WO2011080651A2 - Formes polymorphes de fébuxostat - Google Patents

Formes polymorphes de fébuxostat Download PDF

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Publication number
WO2011080651A2
WO2011080651A2 PCT/IB2010/055897 IB2010055897W WO2011080651A2 WO 2011080651 A2 WO2011080651 A2 WO 2011080651A2 IB 2010055897 W IB2010055897 W IB 2010055897W WO 2011080651 A2 WO2011080651 A2 WO 2011080651A2
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Prior art keywords
febuxostat
crystalline form
solvent
process according
ray diffraction
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PCT/IB2010/055897
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English (en)
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WO2011080651A3 (fr
Inventor
Ram Thaimattam
Pranab Kishore Dash
Raghvendra Prasad
Subhash Dhar
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Ranbaxy Laboratories Limited
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Publication of WO2011080651A2 publication Critical patent/WO2011080651A2/fr
Publication of WO2011080651A3 publication Critical patent/WO2011080651A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents

Definitions

  • the present invention provides crystalline forms of febuxostat, processes for their preparation, pharmaceutical compositions comprising them and their use for the chronic management of hyperuricemia in patients with gout.
  • Febuxostat is a non-purine xanthine oxidase inhibitor known from U.S. Patent No. 5,614,520. It is chemically described as 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4- methylthiazole-5-carboxylic acid, and has a structure as represented by Formula I.
  • Febuxostat is marketed in the United States under the brand name Uloric for the chronic management of hyperuricemia in patients with gout.
  • Crystalline Forms A, B, C, D, G, H, I, J, K and Form I and Form II of febuxostat are disclosed in U.S. Patent No. 6,225,474; WO 2008/067773; and Chinese Patent Nos. 101139325, 101085761 and 101386605.
  • the processes described in the above references involve the preparation of crystalline forms of febuxostat using a mixture of methanol, ethanol or propanol with water, acetonitrile, acetone, ethyl acetate or 1,4-dioxane solvents.
  • the present invention provides for crystalline Form Rl of febuxostat, which includes X-ray diffraction peaks at d-spacing of about 15.11, 10.07, 7.56, 7.19 and 6.04 A.
  • Embodiments of this aspect may include one or more of the following features.
  • the crystalline Form of Rl may further include X-ray diffraction peaks at d- spacing of about 7.37 A, 5.04 A, 3.75 A, 3.53 A and 3.07 A.
  • the crystalline Form of Rl may include an X-ray diffraction pattern as depicted in Figure 1.
  • the crystalline Form Rl of febuxostat may include a DSC having endotherms at about 189.05°C, 201.50°C and 209.38°C, a DSC as depicted in Figure 7, and/or a TGA as depicted in Figure 9.
  • the present invention provides for crystalline Form R2 of febuxostat, which includes X-ray diffraction peaks at d-spacing 12.31, 6.15, 5.46, 3.77 and 3.37 A.
  • Embodiments of this aspect may include one or more of the following features.
  • the crystalline Form R2 may further include X-ray diffraction peaks at d- spacing of about 4.10 A, 4.05 A, 3.94 A, 3.90 A and 3.10 A.
  • the crystalline Form R2 may include an X-ray diffraction pattern as depicted in Figure 2.
  • the present invention provides for crystalline Form R3 of febuxostat, which includes X-ray diffraction peaks at d-spacing of about 11.45, 7.63, 3.57, 3.54 and 3.43 A.
  • Embodiments of this aspect may include one or more of the following features.
  • the crystalline Form R3 may further include X-ray diffraction peaks at d- spacing of about 9.87 A, 6.90 A, 4.92 A, 4.85 A and 3.81 A.
  • the crystalline Form R3 of febuxostat may also include an X-ray diffraction pattern as depicted in Figure 3.
  • the present invention provides for crystalline Form R4 of febuxostat, which includes X-ray diffraction peaks at d-spacing of about 15.96, 14.60, 7.97, 7.78 and 3.52 A.
  • Embodiments of this aspect may include one or more of following features.
  • the crystalline Form R4 may further include X-ray diffraction peaks at d-spacing of about 7.29 A, 5.31 A, 5.21 A, 3.45 A and 3.39 A.
  • the crystalline Form R4 of febuxostat may also include an X-ray diffraction pattern as depicted in Figure 4.
  • the crystalline Form R4 of febuxostat may include endotherms at about 92.23°C, 199.71°C and 209.22°C, a DSC as depicted in Figure 8, and/or a TGA as depicted in Figure 10.
