WO2012098501A1 - Febuxostat co-crystals - Google Patents

Febuxostat co-crystals Download PDF

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Publication number
WO2012098501A1
WO2012098501A1 PCT/IB2012/050230 IB2012050230W WO2012098501A1 WO 2012098501 A1 WO2012098501 A1 WO 2012098501A1 IB 2012050230 W IB2012050230 W IB 2012050230W WO 2012098501 A1 WO2012098501 A1 WO 2012098501A1
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Prior art keywords
febuxostat
crystal
crystals
caffeine
urea
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PCT/IB2012/050230
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French (fr)
Inventor
Poonam KAUSHIK
Ram Thaimattam
Mohan Prasad
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Ranbaxy Laboratories Limited
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Publication of WO2012098501A1 publication Critical patent/WO2012098501A1/en

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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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 relates to co-crystals of febuxostat, processes for their preparation and their use for the chronic management of hyperuricemia in patients with gout.
  • Febuxostat is a non-purine xanthine oxidase inhibitor disclosed in U.S. Patent No. 5,614,520. It is chemically described as 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4- methylthiazole-5-carboxylic acid having the structure as represented by Formula I.
  • Febuxostat is marketed in the United States as a white crystalline powder under the brand name Uloric® for the chronic management of hyperuricemia in patients with gout.
  • Uloric® for the chronic management of hyperuricemia in patients with gout.
  • the present invention provides for a febuxostat-urea co- crystal with X-ray diffraction peaks having d-spacing values at about 1 1.73, 7.78, 5.87, 5.1 1 and 3.55 A.
  • Embodiments of this aspect of the invention may include one or more of the following features.
  • the febuxostat-urea co-crystal may further include X-ray diffraction peaks having d-spacing values at about 6.86, 4.96, 3.90, 3.68 and 3.16 A.
  • the febuxostat-urea co-crystal may also include a DSC having an endotherm at about 170°C.
  • the febuxostat and the urea may be in a 1 : 1 stoichiometric ratio.
  • the present invention provides for a'febuxostat- nicotinamide co-crystal with X-ray diffraction peaks having d-spacing values at about 17.14, 7.18, 5.68, 3.54 and 3.32 A.
  • Embodiments of this aspect of the invention may include one or more of the following features.
  • the febuxostat-nicotinamide co-crystal may further include X-ray diffraction peaks having d-spacing values at about 4.21, 3.87, 3.76, 3.50 and 3.19 A.
  • the febuxostat-nicotinamide co-crystal may also include a DSC having an endotherm at about 143.45°C.
  • the febuxostat and the nicotinamide may be in a 1 : 1 stoichiometric ratio.
  • the present invention provides for a febuxostat- caffeine co-crystal with X-ray diffraction peaks having d-spacing values at about 8.76, 7.63, 7.10, 3.40 and 3.36 A.
  • Embodiments of this aspect of the invention may include one or more of the following features.
  • the febuxostat-caffeine co-crystal may further include X- ray diffraction peaks having d-spacing values at about 5.15, 4.85, 4.30, 3.82, 3.48 and 3.27 A.
  • the febuxostat-caffeine co-crystal may also include a DSC having an endotherm at about 193.54°C.
  • the febuxostat and the caffeine may be in a 1 :2 stoichiometric ratio.
  • the present invention provides for a process for the preparation of co-crystals of febuxostat with a co-crystal forms selected from urea, nicotinamide or caffeine which includes contacting febuxostat of Formula I,
  • Embodiments of this aspect of the present invention may include one or more of the following features.
  • the febuxostat is contacted with the co-crystal former in a solvent selected from water, alcohols, ketones, carboxylic acids, chlorinated hydrocarbons, ethers, amides, sulphoxides, alkyl acetates, or mixtures thereof.
  • the febuxostat may be contacted with the co-crystal former in acetone.
  • the febuxostat may also be contacted with the co-crystal former in ethanol or the febuxostat may be contacted with the co-crystal former in 2-propanol.
  • the febuxostat may be contacted with the co-crystal former at ambient temperature to reflux temperature of solvent(s).
  • the reaction mixture containing febuxostat and the co-crystal former in solvent(s) may also be kept at a temperature of about -18°C to about -20°C.
  • the co-crystals of febuxostat may be purified by crystallization from a solvent selected from the group of alcohols, ketones, water, carboxylic acids, chlorinated hydrocarbons, amides, sulphoxides, ethers, or mixtures thereof.
