, reduced time to T max , (the time to reach peak blood serum levels), or increased C ma ⁇ .
  • the present invention can result in higher plasma concentrations of modafinil when compared to the free form (reference form).
  • AUC is the area under the plot of plasma concentration of API (not logarithm of the concentration) against time after API administration.
  • the area is conveniently determined by the "trapezoidal rule":
  • the data points are connected by straight line segments, perpendiculars are erected from the abscissa to each data point, and the sum of the areas of the triangles and trapezoids so constructed is computed.
  • the AUC from t n to infinite time is estimated by C n kei.
  • the AUC is of particular use in estimating bioavailability of APIs, and in estimating total clearance of APIs (Cl ⁇ ).
  • the present invention provides a process for modulating the bioavailability of modafinil, whereby the AUC is increased, the time to T max is reduced, the length of time the concentration of modafinil is above 1 T max is increased, or C max is increased, which process comprises: (a) providing modafinil; (b) providing a co-crystal former compatible with a functional group of modafinil such that the co-crystal former and the modafinil can form a co-crystal; (c) grinding, heating, co-subliming, co-melting, or contacting in solution the modafinil with the co-crystal former under crystallization conditions, so as to form a solid phase; and (d) isolating co-crystals comprising the modafinil and the co-crystal fonner.
  • Examples of the above embodiments include: co-crystal compositions with a time to T max that is increased by at least 5% as compared to the reference form, co- crystal compositions with a time to T ma ⁇ that is increased by at least 10% over the reference form, co-crystal compositions with a time to T max that is increased by at least 15% over the reference form, co-crystal compositions with a time to T max that is increased by at least 20% over the reference form, co-crystal compositions with a T max that is increased by at least 25% over the reference form, co-crystal compositions with a T max that is increased by at least 30% over the reference form, co-crystal compositions with a T max that is increased by at least 35% over the reference form, co- crystal compositions with a T max that is increased by at least 40% over the reference form, co-crystal compositions with an AUC that is increased by at least 5% over the reference form, co-crystal compositions with an AUC that is increased by at least 10% over
  • the present invention provides a process for modulating the dose response of modafinil for use in a pharmaceutical composition or medicament, which process comprises: (a) providing modafinil; (b) providing a co-crystal former compatible with a functional group of modafinil such that the co-crystal former and the modafinil can form a co-crystal; (c) grinding, heating, co-subliming, co-melting, or contacting in solution the modafinil with the co-crystal former under crystallization conditions, so as to form a solid phase; and (d) isolating co-crystals comprising the modafinil and the co-crystal former.
  • Dose response is the quantitative relationship between the magnitude of response and the dose inducing the response and may be measured by conventional means known in the art.
  • the curve relating effect (as the dependent variable) to dose (as the independent variable) for an API-cell system is the "dose-response curve".
  • the dose-response curve is the measured response to an API plotted against the dose of the API (mg/kg) given.
  • the dose response curve can also be a curve of AUC against the dose of the API given.
  • a co-crystal of the present invention has an increased dose response curve or a more linear dose response curve than the corresponding reference compound.
  • the present invention provides a process for improving the stability of modafinil (as compared to a reference form such as its free form), which process comprises: (a) providing modafinil; (b) providing a co-crystal former compatible with a functional group of modafinil such that the co-crystal former and the modafinil can form a co-crystal; (c) grinding, heating, co-subliming, co-melting, or contacting in solution the modafinil with the co-crystal former under crystallization conditions, so as to form a solid phase; and (d) isolating co-crystals comprising the modafinil and the co-crystal former.
  • compositions of the present invention including modafinil co-crystals, solvates, and formulations comprising modafinil, are suitably stable for pharmaceutical use.
  • modafinil or formulations thereof, of the present invention are stable such that when stored at 30 degrees C for 2 years, less than 0.2 % of any one degradant is formed.
  • degradant refers herein to product(s) of a single type of chemical reaction. For example, if a hydrolysis event occurs that cleaves a molecule into two products, for the purpose of the present invention, it would be considered a single degradant. More preferably, when stored at 40 degrees C for 2 years, less than 0.2 % of any one degradant is formed.
  • a single dose of the present invention comprises less than 0.5 %, 0.2 %, or 0.1 % degradants upon administration to a subject.
  • the present invention provides a process for modifying the morphology of modafinil, which process comprises: (a) providing modafinil; (b) providing a co-crystal former compatible with a functional group of modafinil such that the co-crystal former and the modafinil can form a co-crystal; (c) grinding, heating, co-subliming, co-melting, or contacting in solution the modafinil with the co-crystal former under crystallization conditions, so as to form a solid phase; and (d) isolating co-crystals comprising the modafinil and the co-crystal former.
  • the co-crystal comprises or consists of modafinil and a co- crystal former wherein the interaction between the two, e.g., H-bonding, occurs between the amino group of modafinil and a co-crystal former with a corresponding interacting group of Table III.
  • the co-crystal comprises modafinil and a co-crystal former of Table I or II.
  • only co-crystals having an H-bond acceptor on the first molecule and an H-bond donor on the second molecule, where the first and second molecules are either co-crystal former and modafinil respectively, or modafinil and co-crystal former respectively, are included in the present invention.
  • a co-crystal can comprise more than two chemical entities within its co- crystalline structure.
  • a co-crystal can further comprise a solvent molecule, a water molecule, a salt, etc.
  • a co-crystal can comprise 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-crystal formers.
  • a ternary co-crystal is a co-crystal which comprises three distinct chemical entities in a stoichiometric ratio, where each is a solid at room temperature (with the exception that the API may be a liquid at room temperature).
  • a ternary co-crystal comprises three distinct chemical entities such as APhco-crystal former(l):co-crystal former(2), where the ratio of components can be, for example, but not limited to, 1:1:1, 2:1:1, 2:1:2, 2:1:0.5, 2:2:1, etc.
  • Ternary co- crystals can also comprise other combinations of components such as, but not limited to, API(l):API(2):co-crystal former, API(1):API(2):API(3), and co-crystal former(l):co-crystal former(2):co-crystal former(3).
  • the present invention provides a co-crystal comprising modafinil and a co-crystal former selected from the group consisting of: malonic acid, glycolic acid, fumaric acid, tartaric acid, citric acid, succinic acid, gentisic acid, oxalic acid, l-hydroxy-2-naphthoic acid, orotic acid, glutaric acid, L-tartaric acid, palmitic acid, L-proline, salicylic acid, lauric acid, L-malic acid, and maleic acid.
  • a co-crystal former selected from the group consisting of: malonic acid, glycolic acid, fumaric 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, L-malic acid, and maleic
  • the present invention provides the following co- crystals: modafinihmalonic acid, modafinihglycolic acid, modafinikmaleic acid, modafinil :L-tartaric acid, modafinihcitric acid, modafinihsuccinic acid, modafinikDL-tartaric acid, modafinihfumaric acid (Form I), modafinihfumaric acid (Form II), modafinihgentisic acid, modafinihoxalic acid, modafinil: l-hydroxy-2- naphthoic acid, R-(-)-modafinil:malonic acid, R-(-)-modafinil:succinic acid, R-(-)- modafinihcitric acid, R-(-)-modafinil:DL-tartaric acid, R-(-)-modafinil:l-hydroxy-2- naphthoic acid, R-(-)-modafinil:orotic acid, R-(-)-
  • the present invention provides a novel polymorph or co-crystal of racemic modafinil (form VII).
  • the present invention provides the following modafinil solvates: acetic acid, tetrahydrofuran, 1,4-dioxane, methanol, nitromethane, acetone, o-xylene, benzene, and toluene.
  • Pharmaceutically acceptable co-crystals can be administered by controlled- or delayed-release means. Controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled release counterparts.
  • controlled-release preparations include: 1) extended activity of the drug; 2) reduced dosage frequency; 3) increased patient compliance; 4) usage of less total drug; 5) reduction in local or systemic side effects; 6) minimization of drug accumulation; 7) reduction in blood level fluctuations; 8) improvement in efficacy of treatment; 9) reduction of potentiation or loss of drug activity; and 10) improvement in speed of control of diseases or conditions.
  • Conventional dosage forms generally provide rapid or immediate drug release from the formulation.
  • controlled-release formulations can be used to control a drug's onset of action, duration of action, plasma levels within the therapeutic window, and peak blood levels.
  • controlled- or extended-release dosage forms or formulations can be used to ensure that the maximum effectiveness of a drug is achieved while minimizing potential adverse effects and safety concerns, which can occur both from under dosing a drug (i.e., going below the minimum therapeutic levels) as well as exceeding the toxicity level for the drug.
  • Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.
  • Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, ionic strength, osmotic pressure, temperature, enzymes, water, and other physiological conditions or compounds.
  • various 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 extended-release dosage forms, formulations, and devices can be adapted for use with the co-crystals and compositions of the invention. Examples include, but are not limited to, those described in U.S. Pat.
  • ion exchange materials can be used to prepare immobilized, adsorbed co-crystals and thus effect controlled delivery of the drug.
  • anion exchangers include, but are not limited to, Duolite® A568 and Duolite® AP143 (Rohm & Haas, Spring House, PA. USA).
  • One embodiment of the invention encompasses a unit dosage form which comprises a pharmaceutically acceptable co-crystal, or a solvate, hydrate, dehydrate, anhydrous, or amorphous form thereof, and one or more pharmaceutically acceptable excipients or diluents, wherein the pharmaceutical composition, medicament or dosage form is formulated for controlled-release.
  • Specific dosage forms utilize an osmotic drug delivery system.
  • a particular and well-known osmotic drug delivery system is referred to as OROS® (Alza Corporation, Mountain View, Calif. USA). This technology can readily be adapted for the delivery of compounds and compositions of the invention.
  • OROS® Alza Corporation, Mountain View, Calif. USA
  • OROS® that can be used to administer compounds and compositions of the invention include, but are not limited to, the OROS® Push- PullTM, Delayed Push-PullTM, Multi-Layer Push-PullTM, and Push-StickTM Systems, all of which are well known. See, e.g., http://www.alza.com.
  • OROS®-CT and L-OROS® Additional OROS® systems that can be used for the controlled oral delivery of compounds and compositions of the invention include OROS®-CT and L-OROS®. Id.; see also, Delivery Times, vol. II, issue II (Alza Corporation).
  • Conventional OROS® oral dosage forms are made by compressing a drug powder (e.g. co-crystal) into a hard tablet, coating the tablet with cellulose derivatives to form a semi-permeable membrane, and then drilling an orifice in the coating (e.g., with a laser). Kim, Cherng-ju, Controlled Release Dosage Form Design, 231-238 (Technomic Publishing, Lancaster, Pa.: 2000).
  • the advantage of such dosage forms is that the delivery rate of the drug is not influenced by physiological or experimental conditions.
  • a specific dosage form of the invention comprises: a wall defining a cavity, the wall having an exit orifice formed or formable therein and at least a portion of the wall being semipermeable; an expandable layer located within the cavity remote from the exit orifice and in fluid communication with the semipermeable portion of the wall; a dry or substantially dry state drug layer located within the cavity adjacent to the exit orifice and in direct or indirect contacting relationship with the expandable layer; and a flow-promoting layer interposed between the inner surface of the wall and at least the external surface of the drug layer located within the cavity, wherein the drug layer comprises a co-crystal, or a solvate, hydrate, dehydrate, anhydrous, or amorphous form thereof. See U.S. Pat. No.
  • Another specific dosage form of the invention comprises: a wall defining a cavity, the wall having an exit orifice formed or formable therein and at least a portion of the wall being semipermeable; an expandable layer located within the cavity remote from the exit orifice and in fluid communication with the semipermeable portion of the wall; a drug layer located within the cavity adjacent the exit orifice and in direct or indirect contacting relationship with the expandable layer; the drug layer comprising a liquid, active agent formulation absorbed in porous particles, the porous particles being adapted to resist compaction forces sufficient to form a compacted drug layer without significant exudation of the liquid, active agent formulation, the dosage form optionally having a placebo layer between the exit orifice and the drug layer, wherein the active agent formulation comprises a co-crystal, or a solvate, hydrate, dehydrate, anhydrous, or amorphous form thereof.