  • the present invention provides for crystalline Form R5 of febuxostat, which includes X-ray diffraction peaks at d-spacing of about 11.96, 5.98, 5.01 and 3.34 A.
  • Embodiments of this aspect may include one or more of the following features.
  • the crystalline Form R5 may further include X-ray diffraction peaks at d- spacing of about 7.94 A, 5.29 A, 3.99 A and 3.42 A.
  • the crystalline Form R5 of febuxostat may include an X-ray diffraction pattern as depicted in Figure 5.
  • the present invention provides for a process for the preparation of crystalline Form Rl of febuxostat.
  • the process includes the steps of:
  • Embodiments of this aspect may include one or more of the following features.
  • the febuxostat to be used as starting material for the preparation of crystalline Form Rl is obtained as a solution directly from a reaction in which it is formed and is used as such without isolation.
  • the chlorinated solvent may be dichloromethane or chloroform.
  • the febuxostat is contacted with the chlorinated solvent at a temperature of about 15°C to the reflux temperature of the solvent.
  • the crystallization is carried out by cooling the reaction mixture containing the febuxostat in the chlorinated solvent to about -10°C to about 25°C.
  • the crystallization may also be carried out by adding an anti-solvent selected from hydrocarbons, alkyl acetates, or mixtures thereof, to the solution of the febuxostat in the chlorinated solvent.
  • the hydrocarbon solvent is selected from hexane, cyclohexane, benzene, toluene, heptanes or octane.
  • a seed crystal of crystalline Form Rl may also be added to the solution of the febuxostat in the chlorinated solvent.
  • the present invention provides for a process for the preparation of crystalline Form R2 of febuxostat.
  • the process includes contacting febuxostat with a sulphoxide solvent.
  • Embodiments of this aspect may include one or more of the following features.
  • the febuxostat to be used as starting material for the preparation of crystalline Form R2 is obtained as a solution directly from a reaction in which it is formed and is used as such without isolation.
  • the sulphoxide solvent is selected from dimethyl sulphoxide or diethyl sulphoxide.
  • the febuxostat is contacted with the sulphoxide solvent at a temperature of about 40°C to about 80°C.
  • the crystallization is carried out by cooling the reaction mixture containing the febuxostat in the sulphoxide solvent to about -10°C to about 35°C.
  • the present invention provides for a process for the preparation of crystalline Form R3 of febuxostat.
  • the process includes contacting febuxostat with an amide solvent.
  • Embodiments of this aspect may include one or more of the following features.
  • the febuxostat to be used as starting material for the preparation of crystalline Form R3 is obtained as a solution directly from a reaction in which it is formed and is used as such without isolation.
  • the amide solvent may be selected from N, N- dimethylformamide or N, N-dimethylacetamide.
  • the febuxostat may be contacted with the amide solvent at a temperature of about 40°C to about 80°C.
  • the crystallization is carried out by cooling the reaction mixture containing the febuxostat in the amide solvent to about 15°C to about 35°C.
  • the present invention provides for a process for the preparation of crystalline Form R4 of febuxostat.
  • the process includes the steps of:
  • Embodiments of this aspect may include one or more of the following features.
  • the febuxostat to be used as starting material for the preparation of crystalline Form R4 is obtained as a solution directly from a reaction in which it is formed and is used as such without isolation.
  • the ketone solvent is selected from acetone, dimethyl ketone, ethyl methyl ketone or methyl iso-butyl ketone.
  • the ether solvent is selected from diethyl ether, ethyl methyl ether, di-isopropyl ether, tetrahydrofuran or 1,4-dioxane.
  • the febuxostat is contacted with the ketone or the ether solvent at a temperature of about 15°C to about 35°C.
  • the crystallization may be carried out by adding an anti- solvent selected from hydrocarbons, alkyl acetates, or mixtures thereof, to the solution of febuxostat in a ketone or ether.
  • the hydrocarbon solvent is selected from hexane, cyclohexane, benzene, toluene, heptanes or octane.
  • the present invention provides for a process for the preparation of crystalline Form R5 of febuxostat.
  • the process includes the steps of:
  • Embodiments of this aspect may include one or more of the following features.
  • the febuxostat to be used as starting material for the preparation of crystalline Form R5 is obtained as a solution directly from a reaction in which it is formed and is used as such without isolation.
  • the carboxylic acid solvent is selected from formic acid, acetic acid or propionic acid.