  • the present invention provides for a pharmaceutical composition which includes co-crystals of febuxostat selected from febuxostat-urea, febuxostat-nicotinamide or febuxostat-caffeine and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present invention provides for the use of co- crystals of febuxostat selected from febuxostat-urea, febuxostat-nicotinamide or febuxostat-caffeine for chronic management of hyperuricemia in patients with gout.
  • Figure 1 X-ray diffraction pattern (XRD) of febuxostat-urea co-crystal.
  • FIG. 1 Differential Scanning Thermogram (DSC) of febuxostat-urea co-crystal.
  • Figure 4 X-ray diffraction pattern of febuxostat-nicotinamide co-crystal.
  • Figure 5 Differential Scanning Thermogram of febuxostat-nicotinamide co- crystal.
  • Figure 7 X-ray diffraction pattern of febuxostat-caffeine co-crystal.
  • Figure 8 Differential Scanning Thermogram of febuxostat-caffeine co-crystal.
  • Figure 9 Thermogravimetric Analysis of febuxostat-caffeine co-crystal.
  • Figure 10 X-ray diffraction pattern overlay of febuxostat, urea, and febuxostat- urea co-crystal.
  • Figure 1 1 X-ray diffraction pattern overlay of febuxostat, nicotinamide, and
  • Figure 12 X-ray diffraction pattern overlay of febuxostat, caffeine, and febuxostat- caffeine co-crystal.
  • Figure 13 DSC overlay of febuxostat, urea, and febuxostat-urea co-crystal.
  • Figure 14 DSC overlay of febuxostat, nicotinamide, and febuxostat-nicotinamide co-crystal.
  • Figure 15 DSC overlay of febuxostat, caffeine, and febuxostat-caffeine co-crystal.
  • Febuxostat-urea co-crystals of the present invention may be characterized by XRD peaks at about 7.54 (d-spacing at about 1 1.73 A), 1 1.37 (7.78 A), 15.09 (5.87 A), 17.33 (5.1 1 A) and 25.10 (3.55 A) ⁇ 0.2° 2 ⁇ . It may be further characterized by XRD peaks at about 12.90 (6.86 A), 17.87 (4.96 A), 22.81 (3.90 A), 24.21 (3.68 A) and 28.23 (3.16 A) ⁇ 0.2° 2 ⁇ .
  • Febuxostat-urea co-crystal may also be characterized by DSC having endoderm at about 170°C.
  • Table 1 provides the d-spacing in A and the corresponding 2 ⁇ values of febuxostat-urea co-crystals.
  • Febuxostat-nicotinamide co-crystals of the present invention may be characterized by XRD peaks at about 5.16 (d-spacing at about 17.14A), 12.32 (7.18 A), 15.61 (5.68 A), 25.17 (3.54 A) and 26.87 (3.32 A) ⁇ 0.2° 2 ⁇ . It may be further characterized by XRD peaks at about 21.09 (4.21 A), 22.96 (3.87 A), 23.63 (3.76 A), 25.41 (3.50 A) and 27.96 (3.19 A) ⁇ 0.2° 2 ⁇ .
  • Febuxostat-nicotinamide co-crystal may also be characterized by DSC having endoderm at about 143.45°C.
  • Febuxostat-caffeine co-crystals of the present invention may be characterized by XRD peaks at about 10.10 (d-spacing at about 8.76 A), 1 1.59 (7.63 A), 12.47 (7.10 A), 26.24 (3.40 A) and 26.52 (3.36 A) ⁇ 0.2° 2 ⁇ . It may be further characterized by XRD peaks at about 17.21 (5.15 A), 18.28 (4.85 A), 20.65 (4.30 A), 23.28 (3.82 A), 25.57 (3.48 A) and 27.31 (3.27 A) ⁇ 0.2° 2 ⁇ .
  • Febuxostat-caffeine co-crystal may also be characterized by DSC having endotherm at about 193.54°C.
  • Febuxostat to be used for the preparation of febuxostat co-crystals 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. 5,614,520; U.S. Publication No. 2009/0203919; and U.S. Patent No.7,541 ,475, which are incorporated herein by reference.
  • Febuxostat to be used as starting material for the preparation of febuxostat co-crystals 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.
  • ambient temperature refers to a temperature in the range of about 20°C to about 30°C.