  • a pharmaceutical composition or medicament comprises a mixture of a novel form of modafinil of the present invention (e.g., a co- crystal) and the free form of modafinil.
  • This embodiment can be used, for example, as a controlled-, sustained-, or extended-release dosage form.
  • an extended-release dosage form comprises free form modafinil and a co-crystal or a solvate of the present invention.
  • Such an extended-release dosage form contains modafinil in a form (e.g. modafinihmalonic acid co-crystal) which has a greater bioavailability than that of free form modafinil.
  • a pharmaceutical composition or medicament comprises a modified release profile of one or more of racemic modafinil, R-(-)- modafmil, and S-(+)-modafinil.
  • the modified release profile can comprise, for example, two or more maxima of plasma concentration, such as a dual-release profile.
  • Such a modified release profile may aid a patient treated with a composition or medicament of the present invention who experiences loss of wakefulness in the afternoon, for example.
  • a second "burst" or release of API at least 2, 3, 4, 5, or 6 hours after administration may help to overcome such an effect.
  • a pharmaceutical composition or medicament comprising a small loading dose released immediately following administration can be employed, followed by an approximate zero-order release profile over the following 2, 3, 4, 5, or 6 hours.
  • peak plasma levels can be reached at about midday.
  • a pharmaceutical composition or medicament comprising a modified release profile of modafinil can comprise R-(-)-modafinil and S-(+)-modafinil wherein the R-(-)-modafinil provides an initial increase (initial C ma ⁇ due to R-(-)-modafinil) in plasma concentration and the S-(+)-modafinil provides a delayed increase (subsequent C max due to S-(+)-modafinil) in plasma concentration.
  • 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.
  • the delayed C max is approximately equal to the initial C ma ⁇ .
  • the delayed C max is greater than the initial C max .
  • the delayed C ma is less than the initial C max .
  • the delayed C max is due to racemic modafinil, instead of S-(+)-modafinil.
  • the delayed C max is due to R-(-)- modafmil, instead of S-(+)-modafinil.
  • the initial C max is due to racemic modafinil, instead of R-(-)-modafinil.
  • the initial Cmax is due to S-(+)-modafinil, instead of R-(-)-modafinil.
  • the modified release profile has 3, 4, 5, or more "bursts" in plasma concentration.
  • a pharmaceutical composition or medicament comprising a modified release profile of modafinil wherein one or more of racemic modafinil, R-(-)-modafinil, or S-(+)-modafinil are present in the form of a co-crystal, solvate, free form, or a polymorph thereof.
  • a pharmaceutical composition or medicament comprising a modified release profile wherein R-(-)-modafinil is used in an oral formulation.
  • a composition can minimize first-pass metabolism of modafinil to the sulfone.
  • a pharmaceutical composition or medicament comprising a modified release profile wherein racemic modafinil is used in an oral formulation.
  • a pharmaceutical composition or medicament comprising a modified release profile wherein S-(+)-modafinil is used in an oral formulation.
  • a pharmaceutical composition or medicament comprising a modified release profile wherein racemic modafinil and R-(-)-modafinil are used in an oral formulation.
  • a pharmaceutical composition or medicament comprising a modified release profile wherein racemic modafinil and S-(+)-modafinil are used in an oral formulation.
  • a pharmaceutical composition or medicament comprising a modified release profile wherein S-(+)-modafinil and R-(-)-modafinil are used in an oral formulation.
  • a pharmaceutical composition or medicament comprising a modified release profile wherein racemic modafinil, S-(+)-modafinil and R-(-)-modafmil are used in an oral formulation.
  • a pharmaceutical composition or medicament comprising a modified release profile of modafinil is administered transdermally. Such a transdermal (TD) delivery can avoid first-pass metabolism.
  • compositions and medicaments of the present invention can be solids, semi-solids, liquids or combinations thereof. Preferably, excipients are solids.
  • Compositions and medicaments of the invention containing excipients can be prepared by known technique of pharmacy that comprises admixing an excipient with an API or therapeutic agent.
  • a pharmaceutical composition or medicament of the invention contains a desired amount of API per dose unit and, if intended for oral administration, can be in the form, for example, of a tablet, a caplet, a pill, a hard or soft capsule, a lozenge, a cachet, a dispensable powder, granules, a suspension, an elixir, a dispersion, a liquid, or any other form reasonably adapted for such administration. If intended for parenteral administration, it can be in the form, for example, of a suspension or transdermal patch. If intended for rectal administration, it can be in the form, for example, of a suppository.
  • oral dosage forms that are discrete dose units each containing a predetermined amount of the API, such as tablets or capsules.
  • excipients that can be used to prepare pharmaceutical compositions or medicaments of the invention.
  • Pharmaceutical compositions and medicaments of the invention optionally comprise one or more pharmaceutically acceptable carriers or diluents as excipients.
  • Suitable carriers or diluents illustratively include, but are not limited to, either individually or in combination, lactose, including anhydrous lactose and lactose monohydrate; starches, including directly compressible starch and hydrolyzed starches (e.g., CelutabTM and EmdexTM); mannitol; sorbitol; xylitol; dextrose (e.g., CereloseTM 2000) and dextrose monohydrate; dibasic calcium phosphate dihydrate; sucrose-based diluents; confectioner's sugar; monobasic calcium sulfate monohydrate; calcium sulfate dihydrate; granular calcium lactate trihydrate; dextrates; inositol; hydrolyzed cereal solids; amylose; celluloses including microcrystalline cellulose, food grade sources of alpha- and amorphous cellulose (e.g., RexcelJ), powdered cellulose, hydroxypropylcellulose (H
  • Such carriers or diluents constitute in total about 5% to about 99%, preferably about 10% to about 85%, and more preferably about 20% to about 80%, of the total weight of the composition.
  • the carrier, carriers, diluent, or diluents selected preferably exhibit suitable flow properties and, where tablets are desired, compressibility. Lactose, mannitol, dibasic sodium phosphate, and microcrystalline cellulose (particularly Avicel PH microcrystalline cellulose such as Avicel PH 101), either individually or in combination, are preferred diluents. These diluents are chemically compatible with APIs.
  • extragranular microcrystalline cellulose that is, microcrystalline cellulose added to a granulated composition
  • lactose especially lactose monohydrate
  • Lactose typically provides compositions having suitable release rates of APIs, stability, pre-compression flowability, and/or drying properties at a relatively low diluent cost. It provides a high density substrate that aids densification during granulation (where wet granulation is employed) and therefore improves blend flow properties and tablet properties.
  • Pharmaceutical compositions and medicaments of the invention optionally comprise one or more pharmaceutically acceptable disintegrants as excipients, particularly for tablet formulations.
  • Suitable disintegrants include, but are not limited to, either individually or in combination, starches, including sodium starch glycolate (e.g., ExplotabTM of Pen West) and pregelatinized corn starches (e.g., NationalTM 1551 of National Starch and Chemical Company, NationalTM 1550, and ColocornTM 1500), clays (e.g., VeegumTM HV of R.T.
  • starches including sodium starch glycolate (e.g., ExplotabTM of Pen West) and pregelatinized corn starches (e.g., NationalTM 1551 of National Starch and Chemical Company, NationalTM 1550, and ColocornTM 1500), clays (e.g., VeegumTM HV of R.T.
  • celluloses such as purified cellulose, microcrystalline cellulose, methylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose, croscarmellose sodium (e.g., Ac-Di-SolTM of FMC), alginates, crospovidone, and gums such as agar, guar, locust bean, karaya, pectin and tragacanth gums.
  • Disintegrants may be added at any suitable step during the preparation of the composition, particularly prior to granulation or during a lubrication step prior to compression. Such disintegrants, if present, constitute in total about 0.2% to about 30%, preferably about 0.2% to about 10%, and more preferably about 0.2% to about 5%, of the total weight of the composition.
  • Croscarmellose sodium is a preferred disintegrant for tablet or capsule disintegration, and, if present, preferably constitutes about 0.2% to about 10%, more preferably about 0.2% to about 7%, and still more preferably about 0.2% to about 5%, of the total weight of the composition. Croscarmellose sodium confers superior intragranular disintegration capabilities to granulated pharmaceutical compositions and medicaments of the present invention.
  • Pharmaceutical compositions and medicaments of the invention optionally comprise one or more pharmaceutically acceptable binding agents or adhesives as excipients, particularly for tablet formulations.
  • binding agents and adhesives preferably impart sufficient cohesion to the powder being tableted to allow for 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.
  • binding agents may also prevent or inhibit crystallization or recrystallization of an API of the present invention once the salt has been dissolved in a solution.
  • Suitable binding agents and adhesives include, but are not limited to, either individually or in combination, acacia; tragacanth; sucrose; gelatin; glucose; starches such as, but not limited to, pregelatinized starches (e.g., NationalTM 1511 and NationalTM 1500); celluloses such as, but not limited to, methylcellulose and carmellose sodium (e.g., TyloseTM); alginic acid and salts of alginic acid; magnesium aluminum silicate; PEG; guar gum; polysaccharide acids; bentonites; povidone, for example povidone K-15, K-30 and K-29/32; polymethacrylates; HPMC; hydroxypropylcellulose (e.g., KlucelTM of Aqualon); and ethylcellulose (e.g., EthocelTM of the Dow Chemical Company).
  • acacia tragacanth
  • sucrose gelatin
  • glucose starches
  • starches such as, but not limited to, pregelatinized starches (
  • binding agents and/or adhesives constitute in total about 0.5% to about 25%, preferably about 0.75% to about 15%, and more preferably about 1% to about 10%, of the total weight of the pharmaceutical composition or medicament.
  • Many of the binding agents are polymers comprising amide, ester, ether, alcohol or ketone groups and, as such, are preferably included in pharmaceutical compositions and medicaments of the present invention.
  • Polyvinylpyrrolidones such as povidone K-30 are especially preferred.
  • Polymeric binding agents can have varying molecular weight, degrees of crosslinking, and grades of polymer.
  • Polymeric binding agents can also be copolymers, such as block co-polymers that contain mixtures of ethylene oxide and propylene oxide units.
  • compositions and medicaments of the invention optionally comprise one or more pharmaceutically acceptable wetting agents as excipients. Such wetting agents are preferably selected to maintain the API in close association with water, a condition that is believed to improve bioavailability of the composition.
  • Non-limiting examples of surfactants that can be used as wetting agents in pharmaceutical compositions and medicaments of the invention include quaternary ammonium compounds, for example benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride, dioctyl sodium sulfosuccinate, polyoxyethylene alkylphenyl ethers, for example nonoxynol 9, nonoxynol 10, and octoxynol 9, poloxamers (polyoxyethylene and polyoxypropylene block copolymers), polyoxyethylene fatty acid glycerides and oils, for example polyoxyethylene (8) caprylic/capric mono- and diglycerides (e.g., LabrasolTM of Gattefosse), polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkyl ethers, for example polyoxyethylene (20) cetostearyl ether, polyoxyethylene fatty acid esters, for example polyoxyethylene (40) ste
  • Such wetting agents if present, constitute in total about 0.25% to about 15%, preferably about 0.4% to about 10%, and more preferably about 0.5% to about 5%, of the total weight of the pharmaceutical composition or medicament.
  • Wetting agents that are anionic surfactants are preferred.
  • Sodium lauryl sulfate is a particularly preferred wetting agent.
  • Sodium lauryl sulfate if present, constitutes about 0.25% to about 7%, more preferably about 0.4% to about 4%, and still more preferably about 0.5% to about 2%, of the total weight of the pharmaceutical composition or medicament.
  • Pharmaceutical compositions and medicaments of the invention optionally comprise one or more pharmaceutically acceptable lubricants (including anti- adherents and/or glidants) as excipients.
  • Suitable lubricants include, but are not limited to, either individually or in combination, glyceryl behapate (e.g., CompritolTM 888 of Gattefosse); stearic acid and salts thereof, including magnesium, calcium and sodium stearates; hydrogenated vegetable oils (e.g., SterotexTM of Abitec); colloidal silica; talc; waxes; boric acid; sodium benzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine; PEG (e.g., CarbowaxTM 4000 and CarbowaxTM 6000 of the Dow Chemical Company); sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate.