  • the febuxostat is contacted with carboxylic acid solvent at about 25°C to about 80°C.
  • the crystallization may be carried out by cooling the reaction mixture containing the febuxostat in the carboxylic acid solvent to a temperature of about 15°C to about 35°C.
  • the crystallization may also be carried out by adding an anti-solvent selected from hydrocarbons, alkyl acetates, or mixtures thereof, to a reaction mixture containing febuxostat in a carboxylic acid solvent.
  • the hydrocarbon solvent is selected from hexane, cyclohexane, benzene, toluene, heptanes or octane.
  • the present invention provides for a pharmaceutical composition that includes one or more of crystalline Form Rl, R2, R3, R4 or R5 of febuxostat and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present invention provides for a method of treating hyperuricemia.
  • the method includes administering a pharmaceutical composition that includes one or more of crystalline Form Rl, R2, R3, R4 or R5 of febuxostat and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • Crystalline Form Rl of febuxostat may be characterized by XRD peaks at about 5.84 (d-spacing at 15.11 A), 8.77 (10.07 A), 11.70 (7.56 A), 12.29 (7.19 A) and 14.64 (6.04 A) + 0.2° 2 ⁇ . It may be further characterized by XRD peaks at about 11.99 (7.37 A), 17.58 (5.04 A), 23.71 (3.75 A), 25.20 (3.53 A) and 29.07 (3.07 A) + 0.2° 2 ⁇ . Crystalline Form Rl of febuxostat may also be characterized by XRD pattern as depicted in Figure 1.
  • Table 1 summarizes the d-spacing in A and the corresponding 2 ⁇ values.
  • Crystalline Form Rl may also be characterized by a DSC having endotherms at about 189.05°C, 201.50°C and 209.38°C. Crystalline Form Rl may also be characterized by the DSC as depicted in Figure 7 or the TGA as depicted in Figure 9.
  • Crystalline Form R2 of febuxostat may be characterized by XRD peaks at about 7.17 (12.31 A), 14.38 (6.15 A), 16.21 (5.46 A), 23.59 (3.77 A) and 26.44 (3.37 A) + 0.2° 2 ⁇ . It may be further characterized by XRD peaks at about 21.64 (4.10 A), 21.89 (4.05 A), 22.56 (3.94 A), 22.77 (3.90 A) and 28.74 (3.10 A) + 0.2° 2 ⁇ . Crystalline Form R2 of febuxostat may also be characterized by the XRD pattern as depicted in Figure 2. Table 2 below summarizes the d-spacing in A and the corresponding 2 ⁇ values. Table 2: XRD Peaks of Crystalline Form R2
  • Crystalline Form R3 of febuxostat may be characterized by XRD peaks at about 7.72 (11.45 A), 11.59 (7.63 A), 24.88 (3.57 A), 25.10 (3.54 A) and 25.90 (3.43 A) + 0.2° 2 ⁇ . It may be further characterized by XRD peaks at about 8.95 (9.87 A), 12.81 (6.90 A), 17.99 (4.92 A), 18.27 (4.85 A) and 23.31 (3.81 A) + 0.2° 2 ⁇ . Crystalline Form R3 of febuxostat may also be characterized by the XRD pattern as depicted in Figure 3. Table 3 below summarizes the d- spacing in A and the corresponding 2 ⁇ values. Table 3: XRD Peaks of Crystalline Form R3
  • Crystalline Form R4 of febuxostat may be characterized by XRD peaks at about 5.53 (15.96 A), 6.05 (14.60 A), 11.09 (7.97 A), 11.36 (7.78 A) and 25.25 (3.52 A) and + 0.2° 2 ⁇ . It may be further characterized by XRD peaks at about 12.14 (7.29 A), 16.67 (5.31 A), 16.99 (5.21 A), 25.78 (3.45 A) and 26.24 (3.39 A) + 0.2° 2 ⁇ . Crystalline Form R4 of febuxostat may also be characterized by the XRD pattern as depicted in Figure 4.
  • Table 4 summarizes the d-spacing in A and the corresponding 2 ⁇ values.
  • Crystalline Form R4 may also be characterized by a DSC having endotherms at about 92.23°C, 199.71°C and 209.22°C. Crystalline Form R4 may also be characterized by the DSC as depicted in Figure 8 or the TGA as depicted in Figure 10.