  • co-crystal refers to a crystalline material that includes two or more unique components held together by a weak interaction in a stoichiometric ratio, wherein at least one of the compounds is a co-crystal former, and wherein each component of the co-crystal has distinctive physical characteristics such as structure, melting point and heat of fusion.
  • weak interaction refers to an interaction which is neither ionic nor covalent and includes interactions such as hydrogen bonds, Vander Waals forces and ⁇ - ⁇ interactions.
  • co-crystal former refers to a compound capable of interacting with febuxostat through hydrogen bonding, Vander Waals forces or ⁇ - ⁇ interactions.
  • the co-crystal former may be selected from the compounds having at least one functional group selected from urea, amide or ketone.
  • co-crystal formers having urea functional group may include urea or 4-ethoxyphenyl urea.
  • co- crystal formers having amide group may include nicotinamide or iso-nicotinamide.
  • co-crystal forms having a ketone group may include caffeine.
  • the co-crystal formers of the present invention are acceptable food additives.
  • the febuxostat co-crystals of the present invention may have a specific
  • the co-crystal former is urea and the febuxostat-urea co-crystals are formed by the interaction of febuxostat and urea in 1 : 1 stoichiometric ratio.
  • the co-crystal former is nicotinamide and the febuxostat-nicotinamide co-crystals are formed by the interaction of febuxostat and nicotinamide in 1 : 1 stoichiometric ratio.
  • the co-crystal former is caffeine and the febuxostat- caffeine co-crystals are formed by the interaction of febuxostat and caffeine in 1 :2 stoichiometric ratio.
  • the preparation of febuxostat co-crystals may be carried out by contacting febuxostat with a co-crystal former in a solvent.
  • the solvent may be selected from the group of water, alcohols, ketones, carboxylic acids, chlorinated hydrocarbons, ethers, amides, sulphoxides, alkyl acetates or mixtures thereof.
  • Suitable alcohols may include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol or 2-butanol.
  • Suitable ketones may include acetone, dimethyl ketone, ethyl methyl ketone or methyl iso-butyl ketone.
  • Suitable carboxylic acids may include formic acid, acetic acid or propionic acid.
  • Suitable chlorinated hydrocarbons may include dichloromethane, carbon tetrachloride or chloroform.
  • Suitable ethers may include diethyl ether, ethyl methyl ether, di-isopropyl ether, tetrahydrofuran or 1, 4-dioxane.
  • Suitable amides may include N, N- dimethylformamide or N, N-dimethylacetamide.
  • Suitable sulphoxides may include dimethyl sulfoxide or diethyl sulphoxide.
  • Suitable alkyl acetates may include ethyl acetate or di-isopropyl acetate.
  • the solvent may be selected from the group of ketones and alcohols.
  • Febuxostat may be contacted with the co-crystal former at ambient temperature to the reflux temperature of the solvent.
  • febuxostat may be contacted with the co-crystal former in a solvent at ambient temperature. In another embodiment, febuxostat may be contacted with the co-crystal former in a solvent at a temperature of about 45°C to about 60°C.
  • the reaction mixture formed by contacting febuxostat with the co-crystal former may optionally be kept in a freezer at a temperature of about -18°C to -20°C for about 5 minutes to about 1 hour to cause crystallization.
  • the reaction mixture formed by contacting febuxostat with the co-crystal former may also be stirred at ambient temperature for about 5 days to about 20 days.
  • Febuxostat co-crystals may be further purified by carrying out one or more crystallizations from a solvent.
  • the solvent may be selected from the group comprising of alcohols, ketones, water, carboxylic acids, chlorinated hydrocarbons, amides, sulphoxides, ethers, or mixtures thereof. Suitable alcohols, ketones, carboxylic acids, chlorinated hydrocarbons, amides, sulphoxides and ethers may include those described above for preparing febuxostat co-crystals.
  • the solution may be kept in a freezer at a temperature of about -18°C to -20°C for about 5 minutes to about 1 hour to accomplish crystallization.
  • Isolation may be accomplished by concentration, precipitation, cooling, filtration or centrifugation followed by drying. Any suitable method of drying may be employed, such as air drying, drying under reduced pressure, vacuum tray drying, or a combination thereof.
  • the co-crystals of febuxostat may be dried for a period of about 2 hours to about 25 days.