  • glyceryl behapate e.g., CompritolTM 888 of Gattefosse
  • hydrogenated vegetable oils e.g., SterotexTM
  • Such lubricants constitute in total about 0. 1% to about 10%, preferably about 0.2% to about 8%, and more preferably about 0.25% to about 5%, of the total weight of the pharmaceutical composition or medicament.
  • Magnesium stearate is a preferred lubricant used, for example, to reduce friction between the equipment and granulated mixture during compression of tablet formulations.
  • Suitable anti-adherents include, but are not limited to, talc, cornstarch, DL- leucine, sodium lauryl sulfate and metallic stearates.
  • Talc is a preferred anti-adherent or glidant used, for example, to reduce formulation sticking to equipment surfaces and also to reduce static in the blend.
  • Talc if present, constitutes about 0.1% to about 10%, more preferably about 0.25% to about 5%, and still more preferably about 0.5% to about 2%, of the total weight of the pharmaceutical composition or medicament.
  • Glidants can be used to promote powder flow of a solid formulation. Suitable glidants include, but are not limited to, colloidal silicon dioxide, starch, talc, tribasic calcium phosphate, powdered cellulose and magnesium trisilicate. Colloidal silicon dioxide is particularly preferred. Other excipients such as colorants, flavors and sweeteners are known in the pharmaceutical art and can be used in pharmaceutical compositions and medicaments of the present invention. Tablets can be coated, for example with an enteric coating, or uncoated.
  • compositions of the invention can further comprise, for example, buffering agents.
  • one or more effervescent agents can be used as disintegrants and/or to enhance organoleptic properties of pharmaceutical compositions and medicaments of the invention.
  • one or more effervescent agents are preferably present in a total amount of about 30% to about 75%, and preferably about 45% to about 70%, for example about 60%, by weight of the pharmaceutical composition or medicament.
  • an effervescent agent present in a solid dosage form in an amount less than that effective to promote disintegration of the dosage form, provides improved dispersion of the API in an aqueous medium.
  • an effervescent agent is effective to accelerate dispersion of the API, from the dosage form in the gastrointestinal tract, thereby further enhancing absorption and rapid onset of therapeutic effect.
  • an effervescent agent is preferably present in an amount of about 1% to about 20%, more preferably about 2.5% to about 15%, and still more preferably about 5% to about 10%, by weight of the pharmaceutical composition or medicament.
  • An "effervescent agent” herein is an agent comprising one or more compounds which, acting together or individually, evolve a gas on contact with water. The gas evolved is generally oxygen or, most commonly, carbon dioxide.
  • Preferred effervescent agents comprise an acid and a base that react in the presence of water to generate carbon dioxide gas.
  • the base comprises an alkali metal or alkaline earth metal carbonate or bicarbonate and the acid comprises an aliphatic carboxylic acid.
  • suitable bases include carbonate salts (e.g., calcium carbonate), bicarbonate salts (e.g., sodium bicarbonate), sesquicarbonate salts, and mixtures thereof. Calcium carbonate is a preferred base.
  • Non-limiting examples of suitable acids as components of effervescent agents and/or solid acids useful in the invention include citric acid, tartaric acid (as D-, L-, or D/L-tartaric acid), malic acid, maleic acid, fumaric acid, adipic acid, succinic acid, acid anhydrides of such acids, acid salts of such acids, and mixtures thereof.
  • Citric acid is a preferred acid.
  • the weight ratio of the acid to the base is about 1 : 100 to about 100:1, more preferably about 1:50 to about 50:1, and still more preferably about 1:10 to about 10:1.
  • the ratio of the acid to the base is approximately stoichiometric.
  • Excipients which solubilize metal salts of APIs typically have both hydrophilic and hydrophobic regions, or are preferably amphiphilic or have amphiphilic regions.
  • One type of amphiphilic or partially-amphiphilic excipient comprises an amphiphilic polymer or is an amphiphilic polymer.
  • a specific amphiphilic polymer is a polyalkylene glycol, which is commonly comprised of ethylene glycol and/or propylene glycol subunits.
  • Such polyalkylene glycols can be esterified at their termini by a carboxylic acid, ester, acid anhyride or other suitable moiety.
  • excipients include poloxamers (symmetric block copolymers of ethylene glycol and propylene glycol; e.g., poloxamer 237), polyalkyene glycolated esters of tocopherol (including esters formed from a di- or multi-functional carboxylic acid; e.g., d-alpha-tocopherol polyethylene glycol- 1000 succinate), and macrogolglycerides (formed by alcoholysis of an oil and esterification of a polyalkylene glycol to produce a mixture of mono-, di- and tri-glycerides and mono- and di-esters; e.g., stearoyl macrogol-32 glycerides).
  • compositions and medicaments of the present invention can comprise about 10% to about 50%, about 25% to about 50%, about 30% to about 45%, or about 30% to about 35% by weight of API; about 10% to about 50%, about 25% to about 50%, about 30% to about 45%, or about 30% to about 35% by weight of a an excipient which inhibits 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 of a binding agent.
  • the weight ratio of the API to the excipient which inhibits crystallization to binding agent is about 1 to 1 to 1.
  • Solid dosage forms of the invention can be prepared by any suitable process, not limited to processes described herein.
  • An illustrative process comprises (a) a step of blending a salt of the invention with one or more excipients to form a blend, and (b) a step of tableting or encapsulating the blend to form tablets or capsules, respectively.
  • solid dosage forms are prepared by a process comprising (a) a step of blending an API salt of the invention with one or more excipients to form a blend, (b) a step of granulating the blend to form a granulate, and (c) a step of 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.
  • a salt of the present invention is advantageously granulated to form particles of about 1 micrometer to about 100 micrometer, about 5 micrometer to about 50 micrometer, or about 10 micrometer to about 25 micrometer.
  • One or more diluents, one or more disintegrants and one or more binding agents are preferably added, for example in the blending step, a wetting agent can optionally be added, for example in the granulating step, and one or more disintegrants are preferably added after granulating but before tableting or encapsulating.
  • a lubricant is preferably added before tableting. Blending and granulating can be performed independently under low or high shear.
  • a process is preferably selected that forms a granulate that is uniform in API content, that readily disintegrates, that flows with sufficient ease so that weight variation can be reliably controlled during capsule filling or tableting, and that is dense enough in bulk so that a batch can be processed in the selected equipment and individual doses fit into the specified capsules or tablet dies.
  • solid dosage forms are prepared by a process that includes a spray drying step, wherein the API is suspended with one or more excipients in one or more sprayable liquids, preferably a non-protic (e.g., non-aqueous or non-alcoholic) sprayable liquid, and then is rapidly spray dried over a current of warm air.
  • a granulate or spray dried powder resulting from any of the above illustrative processes can be compressed or molded to prepare tablets or encapsulated to prepare capsules.
  • Conventional tableting and encapsulation techniques known in the art can be employed. Where coated tablets are desired, conventional coating techniques are suitable.
  • Excipients for tablet compositions of the invention are preferably selected to provide a disintegration time of less than about 30 minutes, preferably about 25 minutes or less, more preferably about 20 minutes or less, and still more preferably about 15 minutes or less, in a standard disintegration assay.
  • a pharmaceutical composition or medicament comprising modafinil and an additional API can be prepared.
  • the modafinil and the additional API can be in the form of a co-crystal, or may be included as a mixture or a combination of active pharmaceutical ingredients.
  • a composition can comprise modafinil and caffeine as a combination.
  • a composition comprising modafinil and caffeine can be used as a therapeutic agent to treat the same conditions as modafinil.
  • the caffeine can yield a quick release characteristic (small T ma ⁇ relative to modafinil) to the dissolution profile while the modafinil causes the therapeutic effect to be present for hours after administration.
  • the T ma ⁇ of caffeine may be 0.001, 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, or 0.8 times that of modafinil.
  • Combination therapies comprise the administration of two or more APIs in the same formulation, or in two or more co-administered formulations.
  • the APIs can be administered together at the same time, or individually at specified intervals.
  • Uses for modafinil are well known in the art and include the treatment of narcolepsy, multiple sclerosis related fatigue, infertility, eating disorders, attention deficit hyperactivity disorder (ADHD), Parkinson's disease, incontinence, sleep apnea, or myopathies.
  • ADHD attention deficit hyperactivity disorder
  • any one or more of the modafinil compositions of the present invention may be used in the treatment of one or more of the above conditions.
  • the dosage and administration for modafinil compositions of the present invention can be determined using routine methods in the art but will generally fall between about 50 and about 700 mg/day.
  • a composition of the present invention can be administered to a mammal via an injection. Injections include, but are not limited to, intravenous, subcutaneous, and intramuscular injections.
  • a composition of the present invention is formulated for injection into a mammal in need of therapeutic effect.
  • CrystalMax® comprises a sequence of automated, integrated high throughput robotic stations capable of rapid generation, identification and characterization of polymorphs, salts, and co-crystals of APIs and API candidates. Worksheet generation and combinatorial mixture design is carried out using proprietary design software ArchitectTM. Typically, an API or an API candidate is dispensed from an organic solvent into tubes and dried under a stream of nitrogen. Salts and/or co-crystal formers may also be dispensed and dried in the same fashion. Water and organic solvents may be combinatorially dispensed into the tubes using a multi-channel dispenser.
  • Each tube in a 96-tube array is then sealed within 15 seconds of combinatorial dispensing to avoid solvent evaporation.
  • the mixtures are then rendered supersaturated by heating to 70 degrees C for 2 hours followed by a 1 degree C/minute cooling ramp to 5 degrees C.
  • Optical checks are then conducted to detect crystals and/or solid material. Once a solid has been identified in a tube, it is isolated through aspiration and drying. Raman spectra are then obtained on the solids and cluster classification of the spectral patterns is performed using proprietary software (InquireTM).
  • Co-crystals may be obtained by dissolving the separate components in a solvent and adding one to the other. The co-crystal may then precipitate or crystallize as the solvent mixture is evaporated slowly. The co-crystal may also be obtained by dissolving the two components in the same solvent or a mixture of solvents. The co- crystal may also be obtained by seeding a saturated solution of the two components and seeding with a ground mixture of the co-crystal.
  • a co-crystal may be obtained by melting the two components together (i.e., co- melting) and allowing recrystallization to occur.
  • an anti-solvent may be added to facilitate crystallization.
  • a co-crystal may be obtained by melting the higher melting component on a glass slide and allowing it to recrystallize. The second component is then melted and is also allowed to recrystallize. The co-crystal may form as a separated phase/band in between the eutectic bands of the two original components.
  • a co-crystal may be obtained by mixing or grinding two components together in the solid state.
  • Example 12 describes the synthesis of a modafinil: 1- hydroxy-2-naphthoic acid co-crystal obtained by milling with the addition of a small amount of an appropriate solvent (wet grinding).
  • Example 5 describes the synthesis of a modafinihcitric acid monohydrate co-crystal obtained by milling both with and without the addition of a small amount of an appropriate solvent.
  • a co-crystal is prepared via milling or grinding modafinil with a co- crystal former (dry grinding).
  • a co-crystal is prepared via milling or grinding modafinil, a co-crystal former, and a small amount of solvent (wet grinding).
  • a co-crystal is prepared with the addition of solvent, without the addition of solvent, or both.
  • Solvents used in such a co-crystallization process can be, for example, but not limited to, acetone, methanol, ethanol, isopropyl alcohol, ethyl acetate, isopropyl acetate, nitromethane, dichloromethane, chloroform, toluene, propylene glycol, dimethyl sulfoxide (DMSO), dimethyl formamide (DMF), diethyl ether (ether), ethyl formate, hexane, acetonitrile, benzyl alcohol, water, or another organic solvent including alcohols.
  • DMSO dimethyl sulfoxide
  • DMF dimethyl formamide
  • ether diethyl ether
  • ethyl formate hexane
  • acetonitrile benzyl alcohol
  • water or another organic solvent including alcohols.
  • a co-crystal may be obtained by co-subliming a mixture of an API and a co-crystal former in the same sample cell as an intimate mixture either by heating, mixing or placing the mixture under vacuum.