  • Crystalline Form R5 of febuxostat may be characterized by XRD peaks at about 7.38 (11.96 A), 14.79 (5.98 A), 17.68 (5.01 A) and 26.64 (3.34 A) + 0.2° 2 ⁇ . It may be further characterized by the XRD peaks at about 11.14 (7.94 A), 16.73 (5.29 A), 22.24 (3.99 A) and 25.99 (3.42 A) + 0.2° 2 ⁇ . Crystalline Form R5 of febuxostat may also be characterized by XRD pattern as depicted in Figure 5. Table 5 below summarizes the d- spacing in A and the corresponding 2 ⁇ values. Table 5: XRD Peaks of Crystalline Form R5
  • Febuxostat to be used for the preparation of crystalline forms of the present invention, may be obtained by any of the methods known in the literature such as those described in U.S. Patent No. 5,614520, U.S. Publication 2009/0203919 or U.S. Patent 7,541,475, which are incorporated herein by reference.
  • Febuxostat, to be used as starting material for the preparation of crystalline forms of the present invention may be obtained as a solution directly from a reaction in which it is formed and used as such without isolation.
  • contacting may include dissolving, slurrying, stirring, or a combination thereof.
  • the solvent may be C 3 -C 10 alcohols, carboxylic acids, chlorinated hydrocarbons, ketones, amides, sulphoxides, ethers, water, or mixtures thereof.
  • C 3 -C 10 alcohols may include 1-propanol, 1-butanol or 2-butanol.
  • carboxylic acids may include formic acid, acetic acid or propionic acid.
  • chlorinated hydrocarbons may include dichloromethane or chloroform.
  • ketones may include acetone, dimethyl ketone, ethyl methyl ketone or methyl iso-butyl ketone.
  • ethers may include diethyl ether, ethyl methyl ether, di-isopropyl ether, tetrahydrofuran or 1, 4-dioxane.
  • amides may include N, N- dimethylformamide or N, N-dimethylacetamide.
  • sulphoxides may include dimethyl sulfoxide or diethyl sulphoxide.
  • cyclic ethers may include tetrahydrofuran . Crystallization may be carried out by cooling the reaction mixture containing febuxostat in a solvent to a temperature of about -10°C to about 10°C. Crystallization may also be carried out by allowing the reaction mixture containing febuxostat to stand at a temperature of about 15°C to about 40°C for about 1 hour to about 2 weeks.
  • Crystallization may also be carried out by adding an anti- solvent to a solution of febuxostat in a solvent.
  • the anti-solvent may be selected from hydrocarbons, alkyl acetates, or mixtures thereof.
  • hydrocarbons may include hexane, cyclohexane, benzene, toluene, heptane or octane.
  • alkyl acetates may include ethyl acetate, propyl acetate, or butyl acetate.
  • the crystalline form(s) of the present invention may be prepared by dissolving febuxostat in a solvent and cooling the solution to a temperature of about -10°C to about 10°C. In other embodiments, the crystalline form(s) of the present invention may be prepared by dissolving febuxostat in a solvent and allowing the solution to stand at a temperature of about 15°C to about 40°C for about 1 hour to about 2 weeks.
  • the crystalline form(s) of the present invention may be prepared by adding an anti-solvent to a solution of febuxostat in a solvent and optionally cooling the reaction mixture to a temperature of about 0°C to about 10°C.
  • the crystalline form(s) of the present invention may be prepared by suspending febuxostat in a solvent and cooling the solution to a temperature of about -10°C to about 10°C. In other embodiments, the crystalline form(s) of the present invention may be prepared by suspending febuxostat in a solvent and allowing the solution to stand at a temperature of about 15°C to about 40°C for about 1 hour to about 2 weeks. In other embodiments, the crystalline form(s) of the present invention may be prepared by adding an anti-solvent to a suspension of febuxostat in a solvent. A seed crystal may also be added for obtaining the crystalline form(s) of febuxostat of the present invention. The seed crystal may be prepared by the methods described herein for the preparation of the crystalline form(s) of the present invention.
  • Isolation may be accomplished by concentration, precipitation, cooling, filtration or centrifugation followed by drying. Any suitable method of drying may be employed, such as, drying under reduced pressure, vacuum tray drying, air drying, or a combination thereof.
  • the crystalline form(s) may be dried at a temperature of about 20°C to about 60°C, preferably at about 45°C, for a period of about 1 hour to about 8 hours, preferably, for about 4 hours.
  • the present invention provides a process for the preparation of crystalline Form Rl by dissolving febuxostat in a chlorinated hydrocarbon solvent at a temperature of about 25 °C to about 60°C and cooling to a temperature of about -10°C to about 10°C.