  • Febuxostat co-crystals of the present invention may be used to prepare new solid drug forms of febuxostat. Thus, improving the physicochemical properties of febuxostat. Further advantages of the co-crystals of the present invention include ease of preparation and formulation, improved bioavailability and efficacy, better solubility, and improved stability. Febuxostat co-crystals of the present invention may provide new routes of administration and reduced side-effects.
  • Table 4 provides thermal stability for febuxostat-urea co-crystals, febuxostat- nicotinamide co-crystals and febuxostat-caffeine co-crystals.
  • Table 5 provides solubility data for febuxostat Form A, febuxostat-urea co- crystals, febuxostat-nicotinamide co-crystals and febuxostat-caffeine co-crystals.
  • the solubility of febuxostat-nicotinamide and febuxostat-caffeine co-crystals are significantly better than Form A, which is the marketed form of febuxostat.
  • Table 5 Solubility Data of Febuxostat Form A and Febuxostat Co-crystals
  • Febuxostat co-crystal(s) of the present invention may be administered as part of a pharmaceutical composition for the chronic management of hyperuricemia in patients with gout.
  • pharmaceutical composition(s) which include febuxostat co-crystal(s) of the present invention, and one or more pharmaceutically acceptable carriers, diluents or excipients and optionally other therapeutic ingredients.
  • the febuxostat co-crystal(s) 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.
  • 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-urea co-crystals 1.75 g of febuxostat-urea co-crystals were dissolved in acetone (17.5 mL) at about 55°C. The solution was kept in freezer at about -18°C to -20°C for about 20 minutes. The contents were filtered and air dried at ambient temperature for about 5 hours to obtain febuxostat-urea co-crystals.
  • febuxostat-nicotinamide co-crystals 1.75 g of febuxostat-nicotinamide co-crystals were dissolved in acetone (17.5 mL) at about 55°C. The solution was kept in freezer at about -18°C to -20°C for about 15 minutes. The contents were filtered and air dried at ambient temperature for about 5 hours to obtain febuxostat-nicotinamide co-crystals.
  • Febuxostat-caffeine co-crystals (1.500 g) were dissolved in acetone (25 mL) at about 55°C. The solution was kept in a freezer at about -18°C to -20°C for about 15 minutes. The contents were filtered and air dried at ambient temperature for about 5 hours to obtain febuxostat-caffeine co-crystals. Yield: 55.64% b) Febuxostat (0.9800 g) and caffeine (1.2050 g) were dissolved in 2-propanol (250 mL) at about 65°C. The solution was kept aside at ambient temperature for about 18 days for slow solvent evaporation. Co-crystals formation was observed.
  • Febuxostat-caffeine co-crystals (1.500 g) were dissolved in acetone (25 mL) at about 55°C. The solution was kept in a freezer at about -18°C to -20°C for about 15 minutes to accomplish crystallization. The contents were filtered and air dried at ambient temperature for about 5 hours to obtain febuxostat-caffeine co-crystals (0.8565 g).

Abstract

The present invention provides co-crystals of febuxostat, processes for their preparation and their use for the chronic management of hyperuricemia in patients with gout.

Description

FEBUXOSTAT CO-CRYSTALS
Field of the Invention
The present invention relates to co-crystals of febuxostat, processes for their preparation and their use for the chronic management of hyperuricemia in patients with gout.
Background of the Invention
Febuxostat is a non-purine xanthine oxidase inhibitor disclosed in U.S. Patent No. 5,614,520. It is chemically described as 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4- methylthiazole-5-carboxylic acid having the structure as represented by Formula I.
Figure imgf000002_0001
Formula I
Febuxostat is marketed in the United States as a white crystalline powder under the brand name Uloric® for the chronic management of hyperuricemia in patients with gout. Although literature reports several polymorphs of febuxostat, co-crystals of febuxostat are not reported.
Summary of the Invention
In one general aspect, the present invention provides for a febuxostat-urea co- crystal with X-ray diffraction peaks having d-spacing values at about 1 1.73, 7.78, 5.87, 5.1 1 and 3.55 A.
Embodiments of this aspect of the invention may include one or more of the following features. For example, the febuxostat-urea co-crystal may further include X-ray diffraction peaks having d-spacing values at about 6.86, 4.96, 3.90, 3.68 and 3.16 A. The febuxostat-urea co-crystal may also include a DSC having an endotherm at about 170°C. The febuxostat and the urea may be in a 1 : 1 stoichiometric ratio. In another general aspect, the present invention provides for a'febuxostat- nicotinamide co-crystal with X-ray diffraction peaks having d-spacing values at about 17.14, 7.18, 5.68, 3.54 and 3.32 A.