  • a co-crystal may also be obtained by co- sublimation using a Kneudsen apparatus where the API and the co-crystal former are contained in separate sample cells, connected to a single cold finger, each of the sample cells is maintained at the same or different temperatures under a vaccum atmosphere in order to co-sublime the two components onto the cold-finger forming the desired co-crystal.
  • DSC Differential scanning calorimetric
  • DSC analysis of the sample was performed by placing the modafinil sample in an aluminum pan with a crimped pan closure.
  • the starting temperature was typically 20 degrees C with a heating rate of 10 degrees C/minute, and the ending temperature was 200 degrees C. All reported DSC transitions represent the temperature of endothermic or exothermic transition at their respective peaks with an error of +/- 2 degrees C, unless otherwise indicated.
  • Thermogravimetric analysis (TGA) of samples was performed using a Q500 Thermogravimetric Analyzer (TA Instruments, New Castle, DE, U.S.A.), which uses Advantage for QW-Series, version 1.0.0.78, Thermal Advantage Release 2.0 (2001 TA Instruments- Water LLC).
  • 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).
  • the purge gas used was dry nitrogen, the balance purge was 40 mL/minute N 2 , and the sample purge was 60 mL/minute N 2 .
  • TGA was performed on the sample by placing the modafinil sample in a platinum pan. The starting temperature was typically 20 degrees C with a heating rate of 10 degrees C/minute, and the ending temperature was 300 degrees C.
  • a powder X-ray diffraction (PXRD) pattern for the samples was obtained using a D/Max Rapid, Contact (Rigaku/MSC, The Woodlands, TX, U.S.A.), which uses as its control software RINT Rapid Control Software, Rigaku Rapid/XRD, version 1.0.0 (1999 Rigaku Co.).
  • RINT Rapid Control Software Rigaku Rapid/XRD, version 1.0.0 (1999 Rigaku Co.
  • analysis software used were 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.).
  • the acquisition parameters were as follows: source was Cu with a K line at 1.5406 A; x-y stage was manual; collimator size was 0.3 mm; capillary tube (Charles Supper Company, Natick, MA, U.S.A.) was 0.3 mm ID; reflection mode was used; the power to the X-ray tube was 46 kV; the current to the X-ray tube was 40 mA; the omega-axis was oscillating in a range of 0-5 degrees at a speed of 1 degree/minute; the phi-axis was spinning at an angle of 360 degrees at a speed of 2 degrees/second; 0.3 mm collimator; the collection time was 60 minutes; the temperature was room temperature; and the heater was not used.
  • the sample was presented to the X-ray source in a boron rich glass capillary.
  • the analysis parameters were as follows: the integration 2-theta range was 2-60 degrees; the integration chi range was 0-360 degrees; the number of chi segments was 1; the step size used was 0.02; the integration utility was cylint; normalization was used; dark counts were 8; omega offset was 180; and chi and phi offsets were 0.
  • PXRD diffractograms were also acquired via the Bruker AXS D8 Discover X- ray Diffractometer.
  • This instrument was equipped with GADDSTM (General Area Diffraction Detection System), a Bruker AXS HI-STAR Area Detector at a distance of 15.05 cm as per system calibration, a copper source (Cu/K ⁇ 1.54056 angstroms), automated x-y-z stage, and 0.5mm collimator.
  • the sample was compacted into pellet form and mounted on the x-y-z stage.
  • a diffractogram was acquired under ambient conditions (25 degrees C) at a powder setting of 40kV and 40mA in reflection mode while the sample remained stationary. The exposure time was varied and specified for each sample.
  • the diffractogram obtained underwent a spatial remapping procedure to account for the geometrical pincushion distortion of the area detector then integrated along chi from -118.8 to -61.8 degrees and 2-theta 2.1-37 degrees at a step size of 0.02 degrees with normalization set to bin normalize.
  • the relative intensity of peaks in a diffractogram is not necessarily a limitation of the PXRD pattern because peak intensity can vary from sample to sample, e.g., due to crystalline impurities. Further, the angles of each peak can vary by about +/- 0.1 degrees, preferably +/- 0.05.
  • each composition of the present invention may be characterized by any one, any two, any three, any four, any five, any six, any seven, or any eight or more of the 2 theta angle peaks. Any one, two, three, four, five, or six DSC transitions, can also be used to characterize the compositions of the present invention.
  • Thermal (hotstage) microscopy was completed on a Zeiss Axioplan 2 microscope equipped with a Mettler Toledo FP90 controller.
  • the hotstage used was a Mettler Toledo FP82HT. All melting point determinations were completed by placing the sample on a microscope slide and covered with a coverslip. The initial temperature was set at 30 degrees C and the temperature was increased at a rate of 10 degrees C/minute. Melting was observed through a 5x microscope objective.
  • HPLC Method (adapted from Donovan et al. Therapeutic Drug Monitoring 25:197-202.
  • Prep 1 M sodium phosphate monobasic dissolve 120 g of sodium phosphate monobasic in water and make up to 1000 mL; filter.
  • Prep Mobile Phase A (20 mM sodium phosphate, pH 3.0): for each liter, dilute 20 mL 1 M sodium phosphate to 1000 mL with water; adjust pH to 3.0 with phosphoric acid.
  • Prep Mobile Phase B 70:30 (v/v) 20 mM sodium phosphate, pH 3.0:acetonitrile: for each liter, mix 700 mL Mobile Phase A and 300 mL of acetonitrile.
  • Sample Prep 1. Dissolve samples in 90:10 (v/v) 20 mM sodium phosphate, pH 3.0:acetonitrile to an approximate concentration of 20 micrograms/mL
  • the sample was either left in the glass vial in which it was processed or an aliquot of the sample was transferred to a glass slide.
  • the glass vial or slide was positioned in the sample chamber.
  • the measurement was made using an AlmegaTM Dispersive Raman (AlmegaTM Dispersive Raman, Thermo-Nicolet, 5225 Verona , Road, Madison, WI 53711-4495) system fitted with a 785 nm laser source.
  • the sample was manually brought into focus using the microscope portion of the apparatus with a lOx power objective (unless otherwise noted), thus directing the laser onto the surface of the sample.
  • the spectrum was acquired using the parameters / outlined in Table A. (Exposure times and number of exposures may vary; changes to parameters will be indicated for each acquisition.)
  • IR acquisitions IR spectra were obtained using NexusTM 470 FT-IR, Thermo-Nicolet, 5225 Verona Road, Madison, WI 53711-4495 and were analyzed with Control and Analysis software: OMNIC, Version 6.0a, (C) Thermo-Nicolet, 1995-2004.
  • Racemic Modafinil Malonic acid Co-crystal
  • acetic acid 600 microliters
  • malonic acid 114.9 mg, 1.104 mmol
  • the solution was then dried under a flow of nitrogen to give a 1:1 modafinihmalonic acid co-crystal as a colorless solid.
  • the solid material was characterized using PXRD. The material was then dried further under a flow of nitrogen overnight to give 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 modafinihmalonic acid (1:1) co-crystal are listed in Table IV, and the diffractogram is shown in Figure 1 (Data as collected/received).
  • DSC showed an endothermic transition at about 106 degrees C, and the thermogram is shown in Figure 2.
  • TGA thermogram is shown in Figure 3.
  • Figures 4 A and 4B show a Raman spectrum of the modafinihmalonic acid co-crystal and three Raman spectra of modafinil, malonic acid, and the co-crystal, respectively.
  • Figures 5A and 5B show an IR spectrum of the modafinihmalonic acid co-crystal and three IR spectra of modafinil, malonic acid, and the co-crystal, respectively.
  • the modafinihmalonic acid co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 1 including, but not limited to, 5.00, 9.17, 10.08, 16.81, 18.26, 19.43, 21.36, 21.94, 22.77, 24.49, 25.63, 26.37, and 28.45 degrees 2-theta.
  • the modafinihmalonic acid co-crystal was also prepared by grinding the API and co-crystal former together.
  • Racemic modafinil (2.50 g, 0.009 mol) and malonic acid (1.01 g, 0.0097 mmol) were mixed in a large mortar and pestle over a period of seven days (malonic acid added in increments over 7 days with about a 1:1.05 ratio made on the first day and increments added over the next seven days which resulted in a 1:2 modafinihmalonic acid ratio).
  • the mixture was ground for 45 minutes initially and 20 minutes each time more malonic acid was added.
  • the mixture of co-crystal and starting components was heated in a sealed 20 mL vial at 80 degrees C for about 35 minutes to facilitate completion of the co-crystal formation.
  • the modafinihmalonic acid co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 6A including, but not limited to, 5.08, 9.28, 16.81, 18.27, 19.45, 21.39, 21.99, 22.83, 23.50, 24.58, 25.12, and 28.49 degrees 2-theta.
  • DSC thermogram for the co-crystal shows, in Figure 6B, an endothermic transition at about 116 degrees C. Single crystal data of the modafinihmalonic acid co-crystal were acquired and are reported below.
  • Figure 7 shows a packing diagram of the modafinihmalonic acid.
  • Racemic ModafinihGlycolic acid Co-crystal Racemic modafinil (1 mg, 0.0037mmol) and glycolic acid (0.30 mg, 0.0037 mmol) were dissolved in acetone (400 microliters). The solution was allowed to evaporate to dryness and the resulting solid was characterized using PXRD (Rigaku). PXRD data for the modafinihglycolic acid co-crystal are listed in Table IV. See Figures 8 A and 8B.
  • Figure 8A shows the PXRD diffractogram after subtraction of background noise.
  • Figure 8B shows the raw PXRD data as collected.
  • An alternative method for the preparation of modafinihglycolic acid co- crystals was also completed.
  • the modafinihglycolic acid co-crystal was characterized by PXRD.
  • the modafinihglycolic acid co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 8 A including, but not limited to, 9.51, 14.91, 15.97, 19.01, 20.03, 21.59, 22.75, 25.03, and 25.71 degrees 2-theta.
  • the modafinihglycolic acid co-crystal can, likewise, be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 8B including, but not limited to, 9.53, 14.93, 15.99, 19.05, 20.05, 21.61, 22.77, and 25.05 degrees 2-theta.
  • Figure 9A shows the PXRD diffractogram after subtraction of background noise.
  • Figure 9B shows the raw PXRD data.
  • PXRD data for the modafinihmaleic acid co- crystal are listed in Table IV.
  • the modafinihmaleic acid co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 9A including, but not limited to, 4.69, 6.15, 9.61, 10.23, 15.65, 16.53, 17.19, 18.01, 19.97, 21.83, and 22.45 degrees 2-theta.
  • the modafinihmaleic acid co-crystal can, likewise, be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 9B including, but not limited to, 4.69, 6.17, 9.63, 10.25, 15.67, 16.53, 17.21, 18.05, 19.99, 21.85, and 22.47 degrees 2-theta.
  • Racemic Modafinil L-tartaric acid Co-crystal
  • L-tartaric acid 5.83 mg, 0.039 mmol
  • the solution was then left to evaporate at room temperature to give a clear, viscous material.
  • the material was dried further under flowing nitrogen for 2 days, and then placed in a vial and capped. After 6 days, a small amount of colorless solid formed. One day after the first solids are seen approximately 60 % of the remaining clear amorphous volume converted to the solid form.
  • PXRD Bruker
  • the modafinihL-tartaric acid co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 10 including, but not limited to, 6.10, 7.36, 9.38, 14.33, 16.93, 17.98, 18.81, 20.15, 20.71, 22.49, and 25.04 degrees 2-theta.
  • Racemic Modafinil Citric acid Co-crystal
  • Racemic modafinil (25.3 mg, 93 mmol) and citric acid monohydrate (26.8 mg, 128 mmol) were ground together for 3 minutes. 1 mg of the resulting mixture was then dissolved in acetone (100 microliters) and heated to 70 degrees C and maintained at that temperature for 2 hours. The solution was then cooled to 5 degrees C and was left at that temperature for 2 days. After 2 days the cap was removed from the vial and one drop of water was added. The solvent was then evaporated to give a modafinihcitric acid monohydrate co-crystal as a colorless solid.
  • the modafinihcitric acid monohydrate co-crystal was characterized by PXRD (Rigaku), as shown in Figure 11 A (background subtracted).