  • crystalline Form Rl may be prepared by dissolving febuxostat in a chlorinated hydrocarbon solvent at a temperature of about 40°C and cooling to a temperature of about 0°C to about 5°C.
  • the chlorinated solvent may be selected from dichloromethane or chloroform, preferably, dichloromethane.
  • the present invention provides a process for the preparation of crystalline Form Rl by dissolving febuxostat in a chlorinated hydrocarbon at a temperature of 25 °C to about 60°C and allowing the solution to stand at a temperature of about 20°C to about 25°C for complete evaporation.
  • crystalline Form Rl may be prepared by dissolving febuxostat in a chlorinated hydrocarbon solvent at a temperature of about 40°C and allowing the solution to stand at a temperature of about 20°C to about 25°C for complete evaporation.
  • the chlorinated solvent may be selected from dichloromethane or chloroform, preferably, dichloromethane.
  • the present invention provides a process for the preparation of crystalline Form Rl by dissolving febuxostat in a chlorinated hydrocarbon at a temperature of 25°C to about 60°C and adding an anti-solvent to the solution.
  • crystalline Form Rl may be prepared by dissolving febuxostat in a chlorinated hydrocarbon solvent at a temperature of about 40°C and adding an anti-solvent to the solution.
  • Crystalline Form Rl may also be prepared by dissolving febuxostat in a chlorinated hydrocarbon solvent at a temperature of about 40°C, adding an anti-solvent and cooling the reaction mixture to a temperature of about 5°C.
  • Crystalline Form Rl may also be prepared by seeding.
  • the chlorinated solvent may be selected from
  • the anti-solvent may be selected from hydrocarbons, alkyl acetates, or mixtures thereof.
  • hydrocarbons such as, hexane, cyclohexane, benzene, toluene, heptane or octane may be used as anti-solvent.
  • the anti-solvent may be heptane.
  • the present invention provides a process for the preparation of crystalline Form Rl by stirring a suspension of febuxostat in a chlorinated solvent at about 25 °C to about 60°C for about 3 hours to about 10 hours.
  • crystalline Form Rl may be prepared by stirring a suspension of febuxostat in a chlorinated solvent at about 40°C for about 6 hours.
  • the chlorinated solvent may be selected from dichloromethane or chloroform, preferably, dichloromethane.
  • the present invention provides a process for the preparation of crystalline Form R2 by dissolving febuxostat in a sulphoxide solvent at a temperature of about 40°C to about 80°C and allowing the solution to stand at a temperature of about 15°C to about 35°C for about 30 minutes to about 5 hours.
  • crystalline Form R2 may be prepared by dissolving febuxostat in a sulphoxide solvent at a temperature of about 65 °C and allowing the solution to stand at a temperature of about 15°C to about 35°C for about 3 hours.
  • the sulphoxide solvent may be selected from dimethyl sulfoxide or diethyl sulphoxide, preferably, dimethyl sulfoxide.
  • the present invention provides a process for the preparation of crystalline Form R2 by dissolving febuxostat in a sulphoxide solvent at a temperature of about 40°C to about 80°C and cooling in an ice bath for about 1 hour.
  • crystalline Form R2 may be prepared by dissolving febuxostat in the sulphoxide solvent at a temperature of about 65 °C and cooling in an ice bath for about 15 minutes.
  • the sulphoxide solvent may be selected from dimethyl sulfoxide or diethyl sulphoxide, preferably, dimethyl sulfoxide.
  • the present invention provides a process for the preparation of crystalline Form R2 by dissolving febuxostat in sulphoxide solvent at a temperature of about 40°C to about 80°C and allowing the solution to stand at a temperature of about 15°C to about 35°C for about 12 hours to about 36 hours.
  • crystalline Form R2 may be prepared by dissolving febuxostat in a sulphoxide solvent at a temperature of about 65 °C and allowing the solution to stand at a temperature of about 15°C to about 35°C for about 24 hours.
  • the sulphoxide solvent may be selected from dimethyl sulfoxide or diethyl sulphoxide, preferably, dimethyl sulfoxide.
  • the present invention provides a process for the preparation of crystalline Form R3 by dissolving febuxostat in an amide solvent at a temperature of about 40°C to about 80°C and allowing the solution to stand at a temperature of about 15°C to about 35°C for about 12 hours to about 36 hours.