Embodiments of this aspect of the invention may include one or more of the following features. For example, the febuxostat-nicotinamide co-crystal may further include X-ray diffraction peaks having d-spacing values at about 4.21, 3.87, 3.76, 3.50 and 3.19 A. The febuxostat-nicotinamide co-crystal may also include a DSC having an endotherm at about 143.45°C. The febuxostat and the nicotinamide may be in a 1 : 1 stoichiometric ratio.
In yet another general aspect, the present invention provides for a febuxostat- caffeine co-crystal with X-ray diffraction peaks having d-spacing values at about 8.76, 7.63, 7.10, 3.40 and 3.36 A.
Embodiments of this aspect of the invention may include one or more of the following features. For example, the febuxostat-caffeine co-crystal may further include X- ray diffraction peaks having d-spacing values at about 5.15, 4.85, 4.30, 3.82, 3.48 and 3.27 A. The febuxostat-caffeine co-crystal may also include a DSC having an endotherm at about 193.54°C. The febuxostat and the caffeine may be in a 1 :2 stoichiometric ratio.
In another general aspect, the present invention provides for a process for the preparation of co-crystals of febuxostat with a co-crystal forms selected from urea, nicotinamide or caffeine which includes contacting febuxostat of Formula I,
Figure imgf000003_0001
Formula I
with the co-crystal former.
Embodiments of this aspect of the present invention may include one or more of the following features. For example, the febuxostat is contacted with the co-crystal former in a solvent selected from water, alcohols, ketones, carboxylic acids, chlorinated hydrocarbons, ethers, amides, sulphoxides, alkyl acetates, or mixtures thereof.
The febuxostat may be contacted with the co-crystal former in acetone. The febuxostat may also be contacted with the co-crystal former in ethanol or the febuxostat may be contacted with the co-crystal former in 2-propanol.
The febuxostat may be contacted with the co-crystal former at ambient temperature to reflux temperature of solvent(s). The reaction mixture containing febuxostat and the co-crystal former in solvent(s) may also be kept at a temperature of about -18°C to about -20°C.
The co-crystals of febuxostat may be purified by crystallization from a solvent selected from the group of alcohols, ketones, water, carboxylic acids, chlorinated hydrocarbons, amides, sulphoxides, ethers, or mixtures thereof.
In another general aspect, the present invention provides for a pharmaceutical composition which includes co-crystals of febuxostat selected from febuxostat-urea, febuxostat-nicotinamide or febuxostat-caffeine and one or more pharmaceutically acceptable carriers, diluents or excipients.
In yet another general aspect, the present invention provides for the use of co- crystals of febuxostat selected from febuxostat-urea, febuxostat-nicotinamide or febuxostat-caffeine for chronic management of hyperuricemia in patients with gout. Brief Description of the Figures
Figure 1 : X-ray diffraction pattern (XRD) of febuxostat-urea co-crystal.
Figure 2: Differential Scanning Thermogram (DSC) of febuxostat-urea co-crystal.
Figure 3: Thermogravimetric Analysis (TGA) of febuxostat-urea co-crystal.
Figure 4: X-ray diffraction pattern of febuxostat-nicotinamide co-crystal.
Figure 5: Differential Scanning Thermogram of febuxostat-nicotinamide co- crystal.
Figure 6: Thermogravimetric Analysis of febuxostat-nicotinamide co-crystal.
Figure 7: X-ray diffraction pattern of febuxostat-caffeine co-crystal.
Figure 8: Differential Scanning Thermogram of febuxostat-caffeine co-crystal. Figure 9: Thermogravimetric Analysis of febuxostat-caffeine co-crystal.
Figure 10: X-ray diffraction pattern overlay of febuxostat, urea, and febuxostat- urea co-crystal.
Figure 1 1 : X-ray diffraction pattern overlay of febuxostat, nicotinamide, and
febuxostat-nicotinamide co-crystal.
Figure 12: X-ray diffraction pattern overlay of febuxostat, caffeine, and febuxostat- caffeine co-crystal.
Figure 13: DSC overlay of febuxostat, urea, and febuxostat-urea co-crystal.