  • the modafinihcitric acid co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 11A including, but not limited to, 5.29, 7.29, 9.31, 12.41, 13.29, 17.29, 17.97, 18.79, 21.37, and 23.01 degrees 2-theta.
  • Other methods were also used to prepare the modafinihcitric acid monohydrate co-crystal.
  • a second preparation was performed by placing modafinil (30 mg, 0.0001 mol) and excess citric acid monohydrate in a stainless steel vial.
  • Racemic Modafinil Succinic acid Co-crystal
  • Racemic modafinil 25mg, 90 mmol
  • 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 degrees C for 2 hours and then cooled to 5 degrees C and maintained at that temperature for 2 days. After 2 days, the cap was removed from the vial and the solvent was evaporated at 65 degrees 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 two moles of modafinil for every mole of succinic acid.
  • the modafinil succinic acid co-crystal was characterized by PXRD (Rigaku) and DSC, as shown in Figures 12A, 12B, and 13.
  • Figure 12A shows the PXRD diffractogram after subtraction of background noise.
  • Figure 12B shows the raw PXRD data.
  • Figure 13 shows the DSC thermogram.
  • An alternative method for the preparation of modafinihsuccinic acid co- crystals was also completed. To racemic modafinil (49.7 mg, 0.182 mmol) and succinic acid (21.6 mg, 0.182 mmol) in a round bottom flask was added methanol (1.5 mL). The mixture was then dissolved on a hotplate at 65 degress C.
  • the modafinihsuccinic acid co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 12A including, but not limited to, 5.45, 9.93, 15.85, 17.97, 18.73, 19.95, 21.33, 21.93, 23.01, and 25.11 degrees 2-theta.
  • the modafinihsuccinic acid co-crystal can, likewise, be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 12B including, but not limited to, 5.45, 9.93, 15.87, 17.99, 18.75, 19.95, 21.95, 23.03, and 25.07 degrees 2-theta.
  • Figure 14 shows a packing diagram of the modafinihsuccinic acid co-crystal.
  • Racemic Modafinil DL-tartaric acid Co-crystal A suspsension 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. The undissolved DL-tartaric acid was filtered off while the suspension was still hot through a 0.2 micrometer PTFE filter. The remaining solution was allowed to cool to room temperature then to 0 degrees C for 1 hour. After 1 hour, large colorless crystals were observed. The mother liquor was decanted and the solid was allowed to air dry and was characterized by PXRD (Rigaku), as shown in Figure 15.
  • the modafinihDL-tartaric acid co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 15 including, but not limited to, 4.75, 9.53, 10.07, 15.83, 17.61, 19.37, 20.25, 21.53, 22.55, and 23.75 degrees 2-theta (as collected).
  • Racemic Modafinil 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-1-bug, Bratt Technologies, 115V/60Hz) and the solid mixture was milled for 5 minutes. The resultant powder was then collected and characterized as modafinihfumaric acid co-crystal (Form I) using PXRD (Rigaku), as shown in Figure 16.
  • the co-crystal is a 2:1 co-crystal comprising two moles of modafinil for every mole of fumaric acid.
  • the modafinihfumaric acid co-crystal (Form I) can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 16 including, but not limited to, 5.45, 9.95, 10.91, 15.93, 18.03, 18.81, 19.93, 20.25, 21.37, 21.95, 23.09, and 25.01 degrees 2-theta (as collected).
  • Single crystal data of the modafinihfumaric acid co-crystal (Form I) were acquired and are reported below.
  • Figure 17 shows a packing diagram of the modafinihfumaric acid co-crystal (Form I).
  • 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-1-bug, Bratt Technologies, 115V/60Hz) and the solid mixture was milled for 5 minutes. The resultant powder was then collected and characterized as modafinihfumaric acid co-crystal (Form II) using PXRD (Rigaku), as shown in Figure 18.
  • PXRD Raku
  • the modafinihfumaric acid co-crystal (Form II) can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 18 including, but not limited to, 6.47, 8.57, 9.99, 13.89, 14.53, 16.45, 17.13, 17.51, 18.39, 20.05, 20.79, 25.93, and 27.95 degrees 2-theta (as collected).
  • Racemic Modafinil Genetisic 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-1-bug, Bratt Technologies, 115V/60Hz) and the solid mixture was milled for 5 minutes. The resultant powder was then collected and characterized using PXRD (Bruker), as shown in Figure 19.
  • the modafinihgentisic acid co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 19 including, but not limited to, 6.96, 12.92, 14.76, 17.40, 18.26, 20.10, 20.94, 23.46, and 24.36 degrees 2-theta (as collected).
  • Racemic ModafinihOxalic acid Co-crystal A preparation of modafinihoxalic acid co-crystal was performed by placing racemic modafinil (30 mg, 0.0001 mol) and oxalic acid (1-2 mg, 0.0001-0.0002 mol) in a stainless steel vial. 20 microliters of acetone was added to the vial. The vial was then placed in a grinder (wig-1-bug, Bratt Technologies, 115V/60Hz) and the solid mixture was milled for 5 minutes. The resultant powder was then collected and characterized using PXRD (Bruker), as shown in Figure 20. In another preparation of the modafinihoxalic acid co-crystal, the preparation above was completed without the addition of solvent.
  • the modafinihoxalic acid co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 20 including, but not limited to, 5.98, 13.68, 14.80, 17.54, 19.68, 21.12, 21.86, and 28.90 degrees 2-theta (as collected).
  • Racemic Modafinil l-hvdroxy-2-naphthoic acid Co-crystal Racemic modafinil (30 mg, 0.0001 mol) and l-hydroxy-2-naphthoic acid (21 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-1-bug, Bratt Technologies, 115V/60Hz) and the solid mixture was milled for 5 minutes. The resultant powder was then collected and characterized using PXRD (Bruker), as shown in Figure 21.
  • l-hydroxy-2-naphthoic acid co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 21 including, but not limited to, 5.72, 7.10, 11.48, 14.16, 15.66, 17.92, 19.18, 20.26, 21.28, 21.94, 24.38, and 26.86 degrees 2-theta (as collected).
  • PXRD peaks at 10.05 and 26.36 degrees 2-theta may be from excess co-crystal former.
  • R-(-)-Modafmil:Malonic acid Co-crystal was prepared by grinding R-(-)- modafinil (29.7 mg, 0.109 mmol, 82.2 percent R-isomer) with malonic acid (11.9 mg, 0.114 mmol). The ground mixture was then heated to 80 degrees C for 10 minutes. The powder was analyzed by PXRD (Bruker) and DSC, as shown in Figures 22 and 23, respectively. The PXRD pattern confirms that the co-crystal was made and shows many similarities to the PXRD pattern for the racemic modafinihmalonic acid co- crystal.
  • the R-(-)-modafinihmalonic acid co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 22 including, but not limited to, 5.04, 9.26, 16.73, 18.23, 19.37, 21.90, 22.74, 24.44, and 25.67 degrees 2-theta (data as collected).
  • the DSC showed a melting range of 111.5 - 114.7 degrees C with a heat of fusion of 112.9 J/g.
  • R-(-)-Modaf ⁇ nil Succinic acid Co-crystal
  • R-(-)-modafinil succinic acid co-crystal was prepared by grinding R-(-)- modafinil (30.9 mg, 0.113 mmol, 82.2 percent R-isomer) with succinic acid (14.8 mg, 0.125 mmol). The ground mixture was then heated to 145 degrees C for 5 minutes. The powder was analyzed by PXRD (Bruker) and DSC, as shown in Figures 24 and 25, respectively. The PXRD pattern confirms that the co-crystal was made and shows many similarities to the PXRD pattern for the racemic modafinihsuccinic acid co- crystal made from solution.
  • the R-(-)-modafinil:succinic acid co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 24 including, but not limited to, 5.36, 9.83, 15.80, 17.88, 18.70, 19.87, 21.21, 21.85, and 25.96 degrees 2-theta (data as collected).
  • the DSC showed a melting range of 143.3 - 145.2 degrees C with a heat of fusion of 140.7 J/g.
  • R-(-)-Modafinil:Citric acid Co-crystal was prepared by grinding R-(-)-modafinil (30.0 mg, 0.110 mmol, 82.2 percent R-isomer) with citric acid monohydrate (27.1 mg, 0.129 mmol). The powder was analyzed by PXRD (Bruker) and DSC, as shown in Figures 26 and 27, respectively. The PXRD pattern confirms that the co-crystal was made and shows many similarities to the PXRD pattern for the racemic modafinihcitric acid co-crystal.
  • the R-(-)-modafinil:citric acid co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 26 including, but not limited to, 5.18, 7.23, 9.23, 12.32, 13.23, 17.25, 17.92, 18.76, 20.25, 21.30, and 23.71 degrees 2-theta (data as collected).
  • the DSC showed a melting range of 83.5 - 89.0 degrees C with a heat of fusion of 39.8 J/g.
  • R-(-)-Modafinil:DL-tartaric acid co-crystal was found from a high throughput crystallization experiment from dichloromethane.
  • the vial contained a 1:2 mixture of R-(-)-n ⁇ odafinil (greater than 98 percent R-isomer) and DL-tartaric acid.
  • the co-crystal was also found from a 1:1 mixture of R-(-)-modafmil (greater than 98 percent R-isomer) and DL-tartaric acid in nitromethane.
  • the solid materials were collected and characterized using PXRD (Bruker) and DSC, as shown in Figures 28 and 29, respectively.
  • the R-(-)-modafmil:DL-tartaric acid co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 28 including, but not limited to, 4.67, 15.41, 17.97, 19.46, 20.50, 22.91, and 24.63 degrees 2-theta (as collected). Endothermic transitions were present at about 107, 152, and 187 degrees C.
  • R-(-)-Modafinil l-hydroxy-2-naphthoic acid Co-crystal
  • o-xylene 4.5 mL
  • the mixture was heated to reflux for less than one minute at which point both solids dissolved.
  • the solution was then slowly cooled to room temperature at which point a solid crystallized.
  • the solid was collected via filtration and air-dried.
  • the powder was characterized using PXRD (Bruker), as shown in Figure 30.
  • the same material has been prepared from benzene, toluene, and acetone using the above procedure.
  • the R-(-)-modafinil:l-hydroxy-2-naphthoic acid co- crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 30 including, but not limited to, 5.27, 8.85, 10.60, 12.11, 14.47, 17.80, 18.80, 21.20, 23.03, and 25.61 degrees 2-theta (as collected).
  • the R-(-)-modafinil:l-hydroxy-2-naphthoic co-crystal was also obtained from a high throughput crystallization experiment from a vial containing a 1 : 1 mixture of R-(-)-modafinil (greater than 98 percent R-isomer) and l-hydroxy-2-naphthoic acid in nitromethane.
  • the solid material was collected and characterized using DSC and PXRD (Bruker), as shown in Figures 31 and 32, respectively.
  • the R-(-)-modafmihl- hydroxy-2-naphthoic acid co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 32 including, but not limited to 5.34, 8.99, 10.68, 12.15, 14.51, 21.28, 23.14, and 24.50 degrees 2-theta (as collected).
  • DSC shows endothermic transitions at about 118 and 179 degrees C.
  • Example 18 R-(-)-Modafinil:Orotic acid Co-crystal
  • the R-(-)-modafinil:orotic acid co-crystal was obtained from a high throughput crystallization experiment from a vial containing R-(-)-modafinil (1 mg, 0.0036 mmol, greater than 98 percent R-isomer) and orotic acid (1.14 mg, 0.0073 mmol) in acetone (100 microliters).
  • the solid material obtained was characterized using PXRD (Bruker) and DSC, as shown in Figures 33 and 34, respectively.
  • the R- (-)-modafinihorotic acid co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 33 including, but not limited to, 9.77, 17.85, 20.52, 20.95, 24.03, and 26.80 degrees 2-theta (as collected).
  • PXRD peaks at 14.61 and 28.60 may correspond to excess co-crystal former. Endothermic transitions were present at about 116, 130, and 169 degrees C.