  • crystalline Form R3 may be prepared by dissolving febuxostat in an amide solvent at a temperature of about 65 °C and allowing the solution to stand at a temperature of about 15°C to about 35°C for about 24 hours.
  • the amide solvent may be selected from N, N-dimethylformamide or N, N-dimethylacetamide, preferably, N, N- dimethylf ormamide .
  • the present invention provides a process for the
  • crystalline Form R3 by dissolving febuxostat in an amide solvent at a temperature of about 40°C to about 80°C and allowing the solution to stand at a temperature of about 15°C to about 35°C for about 1 week.
  • crystalline Form R3 may be prepared by dissolving febuxostat in an amide solvent at a temperature of about 65°C and allowing the solution to stand at a temperature of about 15°C to about 35°C for about 1 week.
  • the amide solvent may be selected from N, N-dimethylformamide or N, N- dimethylacetamide, preferably, N, N-dimethylformamide.
  • the present invention provides a process for the
  • ком ⁇ онент may be selected from, such as acetone, dimethyl ketone, ethyl methyl ketone or methyl iso- butyl ketone, preferably, methyl iso-butyl ketone.
  • the ether may be selected from diethyl ether, ethyl methyl ether, di-isopropyl ether, tetrahydrofuran or 1,4-dioxane.
  • the anti- solvent may be selected from hydrocarbons, alkyl acetates or mixtures thereof.
  • hydrocarbons such as hexane, cyclohexane, benzene, toluene, heptane or octane may be used as anti-solvent.
  • the anti-solvent may be cyclohexane.
  • crystalline Form R4 may be prepared by adding a solution of febuxostat in methyl iso-butyl ketone to cyclohexane.
  • crystalline Form R4 may be prepared by adding a solution of febuxostat in tetrahydrofuran to cyclohexane.
  • the present invention provides a process for the
  • crystalline Form R5 by dissolving febuxostat in a carboxylic acid at a temperature of about 40°C to about 80°C and allowing the solution to stand at about 15°C to about 35°C for about 30 minutes to about 5 hours.
  • crystalline Form R5 may be prepared by dissolving febuxostat in a carboxylic acid at a temperature of about 65°C and allowing the solution to stand at about 15°C to about 35°C for about 3 hours.
  • the carboxylic acid may be selected from formic acid, acetic acid or propionic acid, preferably, acetic acid.
  • the present invention provides a process for the preparation of crystalline Form R5 by adding a solution of febuxostat in a carboxylic acid to an anti-solvent at a temperature of about 15°C to about 35°C and allowing the solution to stand for about 12 hours to about 24 hours.
  • the carboxylic acid may be selected from formic acid, acetic acid or propionic acid.
  • acetic acid may be used.
  • the anti-solvent may be selected from hydrocarbons, alkyl acetates, or mixtures thereof.
  • Hydrocarbons such as hexane, cyclohexane, benzene, toluene, heptane or octane may be used as anti-solvent.
  • the anti-solvent may be heptane.
  • the present invention provides a process for the preparation of crystalline Form R5 by adding a solution of febuxostat, prepared by dissolving febuxostat in a carboxylic acid solvent at a temperature of about 40°C to about 80°C, to an anti-solvent at a temperature of about 15°C to about 35°C and allowing the solution to stand for about 12 hours to about 24 hours.
  • crystalline Form R5 may be prepared by adding a solution of febuxostat, prepared by dissolving febuxostat in a carboxylic acid solvent at a temperature of about 65°C, to an anti-solvent at a temperature of about 15°C to about 35°C and allowing the solution to stand for about 12 hours to about 24 hours.
  • the carboxylic acid may be selected from formic acid, acetic acid or propionic acid.
  • acetic acid may be used.
  • the anti-solvent may be selected from hydrocarbons, alkyl acetates, or mixtures thereof.
  • Hydrocarbons such as hexane, cyclohexane, benzene, toluene, heptane or octane may be used as anti- solvent.
  • the anti-solvent may be cyclohexane.
  • the present invention provides a process for the preparation of crystalline Form R5 by stirring a suspension of febuxostat in a carboxylic acid solvent at about 40°C to about 80°C for about 3 hours to about 12 hours.
  • crystalline Form R5 may be prepared by stirring a suspension of febuxostat in a carboxylic acid solvent at about 60°C for about 8 hours.
  • the carboxylic acid may be selected from formic acid, acetic acid or propionic acid.
  • acetic acid may be used.
  • crystalline forms of febuxostat of the present invention may be converted into amorphous form of febuxostat by evaporation of the solvent, spray drying, freeze-drying or lyophilization.