Figure 14: DSC overlay of febuxostat, nicotinamide, and febuxostat-nicotinamide co-crystal.
Figure 15: DSC overlay of febuxostat, caffeine, and febuxostat-caffeine co-crystal.
Detailed Description of the Invention
Febuxostat-urea co-crystals of the present invention may be characterized by XRD peaks at about 7.54 (d-spacing at about 1 1.73 A), 1 1.37 (7.78 A), 15.09 (5.87 A), 17.33 (5.1 1 A) and 25.10 (3.55 A) ± 0.2° 2Θ. It may be further characterized by XRD peaks at about 12.90 (6.86 A), 17.87 (4.96 A), 22.81 (3.90 A), 24.21 (3.68 A) and 28.23 (3.16 A) ± 0.2° 2Θ. Febuxostat-urea co-crystal may also be characterized by DSC having endoderm at about 170°C. It may also be characterized by XRD pattern, DSC thermogram and TGA as depicted in Figures 1 , 2 and 3, respectively. Table 1 provides the d-spacing in A and the corresponding 2Θ values of febuxostat-urea co-crystals.
Table 1: XRD Peaks of Febuxostat-Urea Co-crystals
Position (°2Θ) d-spacing (A) Relative Intensity (%)
7.54 1 1.73 86.74
1 1.37 7.78 23.45
12.48 7.09 3.49
12.64 7.00 3.58
12.90 6.86 5.01
15.09 5.87 37.82
16.31 5.43 1.61
16.87 5.25 4.25
17.33 5.1 1 29.25
17.87 4.96 6.02
18.65 4.76 3.74
20.64 4.30 1.33 20.94 4.24 1.46
22.81 3.90 20.00
24.21 3.68 14.53
25.10 3.55 100.00
25.65 3.47 3.84
26.77 3.33 2.90
28.23 3.16 14.06
28.77 3.10 2.34
30.72 2.91 2.43
31.00 2.88 1.46
31.33 2.86 1.76
31.65 2.83 1.55
32.05 2.79 1.08
32.78 2.73 1.53
34.49 2.60 2.35
35.04 2.56 1.63
35.31 2.54 0.87
36.25 2.48 0.68
36.71 2.45 0.45
38.26 2.35 1.94
Febuxostat-nicotinamide co-crystals of the present invention may be characterized by XRD peaks at about 5.16 (d-spacing at about 17.14A), 12.32 (7.18 A), 15.61 (5.68 A), 25.17 (3.54 A) and 26.87 (3.32 A) ± 0.2° 2Θ. It may be further characterized by XRD peaks at about 21.09 (4.21 A), 22.96 (3.87 A), 23.63 (3.76 A), 25.41 (3.50 A) and 27.96 (3.19 A) ± 0.2° 2Θ. Febuxostat-nicotinamide co-crystal may also be characterized by DSC having endoderm at about 143.45°C. It may also be characterized by XRD pattern, DSC thermogram and TGA as depicted in Figures 4, 5 and 6, respectively. Table 2 provides the d-spacing in A and the corresponding 2Θ values of febuxostat-nicotinamide co-crystals. Table 2: XRD Peaks of Febuxostat-Nicotinamide Co-crystals
Position (°2Θ) d-spacing (A) Relative Intensity (%)
5.16 17.14 33.99
6.87 12.87 0.57
7.72 1 1.45 8.54
10.30 8.59 3.1 1
12.32 7.18 100.00
12.88 6.87 5.71
13.10 6.76 6.36
14.33 6.18 4.65
15.61 5.68 35.05
15.88 5.58 6.57 16.85 5.26 2.15
18.03 4.92 10.50
19.43 4.57 8.91
19.71 4.50 9.13
20.66 4.30 3.90
21.09 4.21 15.40
21.75 4.09 7.95
22.96 3.87 22.20
23.63 3.76 22.24
23.98 3.71 10.69
25.17 3.54 30.32
25.41 3.50 21.27
26.25 3.39 12.10
26.87 3.32 56.60
27.96 3.19 18.28
28.70 3.1 1 7.55
29.54 3.02 4.65
30.71 2.91 4.19
31.23 2.86 8.87
33.53 2.67 2.46
35.16 2.55 2.33
36.19 2.48 2.83
37.09 2.42 3.56
38.16 2.36 3.71
38.65 2.33 3.33
39.31 2.29 3.67
Febuxostat-caffeine co-crystals of the present invention may be characterized by XRD peaks at about 10.10 (d-spacing at about 8.76 A), 1 1.59 (7.63 A), 12.47 (7.10 A), 26.24 (3.40 A) and 26.52 (3.36 A) ± 0.2° 2Θ. It may be further characterized by XRD peaks at about 17.21 (5.15 A), 18.28 (4.85 A), 20.65 (4.30 A), 23.28 (3.82 A), 25.57 (3.48 A) and 27.31 (3.27 A) ± 0.2° 2Θ. Febuxostat-caffeine co-crystal may also be characterized by DSC having endotherm at about 193.54°C. It may also be characterized by XRD pattern, DSC thermogram and TGA as depicted in Figures 7, 8 and 9, respectively. Table 3 provides the d-spacing in A and the corresponding 2Θ values of febuxostat-caffeine co- crystals. Table 3: XRD Peaks of Febuxostat-Caffeine Co-crystals
Figure imgf000008_0001
Febuxostat to be used for the preparation of febuxostat co-crystals 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. 5,614,520; U.S. Publication No. 2009/0203919; and U.S. Patent No.7,541 ,475, which are incorporated herein by reference. Febuxostat to be used as starting material for the preparation of febuxostat co-crystals 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.