  • Acetic acid Solvate of Racemic Modafinil To racemic modafinil (12.9 mg, 0.047 mmol) was added acetic acid (40 microliters). The mixture was heated at 50 degrees C to completely dissolve the solid. The solution was allowed to cool to room temperature, and left overnight, which yielded no precipitation. The solution was then evaporated under flowing nitrogen until precipitation was observed. The resulting solid was further dried under flowing nitrogen. Characterization of the product has been achieved via PXRD (Rigaku), TGA, DSC, and Raman spectroscopy, as shown in Figures 35-38, respectively. An alternative method for the preparation of the acetic acid solvate of modafinil was also completed.
  • a sample of modafinil acetic acid solvate was prepared by dissolving racemic modafinil (12.9 mg, 0.047 mmol) in acetic acid (40 microliters) and incubating at 65 degrees C for 30 minutes to dissolve, then cooling to 25 degrees C to incubate overnight. The sample was then evaporated to approximately 1/3 volume. After centrifugation of the sample, rapid nucleation and growth of crystals was observed. An additional 20 microliters of acetic acid was then added. The sample was heated at 50 degrees C until partial dissolution of the crystals was observed. The sample was then cooled to room temperature over a 1 hour period, then to 5 degrees C for 3 hours in an attempt to induce crystal growth. The sample was then dried under nitrogen gas. Rapid appearance of crystals was observed.
  • the modafinil acetic acid solvate can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 35 including, but not limited to, 6.17, 9.63, 15.69, 17.97, 19.99, and 21.83 degrees 2-theta (data as collected).
  • Tetrahydrofuran Solvate of Racemic Modafinil The tetrahydrofuran (THF) solvate of modafinil was prepared by placing racemic modafinil (10.4 mg, 0.038 mmol) in tetrahydrofuran (1 mL). The powder did not completely dissolve in THF and converted overnight into long, fine, needle shaped crystals which were collected and analyzed by PXRD (Rigaku), as shown in Figure 39.
  • the modafinil tetrahydrofuran solvate can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 39 including, but not limited to, 6.97, 9.79, 10.97, 16.19, 19.03, 19.71, 20.59, 22.25, and 25.13 degrees 2-theta (data as collected).
  • Methanol Solvate of Racemic Modafinil The methanol solvate of modafinil is obtained by evaporating 2 mL of a 30 mg/mL racemic modafinil solution in methanol under flowing nitrogen overnight.
  • the methanol solvate was characterized by PXRD (Rigaku), TGA, and DSC, as shown in Figures 41, 42, and 43, respectively.
  • the modafinil methanol solvate can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 41 including, but not limited to, 6.15, 9.89, 12.25, 15.69, 17.97, 20.07, 21.85, and 22.73 degrees 2-theta (data as collected).
  • Acetone Solvate of Racemic Modafinil A solution containing racemic modafinil (300 mg, 0.001 mol) and glutaric acid (150 mg, 0.001 mol) in acetone (3 mL) was heated until it was boiling in order to dissolve all solid material. Once the solids dissolved, the solution was placed on an aluminum block at 5 degrees C. After 15 minutes of sitting at 5 degrees C, crystals began to form at the bottom of the vial. The solution was then decanted and the single crystals were collected and analyzed using PXRD (Rigaku), as shown in Figure 45. The crystals were determined to be an acetone solvate of modafinil.
  • the acetone solvate of modafinil can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 45 including, but not limited to, 6.11, 9.53, 15.81, 18.11, 20.03, 21.63, 22.45, 25.23, 25.65, 28.85, 30.23, and 32.93 degrees 2-theta (as collected).
  • the acetone solvate may also be obtained following the procedure above with several other co-crystal formers including adipic acid, lactobionic acid, maleic acid, and glycolic acid.
  • Example 25 Racemic modafinil (1 mg, 0.0037mmol) and mandelic acid (0.55 mg, 0.0037 mmol) were dissolved in acetone (400 microliters). The solution was allowed to evaporate to dryness and the resulting solid was characterized using PXRD (Rigaku), as shown in Figure 46. The obtained solid is a mixture of the acetone solvate and another product of modafinil. The form can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 46 including, but not limited to, 6.11, 9.53, 15.77, 18.03, 20.01, and 21.61 degrees 2-theta (background removed). Other peaks including 6.75, 10.31, 14.77, and 23.27 may correspond to a modafinil polymorph.
  • Example 26 Racemic modafinil (1 mg, 0.0037mmol) and fumaric acid (0.42 mg, 0.0037 mmol) were dissolved in 1,2-dichloroethane (400 microliters). The solution was allowed to evaporate to dryness and the resulting solid was characterized using PXRD (Rigaku), as shown in Figure 47. The obtained solid may be a solvate of modafinil. The form can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 47 including, but not limited to, 5.87, 8.95, 12.49, 13.99, 18.19, 19.99, 21.57, and 25.01 degrees 2-theta (background removed).
  • Racemic modafinil was dispensed from a stock solution containing 50 mg of modafinil in 20 mL of a 15:5 acetone/methanol mixture. The solution was then evaporated to dryness under a flow of nitrogen. Benzoic acid was dispensed from an acetone solution and the mixture was again evaporated to dryness. 200 microliters of isopropyl alcohol or methanol was then added and the vials were capped. After standing at room temperature for one day, the caps were removed and the solvent was allowed to evaporate. PXRD (Rigaku) was carried out on the sample, as shown in Figure 48.
  • Form VII The novel form of racemic modafinil, which may be a polymorph or a co- crystal, is denoted as form VII.
  • Form VII can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 48 including, but not limited to, 5.47, 9.99, 15.73, 17.85, 18.77, 20.05, 21.23, 22.05, 23.15, and 25.13 degrees 2-theta (data as collected).
  • Racemic ModafmihMalonic acid Co-Crystal Pharrnacokinetic Study in Dogs The racemic modafinihmalonic acid co-crystal (from Example 1) was administered to dogs in a pharrnacokinetic study. Particles of modafinihmalonic acid co-crystal 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 modafinihmalonic acid co-crystal was determined to be 40 to 60 percent higher than that of the pure modafinil. Such a higher bioavailability illustrates the modulation of an important pharrnacokinetic parameter due to an embodiment of the present invention. A compilation of important pharrnacokinetic parameters measured during the animal study are included in Table V.
  • Example 29 Racemic Modafinil Malonic acid Co-crystal Solid-State Stability
  • the stability of the racemic modafinihmalonic acid co-crystal was measured at various temperatures and relative humidities over a four week period. No degradation was found to occur at 20 or 40 degrees C. At 60 degrees C, about 0.14 percent degradation per day was determined based on a simple exponential model. At 80 degrees C, about 8 percent degradation per day was determined. The stability of the modafinihmalonic acid co-crystal was also measured at various temperatures and relative humidities over a 26 week period.
  • Figures 49 and 50 show the % area impurities as measured via HPLC versus time (weeks) for samples stored at various conditions including: 25 degrees C, 60 % RH; 40 degrees C, 75 percent RH; 40 degrees C, ambient RH; 60 degrees C, ambient RH; 80 degrees C, ambient RH; and -20 degrees C. These data show that the compound is stable when stored at or below 40 degrees C for at least 26 weeks.
  • Figure 51 compares PXRD patterns of initial and 26 week old samples of the modafinihmalonic acid co-crystal for several temperatures and RH levels.
  • Example 30 Formulation of Racemic ModafinihMalonic Acid Co-crystal
  • the formulation of a racemic modafinihmalonic acid co-crystal was completed using lactose. Two mixtures, one of modafinil and lactose, and the second of modafinihmalonic acid co-crystal and lactose, were ground together in a mortar an pestle. The mixtures targeted a 1:1 weight ratio of modafinil to lactose. In the modafinil and lactose mixture, 901.2 mg of modafinil and 901.6 mg of lactose were ground together.
  • the DSC of the modafinil and lactose mixture had a melting point of 165.7 degrees C. This is slightly lower then the measured melting point of modafinil (168.7 degrees C).
  • the heat of fusion of the mixture (59.3 J/g) is 46.9 % that of the modafinil alone (126.6 J/g), which is consistent with the estimated value of 50 %.
  • the in vitro dissolution of both the modafinihmalonic acid co-crystal and pure modafinil were tested in capsules. Both gelatin and hydroxypropylmethyl cellulose (HPMC) capsules were used in the dissolution study. The capsules were formulated with and without lactose. All formulations were ground in a mortar and pestle prior to transfer into a capsule. The dissolution of the capsules was tested in 0.01 M HCl (See Figure 52).
  • the capsules were dropped into vessels containing 900 mL 0.01 M HCl and stirred by paddles. Absorbance readings were taken using a Cary 50 Spectrophotometer (wavelength set at 260nm) at the following time points: 0, 5, 10, 15, 20, 25, 30, 40, 50, and 60 minutes. The absorbance values were compared to those of standards and the modafinil concentrations of the solutions were calculated.
  • HPMC capsules (Size 0, Shionogi, Lot # A312A6) were filled with 399.9 mg modafinil and lactose, 560.9 mg modafinihmalonic acid co-crystal and lactose, 199.9 mg modafinil, or 280.5 mg modafinihmalonic acid co-crystal. The dissolution study was carried out as described above.
  • FIG. 53 shows in vitro dissolution data of micronized racemic modafinihmalonic acid co-crystal and of micronized modafinil in simulated gastric fluid (SGF) and in simulated intestinal fluid (SIF). Both samples were blended with lactose and filled into HPMC capsules. The co-crystal releases modafinil into solution more quickly in both SGF and SIF than does the free form of modafinil.
  • Figure 54 compares the dissolution of an HPMC capsule filled with the modafinihmalonic acid co-crystal blended with lactose and that of a PRO VIGIL tablet.
  • Figure 55 shows a dynamic vapor sorption (DVS) isotherm plot of the modafinihmalonic acid co-crystal. This plot shows no appreciable water adsorption up to at least 40 percent RH at 26 degrees C.
  • DVDS dynamic vapor sorption
  • Example 32 In Vivo Studies A pharrnacokinetic study was completed with dogs using both racemic modafinihmalonic acid formulated with lactose and PROVIGIL tablets (200 mg). Seven capsules were filled with the modafinihmalonic acid co-crystal and lactose to 476.24 +/- 2 mg, each containing 200 mg modafinil. Figure 56 shows the co-crystal formulation has an increased C ma ⁇ and an increased bioavailability. Severel important pharrnacokinetic parameters are described in Table VI.
  • C max is the maximum blood plasma concentration
  • AUC (inf) is the extrapolated area under the curve
  • ti /2 is the amount of time for the blood plasma level to decrease to half of the Cmax level beginning at administration
  • T max is the time to maximum blood plasma concentration from administration
  • CL is the clearance rate of modafinil
  • F % is the percent bioavailability.
  • Example 33 R-(-Vmodaf ⁇ nil:Gentisic acid Co-crystal R-(-)-modafinil (50 mg, 0.183 mmol, greater than 98 percent R-isomer) and gentisic acid (28.2 mg, 0.183 mmol) were placed in a stainless steel vial. 10 microliters of acetone was added to the vial. The vial was then placed in a grinder (wig-1-bug, Bratt Technologies, 115V/60Hz) and the solid mixture was milled for 5 minutes. The resultant powder was then collected and characterized using PXRD (Rigaku), as shown in Figure 57.
  • PXRD Raku
  • the R-(-)-modafinih gentisic acid co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 57 including, but not limited to, 7.07, 9.07, 12.31, 13.03, 14.09, 18.93, 19.83, and 21.27 degrees 2-theta (as collected).
  • Other PXRD peaks at 7.51, 16.03, 17.63, 18.39, 23.57, 26,93, and 28.85 degrees 2-theta correspond to excess co- crystal former.
  • Example 34 Channel Solvates of Racemic Modafinil Channel solvates of modafinil have been unexpectedly discovered.
  • Figures 58 and 59 show packing diagrams of the acetone channel solvate of modafinil. The packing diagrams show acetone with a variable position within the channel structure. An ethyl acetate channel solvate has also been prepared according to the method above using ethyl acetate in place of acetone.
  • Example 35 o-Xylene Hemisolvate of Racemic Modafinil
  • An o-xylene hemisolvate was formed by preparing a 1:2 solution of racemic modafinil (49.6 mg, 0.181 mmol) and l-hydroxy-2-napthoic acid (68.3 mg, 0.363 mmol) in o-xylene (4.5 mL). The mixture was heated on a hotplate with swirling until all solids were dissolved. The solution was then left to crystallize in a sealed vial. The resulting powder was collected in a centrifuge filter and analyzed by PXRD (Bruker), as shown in Figure 60.