  • Solvates, pseudomorphs and hydrates of crystalline forms of the present invention are also included within the scope of the present invention.
  • the yield is more than the input material, it may be a solvate form, which is also included within the scope of the present invention.
  • the crystalline forms of febuxostat of the present invention may be administered as part of a pharmaceutical composition for the chronic management of hyperuricemia in patients with gout. Accordingly, in a further aspect, there are provided pharmaceutical compositions that include the crystalline forms of febuxostat of the present invention, and one or more pharmaceutically acceptable carriers, diluents or excipients, and optionally, other therapeutic ingredients.
  • the crystalline forms of febuxostat of the present invention may conventionally be formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms. Any suitable route of administration may be employed, for example, peroral or parental.
  • the X-ray diffraction patterns were recorded using Panalytical Expert PRO with Xcelerator as detector, 3-40 as scan range, 0.02 as step size and 3-40° 2 ⁇ as range.
  • Febuxostat (1 g) was dissolved in dichloromethane (38 mL) at a temperature of about 40°C. The solution was cooled to about 0°C to about 5°C, filtered and dried in a vacuum tray dryer at a temperature of about 45 °C for 4 hours to obtain crystalline Form Rl of febuxostat (0.9 g).
  • Febuxostat (1 g) was dissolved in dichloromethane (60 mL) at a temperature of about 40°C. The solution was allowed to stand at about 25 °C until the complete evaporation of the solvent takes place and dried in a vacuum tray dryer at a temperature of about 45°C for 4 hours to obtain crystalline Form Rl of febuxostat (0.9 g).
  • Febuxostat (0.7 g) was dissolved in dimethyl sulphoxide (12 mL) at a temperature of about 65 °C. The solution was allowed to stand at about 25 °C for 3 hours, filtered and dried in a vacuum tray dryer at a temperature of about 45 °C for 4 hours to obtain crystalline Form R2 of febuxostat (0.6 g).
  • Febuxostat (1 g) was dissolved in dimethyl sulphoxide (3 mL) at a temperature of about 65 °C. The solution was cooled in an ice bath, dried under suction on a filter paper followed by drying in a vacuum tray dryer at a temperature of about 45 °C for 4 hours to obtain crystalline Form R2 of febuxostat ((0.6 g).
  • Febuxostat (1 g) was dissolved in dimethyl sulphoxide (17 mL) at a temperature of about 65°C. The solution was allowed to stand at a temperature of about 25°C for 24 hours, filtered and dried in a vacuum tray dryer at a temperature of about 45 °C for 4 hours to obtain crystalline Form R2 of febuxostat (0.75 g).
  • Febuxostat (0.7 g) was dissolved in N, N-dimethylformamide (10 mL) at a temperature of about 65°C. The solution was allowed to stand at about 25°C for 24 hours, dried under suction on a filter paper followed by drying in a vacuum tray dryer at a temperature of about 45°C for 4 hours to obtain crystalline Form R3 of febuxostat (0.5 g).
  • Febuxostat (1 g) was dissolved in N, N-dimethylformamide (10 mL) at a temperature of about 65°C. The solution was allowed to stand at about 25°C for 1 week. The material was dried in a vacuum tray dryer at a temperature of about 45°C for 4 hours to obtain crystalline Form R3 of febuxostat (1.1 g).
  • Febuxostat (1 g) was dissolved in acetic acid (25 mL) at a temperature of about 65°C. The above solution was added to cyclohexane (100 mL) at about 25°C. The solution was allowed to stand at about 25 °C for 24 hours, filtered and dried in a vacuum tray dryer at a temperature of about 45 °C for 4 hours to obtain crystalline Form R5 of febuxostat (0.95 g).
  • Febuxostat (7 g) was dissolved in dichloromethane (280 mL) at a temperature of about 40°C.
  • Heptane (400 mL) maintained at room temperature was added to the above solution in 30 minutes.
  • the reaction mixture was cooled to a temperature of about 5°C and stirred for 45 minutes.
  • the reaction mixture was filtered and dried at a temperature of about 55°C in a vacuum tray dryer for 5 hours to obtain crystalline Form Rl of febuxostat (6.2 g).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des formes cristallines de fébuxostat, des procédés pour leur préparation, des compositions pharmaceutiques comprenant celles-ci et leur utilisation pour le traitement chronique de l'hyperuricémie chez des patients atteints de goutte.