The term "contacting" may include dissolving, slurrying, stirring or a combination thereof.
The term "ambient temperature", as used herein, refers to a temperature in the range of about 20°C to about 30°C.
The term "co-crystal", as used herein, refers to a crystalline material that includes two or more unique components held together by a weak interaction in a stoichiometric ratio, wherein at least one of the compounds is a co-crystal former, and wherein each component of the co-crystal has distinctive physical characteristics such as structure, melting point and heat of fusion.
The term "weak interaction", as used herein, refers to an interaction which is neither ionic nor covalent and includes interactions such as hydrogen bonds, Vander Waals forces and π- π interactions.
The term "co-crystal former", as used herein, refers to a compound capable of interacting with febuxostat through hydrogen bonding, Vander Waals forces or π- π interactions. The co-crystal former may be selected from the compounds having at least one functional group selected from urea, amide or ketone. Examples of co-crystal formers having urea functional group may include urea or 4-ethoxyphenyl urea. Examples of co- crystal formers having amide group may include nicotinamide or iso-nicotinamide.
Examples of co-crystal forms having a ketone group may include caffeine. The co-crystal formers of the present invention are acceptable food additives.
The febuxostat co-crystals of the present invention may have a specific
stoichiometry ranging from 1 : 1 , 1 :2 or 2: 1 (febuxostat o-crystal former) depending upon the structure of each co-crystal former.
In one embodiment of the present invention, the co-crystal former is urea and the febuxostat-urea co-crystals are formed by the interaction of febuxostat and urea in 1 : 1 stoichiometric ratio. In another embodiment of the present invention, the co-crystal former is nicotinamide and the febuxostat-nicotinamide co-crystals are formed by the interaction of febuxostat and nicotinamide in 1 : 1 stoichiometric ratio. In yet another embodiment of the present invention, the co-crystal former is caffeine and the febuxostat- caffeine co-crystals are formed by the interaction of febuxostat and caffeine in 1 :2 stoichiometric ratio.
The preparation of febuxostat co-crystals may be carried out by contacting febuxostat with a co-crystal former in a solvent. The solvent may be selected from the group of water, alcohols, ketones, carboxylic acids, chlorinated hydrocarbons, ethers, amides, sulphoxides, alkyl acetates or mixtures thereof. Suitable alcohols may include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol or 2-butanol. Suitable ketones may include acetone, dimethyl ketone, ethyl methyl ketone or methyl iso-butyl ketone.
Suitable carboxylic acids may include formic acid, acetic acid or propionic acid. Suitable chlorinated hydrocarbons may include dichloromethane, carbon tetrachloride or chloroform. Suitable ethers may include diethyl ether, ethyl methyl ether, di-isopropyl ether, tetrahydrofuran or 1, 4-dioxane. Suitable amides may include N, N- dimethylformamide or N, N-dimethylacetamide. Suitable sulphoxides may include dimethyl sulfoxide or diethyl sulphoxide. Suitable alkyl acetates may include ethyl acetate or di-isopropyl acetate. In the preferred embodiments of the present invention, the solvent may be selected from the group of ketones and alcohols.