  • Raman spectroscopy ( Figure 61), TGA( Figure 62), and DSC ( Figure 63) were also used to analyze and characterize the hemisolvate.
  • the o-xylene solvate can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 60 including, but not limited to, 5.31, 6.53, 6.96, 10.68, 14.20, 17.64, 19.93, 25.69, and 26.79 degrees 2-theta.
  • the o-xylene solvate can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 61 (middle spectrum) including, but not limited to, 1641, 1407, 1379, 1211, 1024, and 721 cm -1 .
  • Benzene Hemisolvate of Racemic Modafinil A benzene hemisolvate was formed by preparing a 1:2 solution of racemic modafinil (50.6 mg, 0.181 mmol) and l-hydroxy-2-napthoic acid (70.1 mg, 0.373 mmol) in benzene (1.8 mL). The mixture was heated on a hotplate with swirling until all solids were dissolved. The solution was then left to crystallize in a sealed vial. The resulting powder was collected in a centrifuge filter and analyzed by PXRD (Bruker), as shown in Figure 64.
  • Raman spectroscopy ( Figure 65), TGA ( Figure 66), and DSC ( Figure 67) were also used to analyze and characterize the hemisolvate.
  • the benzene solvate can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 64 including, but not limited to, 5.82, 6.09, 8.11, 10.28, 12.06, 13.28, 14.73, 17.03, 19.11, 19.93, 21.23, 25.38, and 26.43 degrees 2-theta.
  • the benzene solvate can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 65 (middle spectrum) including, but not limited to, 1637, 1600, 1409, 1380, 1214, 1025, 998, and 721 cm -1 .
  • Toluene Hemisolvate of Racemic Modafinil A toluene hemisolvate was formed by making a 1:2 solution of racemic modafinil (37.3 mg, 0.136 mmol) and l-hydroxy-2-napthoic acid (51.3 mg, 0.273 mmol) in toluene (1 mL). The mixture was heated on a hotplate with swirling until all solids were dissolved. The solution was then left to crystallize in a sealed vial. The resulting powder was collected in a centrifuge filter and analyzed by PXRD (Bruker), as shown in Figure 68.
  • the toluene solvate can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 68 including, but not limited to, 5.30, 5.96, 10.65, 12.90, 14.51, 17.60, and 18.15 degrees 2-theta.
  • the toluene solvate can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 69 (middle spectrum) including, but not limited to, 1640, 1581, 1408, 1380, 1209, 1024, 1001, and 722 cm .
  • C ma ⁇ is the maximum blood plasma concentration
  • AUC (inf) is the extrapolated area under the curve
  • t ⁇ / is the amount of time for the blood plasma level to decrease to half of the Cmax level beginning at administration
  • Vd is the volume of distribution
  • CL is the clearance rate of modafinil.
  • R-(-)-modafinil Ethanol Solvate A solution containing R-(-)-modafinil (100 mg, 0.366 mmol, 85.4 percent R- isomer) and racemic modafinil (40 mg, 0.146 mmol) in ethanol (3 mL) was prepared. The mixture was heated to reflux in order to dissolve the entire solid and was then cooled to room temperature (25 degrees C). After remaining at room temperature for 15 minutes, the solution was placed at 5 degrees 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 an ethanol solvate of R-(-)- modafinil.
  • R-(-)-modafinil ethanol solvate can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 72 including, but not limited to, 6.13, 9.59, 15.69, 17.97, 20.05, 21.55, 22.35, 25.77, and 29.07 degrees 2-theta (Rigaku PXRD, data as collected).
  • TGA of the R-(-)-modafinil ethanol solvate characterized in Figure 73 showed about a 5.4 percent weight loss between about 25 and about 140 degrees C.
  • R-(-)-modafinil Benzyl alcohol Solvate R-(-)-modafinil (100 mg, 0.366 mmol) was milled with benzyl alcohol (40 microliters) for 5 minutes. The milled powder was then analyzed by PXRD, DSC, and TGA ( Figures 74, 75, and 76). The powder was determined to be a benzyl alcohol solvate of R-(-)-modafinil.
  • R-(-)-modafinil benzyl alcohol solvate can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 74 including, but not limited to, 5.77, 7.76, 10.48, 15.78, 17.80, 18.57, 21.53, 22.97, and 27.73 degrees 2-theta (Bruker PXRD, data as collected).
  • DSC of the R-(-)-modafinil benzyl alcohol solvate characterized in Figure 75 showed an endothermic transition at about 83 degrees C.
  • TGA of the R-(-)-modafinil benzyl alcohol solvate characterized in Figure 76 showed about a 28.5 percent weight loss between about 25 and about 125 degrees C.
  • R-(-)-modafinil Isopropanol Solvate
  • R-(-)-modafinil was slurried overnight in isopropanol. The liquid was filtered out in a centrifuge filter, then dried under flowing nitrogen gas at 5 degrees C. The resulting solid was analyzed via PXRD.
  • R-(-)-modafinil isopropanol solvate can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 77 including, but not limited to, 5.76, 7.77, 10.49, 15.79, 18.58, 21.53, 25.76, and 27.74 degrees 2- theta (Bruker PXRD, data as collected).
  • R-(-)-modafinil Acetonitrile Solvate 100 mg of R-(-)-modafinil was slurrie in acetonitrile for 2 days. The solid was filtered from the suspension and analyzed by PXRD.
  • R-(-)-modafmil acetonitrile solvate can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 78 including, but not limited to, 5.29, 6.17, 8.16, 10.19, 11.19, and 21.86 degrees 2-theta (Bruker PXRD, data as collected).
  • R-(-)-Modafinil Glutaric acid Co-crystal
  • R-(-)-modafinil (20 to 30 mg, greater than 98 percent R-isomer) and glutaric acid (15-20 mg) were ground together in the presence of one drop of benzyl alcohol.
  • the resultant solid was characterized by PXRD (See Figure 79) and may comprise a co-crystal.
  • the R-(-)-modafinil:glutaric acid co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 79 including, but not limited to, 4.30, 8.67, 9.78, 17.99, 18.92, 19.74, 20.50, 21.36, 22.25, 23.87, 27.16, 29.24, and 32.46 degrees 2-theta (Bruker PXRD, data as collected). Wet grinding was also used with acetone and with water, both of which resulted in the formation of the co-crystal.
  • R-(-VModafinil:Citric acid Co-crystal R-(-)-modafinil (20 to 30 mg, greater than 98 percent R-isomer) and citric acid monohydrate (15-20 mg) were ground together in the presence of one drop of benzyl alcohol.
  • the resultant solid was characterized by PXRD (See Figure 80) and may comprise a co-crystal.
  • the R-(-)-modafinil:citric acid co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 80 including, but not limited to, 5.23, 7.06, 9.10, 12.43, 13.18, 14.37, 17.34, 17.95, 20.85, 21.39, 22.03, 22.96, 23.54, and 24.93 degrees 2-theta (Bruker PXRD, data as collected). Wet grinding was also used with acetone which resulted in the formation of the co-crystal.
  • the R-(-)-modafinil:L-tartaric acid co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 81 including, but not limited to, 4.56, 10.33, 14.45, 17.29, 19.91, 21.13, 23.10, 24.10, and 26.76 degrees 2-theta (Bruker PXRD, data as collected). Wet grinding was also used with acetone and with water, both of which resulted in the formation of the co-crystal.
  • R-(-)-Modafinil:Oxalic acid Co-crystal R-(-)-modafinil (20 to 30 mg, greater than 98 percent R-isomer) and oxalic acid (15-20 mg) were ground together in the presence of one drop of benzyl alcohol.
  • the resultant solid was characterized by PXRD (See Figures 82A and 82B) and may comprise one or more co-crystals.
  • the R-(-)-modafinil:oxalic acid (Form I) co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 82A including, but not limited to, 5.99, 14.73, 16.59, 17.38, 18.64, 25.66, and 28.85 degrees 2-theta (Bruker PXRD, data as collected).
  • the R-(-)-modafinil:oxalic acid (Form II) co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 82B including, but not limited to, 5.66, 14.76, 17.20, 17.63, 19.60, 24.90, and 28.84 degrees 2-theta (Bruker PXRD, data as collected). Wet grinding was also used with acetone and with water, both of which resulted in the formation of the co-crystal.
  • R-(-)-Modafinil Palmitic acid
  • Co-crystal R-(-)-modafinil (20 to 30 mg, greater than 98 percent R-isomer) and palmitic acid (15-20 mg) were ground together in the presence of one drop of benzyl alcohol.
  • the resultant solid was characterized by PXRD (See Figure 83) and may comprise a co-crystal.
  • the R-(-)-modaf ⁇ nil:palmitic acid co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 83 including, but not limited to, 3.80, 6.55, 7.66, 1 .24, 11.49, 19.48, 21.09, 21.74, 22.20, 22.97, and 23.99 degrees 2-theta (Bruker PXRD, data as collected).
  • Example 48 R-(-VModafinil:L-proline Co-crystal R-(-)-modafinil (20 to 30 mg, greater than 98 percent R-isomer) and L-proline (15-20 mg) were ground together in the presence of one drop of benzyl alcohol.
  • the resultant solid was characterized by PXRD (See Figure 84) and may comprise a co-crystal.
  • the R-(-)-modafinil:L-proline co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 84 including, but not limited to, 6.52, 8.53, 10.25, 14.69, 19.06, 19.71, 20.75, 22.29, 22.75, 25.08, and 26.27 degrees 2-theta (Bruker PXRD, data as collected). Wet grinding was also used with acetone and with methanol, both of which resulted in the formation of the co-crystal.
  • R-(-VModaf ⁇ nil:Salicylic acid Co-crystal R-(-)-modafinil (20 to 30 mg, greater than 98 percent R-isomer) and salicylic acid (15-20 mg) were ground together in the presence of one drop of benzyl alcohol.
  • the resultant solid was characterized by PXRD (See Figure 85) and may comprise a co-crystal.
  • the R-(-)-modafmil: salicylic acid co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 85 including, but not limited to, 8.92, 10.85, 12.18, 14.04, 17.07, 17.59, 18.81, 21.24, 23.32, 25.22, and 28.59 degrees 2-theta (Bruker PXRD, data as collected).
  • R-(-)-Modafinil Lauric acid
  • R-(-)-modafinil (20 to 30 mg, greater than 98 percent R-isomer) and lauric acid (15-20 mg) were ground together in the presence of one drop of benzyl alcohol.
  • the resultant solid was characterized by PXRD (See Figure 86) and may comprise a co-crystal.
  • the R-(-)-modafmil:lauric acid co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 86 including, but not limited to, 3.12, 6.55, 10.24, 13.97, 16.40, 17.62, 19.02, 20.05, 21.38, 22.24, 23.81, and 25.96 degrees 2-theta (Bruker PXRD, data as collected). Wet grinding was also used with acetone and with methanol, both of which resulted in the formation of the co-crystal.
  • R-(-)-ModafinikL-malic acid Co-crystal R-(-)-modafinil (20 to 30 mg, greater than 98 percent R-isomer) and L-malic acid (15-20 mg) were ground together in the presence of one drop of acetone.
  • the resultant solid was characterized by PXRD (See Figure 87) and may comprise a co-crystal.
  • the R-(-)-modafmil:L-malic acid co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 87 including, but not limited to, 4.62, 9.32, 10.32, 15.83, 16.71, 17.38, 19.30, 19.93, 21.48, 23.07, 24.26, and 27.25 degrees 2-theta (Bruker PXRD, data as collected).
  • Racemic modafinil was obtained from oxidation of benzhydrylthiacetamide using H 2 0 2 following the same method used in the oxidation of benzhydrylthioacetic acid in the preparation of R-(-)-modafinil.

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Abstract

L'invention porte sur la formation de co-cristaux et de solvates de modafinil racémique, énantiomériquement pur, et énantiomériquement mixte et sur la modulation de plusieurs de leurs propriétés physiques importantes. La solubilité, la dissolution, la biodisponibilité, la relation dose-effet et la stabilité du modafinil peuvent modulées pour améliorer l'efficacité des compositions pharmaceutiques.