PCT/IB2010/055897 2009-12-31 2010-12-16 Formes polymorphes de fébuxostat WO2011080651A2 (fr)

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IN2756DE2009 2009-12-31
IN2756/DEL/2009 2009-12-31
IN200DE2010 2010-01-29
IN200/DEL/2010 2010-01-29

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WO2011080651A2 true WO2011080651A2 (fr) 2011-07-07
WO2011080651A3 WO2011080651A3 (fr) 2011-11-24

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012048861A1 (fr) * 2010-10-14 2012-04-19 Gador S.A. Nouvelle forme cristalline du febuxostat et son procédé de préparation
EP2502920A1 (fr) * 2011-03-25 2012-09-26 Sandoz Ag Procédé de cristallisation pour Febuxostat form A
WO2013076738A2 (fr) 2011-11-15 2013-05-30 Mylan Laboratories Ltd Procédé destiné à la préparation de polymorphes du febuxostat
WO2013088449A1 (fr) * 2011-12-16 2013-06-20 Natco Pharma Limited Forme cristalline stable de febuxostat et procédé de préparation correspondant
WO2016091230A1 (fr) 2014-12-12 2016-06-16 Zentiva, K.S. Formulations contenant une solution solide de fébuxostat

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5614520A (en) 1990-11-30 1997-03-25 Teijin Limited 2-arylthiazole derivatives and pharmaceutical composition thereof
US6225474B1 (en) 1998-06-19 2001-05-01 Teijin Limited Polymorphs of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid and method of producing the same
CN101085761A (zh) 2007-06-29 2007-12-12 上海华拓医药科技发展股份有限公司 非布他特微晶及其组合物
CN101139325A (zh) 2006-09-07 2008-03-12 上海医药工业研究院 2-(3-氰基-4-异丁氧基苯基)-4-甲基-5-噻唑甲酸晶型及其制备方法
WO2008067773A1 (fr) 2006-12-07 2008-06-12 Chongqing Pharmaceutical Research Institute Co., Ltd. Nouveaux types de cristaux de febuxostat et procédés de préparation de ceux-ci
CN101386605A (zh) 2008-10-23 2009-03-18 中国科学院上海药物研究所 非布司他新型晶体及其制备方法
US7541475B2 (en) 2003-07-30 2009-06-02 Abbott Laboratories Substituted thiazoles
US20090203919A1 (en) 2006-06-23 2009-08-13 Mitsutaka Kitamura Method for producing crystal polymorphs of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5614520A (en) 1990-11-30 1997-03-25 Teijin Limited 2-arylthiazole derivatives and pharmaceutical composition thereof
US6225474B1 (en) 1998-06-19 2001-05-01 Teijin Limited Polymorphs of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid and method of producing the same
US7541475B2 (en) 2003-07-30 2009-06-02 Abbott Laboratories Substituted thiazoles
US20090203919A1 (en) 2006-06-23 2009-08-13 Mitsutaka Kitamura Method for producing crystal polymorphs of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid
CN101139325A (zh) 2006-09-07 2008-03-12 上海医药工业研究院 2-(3-氰基-4-异丁氧基苯基)-4-甲基-5-噻唑甲酸晶型及其制备方法
WO2008067773A1 (fr) 2006-12-07 2008-06-12 Chongqing Pharmaceutical Research Institute Co., Ltd. Nouveaux types de cristaux de febuxostat et procédés de préparation de ceux-ci
CN101085761A (zh) 2007-06-29 2007-12-12 上海华拓医药科技发展股份有限公司 非布他特微晶及其组合物
CN101386605A (zh) 2008-10-23 2009-03-18 中国科学院上海药物研究所 非布司他新型晶体及其制备方法

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012048861A1 (fr) * 2010-10-14 2012-04-19 Gador S.A. Nouvelle forme cristalline du febuxostat et son procédé de préparation
EP2502920A1 (fr) * 2011-03-25 2012-09-26 Sandoz Ag Procédé de cristallisation pour Febuxostat form A
WO2013076738A2 (fr) 2011-11-15 2013-05-30 Mylan Laboratories Ltd Procédé destiné à la préparation de polymorphes du febuxostat
WO2013088449A1 (fr) * 2011-12-16 2013-06-20 Natco Pharma Limited Forme cristalline stable de febuxostat et procédé de préparation correspondant
WO2016091230A1 (fr) 2014-12-12 2016-06-16 Zentiva, K.S. Formulations contenant une solution solide de fébuxostat

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