PCT/US2004/029013 2000-07-15 2004-09-04 Compositions de modafinil WO2005023198A2 (fr)

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CA2534664A CA2534664C (fr) 2003-09-04 2004-09-04 Compositions de modafinil
US10/570,405 US7566805B2 (en) 2003-09-04 2004-09-04 Modafinil compositions
AU2004270238A AU2004270238B2 (en) 2003-09-04 2004-09-04 Modafinil compositions
JP2006525508A JP4842819B2 (ja) 2003-09-04 2004-09-04 モダフィニル組成物
BRPI0413777-9A BRPI0413777A (pt) 2003-09-04 2004-09-04 composições de modafinil
NZ545133A NZ545133A (en) 2003-09-04 2004-09-04 Modafinil compositions
CN2004800319825A CN1874993B (zh) 2003-09-04 2004-09-04 莫达芬尼组合物
MXPA06002507A MXPA06002507A (es) 2003-09-04 2004-09-04 Composiciones de modafinil.
EP20040783308 EP1670753A4 (fr) 2003-09-04 2004-09-04 Compositions de modafinil
KR1020067004425A KR101184797B1 (ko) 2003-09-04 2004-09-04 모다피닐 조성물
PCT/US2005/002782 WO2005077894A1 (fr) 2004-02-06 2005-02-01 Compositions a base de modafinil
JP2006552169A JP4917441B2 (ja) 2004-02-06 2005-02-01 モダフィニル組成物
AU2005212229A AU2005212229B2 (en) 2004-02-06 2005-02-01 Modafinil compositions
CA002556106A CA2556106A1 (fr) 2004-02-06 2005-02-01 Compositions a base de modafinil
EP10001997A EP2292213A1 (fr) 2004-02-06 2005-02-01 Compositions comprenant une forme polymorphique d'armodafinil
EP05712282A EP1718607A4 (fr) 2004-02-06 2005-02-01 Compositions a base de modafinil
BRPI0507455-0A BRPI0507455A (pt) 2000-07-15 2005-02-01 composição, métodos de fabricação de um polimorfo de r-(-)-modafinil, de fabricação de 2:1 de r-(-)-modafinil: s-(+)-modafinil, de fabricação de formas iii, iv e v de r-(-)modafinil e de tratamento de um indivìduo que sofre de doenças, e, solvato de r-(-)-modafinil,e, métodos de tratamento de um indivìduo que sofre de sono excessivo durante o dia associado com narcolepsia, narcolepsia ou apnéia do sono e de hiperatividade de falta de atenção (adhd)
CN2005800041104A CN1980888B (zh) 2004-02-06 2005-02-01 莫达芬尼组合物
EA200601390A EA009949B1 (ru) 2004-02-06 2005-02-01 Композиции модафинила
US10/587,086 US20090018202A1 (en) 2004-02-06 2005-02-01 Modafinil compositions
IL173575A IL173575A0 (en) 2003-09-04 2006-02-07 Modafinil compositions
NO20060669A NO20060669L (no) 2003-09-11 2006-02-10 Modafinilsammensetninger
IL176934A IL176934A (en) 2004-02-06 2006-07-18 Using v - form of r - (-) - modafinil in the preparation of a drug for over-sleep during the day and attention deficit hyperactivity disorder
NO20063957A NO20063957L (no) 2004-02-06 2006-09-05 Modafinilsammensetninger
IL199140A IL199140A (en) 2003-09-04 2009-06-03 Modafinil preparations
US12/708,998 US8338646B2 (en) 2004-02-06 2010-02-19 Modafinil compositions
US13/706,835 US8809586B2 (en) 2004-02-06 2012-12-06 Modafinil compositions

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US32777203A 2003-09-04 2003-09-04
USUS03/27772 2003-09-04
US10/660,202 US7927613B2 (en) 2002-02-15 2003-09-11 Pharmaceutical co-crystal compositions
US10/660,202 2003-09-11
US50820803P 2003-10-02 2003-10-02
US60/508,208 2003-10-02
US54275204P 2004-02-06 2004-02-06
US60/542,752 2004-02-06
US40628804A 2004-02-26 2004-02-26
USUS04/06288 2004-02-26
US56041104P 2004-04-06 2004-04-06
US60/560,411 2004-04-06
US57341204P 2004-05-21 2004-05-21
US60/573,412 2004-05-21
US57917604P 2004-06-12 2004-06-12
US60/579,176 2004-06-12
US58199204P 2004-06-22 2004-06-22
US60/581,992 2004-06-22
US58675204P 2004-07-09 2004-07-09
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US60/588,236 2004-07-15

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WO2005099822A2 (fr) * 2004-04-13 2005-10-27 Cephalon, Inc. Reduction d'interactions medicamenteuses
EP1755388A1 (fr) * 2004-05-28 2007-02-28 Transform Pharmaceuticals, Inc. Co-cristaux mixtes et compositions pharmaceutiques les renfermant
EP1777295A3 (fr) * 2005-10-18 2007-06-20 Dipharma S.p.A. Procédé pour la préparation de Modafinil
WO2007098273A2 (fr) * 2006-02-21 2007-08-30 Teva Pharmaceutical Industries Ltd. Nouvelles formes cristallines d'armodafinil et leur preparation
WO2007114475A1 (fr) * 2006-04-05 2007-10-11 Astellas Pharma Inc. Cocristal du derive de c-glycoside et de l-proline
EP1909573A2 (fr) * 2005-07-21 2008-04-16 Neurohealing Pharmaceuticals, Inc. Compositions de modafinil a action rapide et de courte duree et procedes d'utilisation de celles-ci
WO2009045488A2 (fr) * 2007-10-02 2009-04-09 Teva Pharmaceutical Industries Ltd. Nouvelles formes cristallines d'armodafinil et procédé d'élaboration
JP2010509254A (ja) * 2006-11-09 2010-03-25 ノバルティス アーゲー アリスキレンとオロチン酸の塩
US7790905B2 (en) 2002-02-15 2010-09-07 Mcneil-Ppc, Inc. Pharmaceutical propylene glycol solvate compositions
US7927613B2 (en) 2002-02-15 2011-04-19 University Of South Florida Pharmaceutical co-crystal compositions
US7960586B2 (en) 2007-08-16 2011-06-14 Teva Pharmaceutical Industries Ltd. Purification of armodafinil
US8183290B2 (en) 2002-12-30 2012-05-22 Mcneil-Ppc, Inc. Pharmaceutically acceptable propylene glycol solvate of naproxen
US8198464B2 (en) 2006-12-21 2012-06-12 Astellas Pharma Inc. Method for producing C-glycoside derivative and intermediate for synthesis thereof
CN102770416A (zh) * 2009-12-23 2012-11-07 诺弗米克斯有限公司 美他沙酮共晶体
US8362062B2 (en) 2002-02-15 2013-01-29 Mcneil-Ppc, Inc. Pharmaceutical compositions with improved dissolution
US8729305B2 (en) 2002-12-20 2014-05-20 Teva Sante Process for the preparation of and crystalline forms of optical enantiomers of modafinil
US10633344B2 (en) 2002-03-01 2020-04-28 University Of South Florida Multiple-component solid phases containing at least one active pharmaceutical ingredient

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Cited By (30)

* Cited by examiner, † Cited by third party
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US7790905B2 (en) 2002-02-15 2010-09-07 Mcneil-Ppc, Inc. Pharmaceutical propylene glycol solvate compositions
US8362062B2 (en) 2002-02-15 2013-01-29 Mcneil-Ppc, Inc. Pharmaceutical compositions with improved dissolution
US7927613B2 (en) 2002-02-15 2011-04-19 University Of South Florida Pharmaceutical co-crystal compositions
US10633344B2 (en) 2002-03-01 2020-04-28 University Of South Florida Multiple-component solid phases containing at least one active pharmaceutical ingredient
US8729305B2 (en) 2002-12-20 2014-05-20 Teva Sante Process for the preparation of and crystalline forms of optical enantiomers of modafinil
US8975442B2 (en) 2002-12-20 2015-03-10 Teva Sante Process for the preparation of and crystalline forms of optical enantiomers of modafinil
US8183290B2 (en) 2002-12-30 2012-05-22 Mcneil-Ppc, Inc. Pharmaceutically acceptable propylene glycol solvate of naproxen
WO2005099822A2 (fr) * 2004-04-13 2005-10-27 Cephalon, Inc. Reduction d'interactions medicamenteuses
WO2005099822A3 (fr) * 2004-04-13 2006-01-12 Cephalon Inc Reduction d'interactions medicamenteuses
EP1755388A1 (fr) * 2004-05-28 2007-02-28 Transform Pharmaceuticals, Inc. Co-cristaux mixtes et compositions pharmaceutiques les renfermant
EP1755388A4 (fr) * 2004-05-28 2009-09-16 Transform Pharmaceuticals Inc Co-cristaux mixtes et compositions pharmaceutiques les renfermant
US7671093B2 (en) 2004-05-28 2010-03-02 Transform Pharmaceuticals, Inc. Mixed co-crystals and pharmaceutical compositions comprising the same
EP1909573A2 (fr) * 2005-07-21 2008-04-16 Neurohealing Pharmaceuticals, Inc. Compositions de modafinil a action rapide et de courte duree et procedes d'utilisation de celles-ci
AU2006272874B2 (en) * 2005-07-21 2010-03-11 Neurohealing Pharmaceuticals, Inc. Rapid onset and short term modafinil compositions and methods of use thereof
EP1909573A4 (fr) * 2005-07-21 2010-09-22 Neurohealing Pharmaceuticals I Compositions de modafinil a action rapide et de courte duree et procedes d'utilisation de celles-ci
EP1777295A3 (fr) * 2005-10-18 2007-06-20 Dipharma S.p.A. Procédé pour la préparation de Modafinil
WO2007098273A3 (fr) * 2006-02-21 2008-06-12 Teva Pharma Nouvelles formes cristallines d'armodafinil et leur preparation
WO2007098273A2 (fr) * 2006-02-21 2007-08-30 Teva Pharmaceutical Industries Ltd. Nouvelles formes cristallines d'armodafinil et leur preparation
WO2007114475A1 (fr) * 2006-04-05 2007-10-11 Astellas Pharma Inc. Cocristal du derive de c-glycoside et de l-proline
US8097592B2 (en) 2006-04-05 2012-01-17 Astellas Pharma Inc. Cocrystal of C-glycoside derivative and L-proline
RU2408595C2 (ru) * 2006-04-05 2011-01-10 Астеллас Фарма Инк. Сокристаллическая форма производного с-гликозида c l-пролином
KR101243039B1 (ko) * 2006-04-05 2013-03-20 고토부키 세이야쿠 가부시키가이샤 Ｃ－글리코시드 유도체와 ｌ－프롤린과의 공결정
JP5210154B2 (ja) * 2006-04-05 2013-06-12 アステラス製薬株式会社 Ｃ−グリコシド誘導体とｌ−プロリンとの共結晶
JP2010509254A (ja) * 2006-11-09 2010-03-25 ノバルティス アーゲー アリスキレンとオロチン酸の塩
US8198464B2 (en) 2006-12-21 2012-06-12 Astellas Pharma Inc. Method for producing C-glycoside derivative and intermediate for synthesis thereof
US7960586B2 (en) 2007-08-16 2011-06-14 Teva Pharmaceutical Industries Ltd. Purification of armodafinil
WO2009045488A3 (fr) * 2007-10-02 2009-07-30 Teva Pharma Nouvelles formes cristallines d'armodafinil et procédé d'élaboration
WO2009045488A2 (fr) * 2007-10-02 2009-04-09 Teva Pharmaceutical Industries Ltd. Nouvelles formes cristallines d'armodafinil et procédé d'élaboration
CN102770416B (zh) * 2009-12-23 2015-10-07 诺弗米克斯有限公司 美他沙酮共晶体
CN102770416A (zh) * 2009-12-23 2012-11-07 诺弗米克斯有限公司 美他沙酮共晶体

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CA2534664C (fr) 2012-10-30
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