Febuxostat may be contacted with the co-crystal former at ambient temperature to the reflux temperature of the solvent.
In one embodiment, febuxostat may be contacted with the co-crystal former in a solvent at ambient temperature. In another embodiment, febuxostat may be contacted with the co-crystal former in a solvent at a temperature of about 45°C to about 60°C.
The reaction mixture formed by contacting febuxostat with the co-crystal former may optionally be kept in a freezer at a temperature of about -18°C to -20°C for about 5 minutes to about 1 hour to cause crystallization. The reaction mixture formed by contacting febuxostat with the co-crystal former may also be stirred at ambient temperature for about 5 days to about 20 days.
Febuxostat co-crystals may be further purified by carrying out one or more crystallizations from a solvent. The solvent may be selected from the group comprising of alcohols, ketones, water, carboxylic acids, chlorinated hydrocarbons, amides, sulphoxides, ethers, or mixtures thereof. Suitable alcohols, ketones, carboxylic acids, chlorinated hydrocarbons, amides, sulphoxides and ethers may include those described above for preparing febuxostat co-crystals. The solution may be kept in a freezer at a temperature of about -18°C to -20°C for about 5 minutes to about 1 hour to accomplish crystallization.
Isolation may be accomplished by concentration, precipitation, cooling, filtration or centrifugation followed by drying. Any suitable method of drying may be employed, such as air drying, drying under reduced pressure, vacuum tray drying, or a combination thereof. The co-crystals of febuxostat may be dried for a period of about 2 hours to about 25 days.
Febuxostat co-crystals of the present invention may be used to prepare new solid drug forms of febuxostat. Thus, improving the physicochemical properties of febuxostat. Further advantages of the co-crystals of the present invention include ease of preparation and formulation, improved bioavailability and efficacy, better solubility, and improved stability. Febuxostat co-crystals of the present invention may provide new routes of administration and reduced side-effects.
Table 4 provides thermal stability for febuxostat-urea co-crystals, febuxostat- nicotinamide co-crystals and febuxostat-caffeine co-crystals.
Table 4: Thermal Stability Data of Febuxostat Co-crystals
Figure imgf000011_0001
Table 5 provides solubility data for febuxostat Form A, febuxostat-urea co- crystals, febuxostat-nicotinamide co-crystals and febuxostat-caffeine co-crystals. The solubility of febuxostat-nicotinamide and febuxostat-caffeine co-crystals are significantly better than Form A, which is the marketed form of febuxostat. Table 5: Solubility Data of Febuxostat Form A and Febuxostat Co-crystals
Figure imgf000012_0001
Febuxostat co-crystal(s) of the present invention may be administered as part of a pharmaceutical composition for the chronic management of hyperuricemia in patients with gout. Accordingly, also provided are pharmaceutical composition(s) which include febuxostat co-crystal(s) of the present invention, and one or more pharmaceutically acceptable carriers, diluents or excipients and optionally other therapeutic ingredients. The febuxostat co-crystal(s) 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.
In the foregoing section, embodiments are described by way of examples to illustrate the processes of invention. However, these are not intended in any way to limit the scope of the present invention. Several variants of the examples would be evident to persons ordinarily skilled in the art which are within the scope of the present invention.
Methods
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° 2Θ as range.
DSC and TGA were recorded using Mettler Toledo DSC 82 le and TA instrument- Q 500, respectively. EXAMPLES
Example 1 : Preparation of Febuxostat-Urea Co-Crystals
a) Febuxostat (1.589 g) and urea (0.3041 g) were dissolved in acetone (25 mL) at about 55°C. The solution was filtered and kept in freezer at about -18°C to 20°C for about 20 minutes to accomplish crystallization. The contents were filtered and air dried at ambient temperature for about 5 hours to obtain febuxostat- urea co-crystals.
Yield: 42.33%
b) Febuxostat (0.3173 g) and urea (0.0707 g) were suspended in ethanol (2 mL). The reaction mixture was slurried for about 1 week at ambient temperature followed by evaporation of solvent at ambient temperature for about 72 hours to obtain febuxostat-urea co-crystals.
Yield: 90.59% c) Febuxostat (3.4705 g) and urea (0.6657 g) were dissolved in acetone (25 mL) at about 55°C. The solution was filtered and kept in freezer at about -18 to -20°C for about 20 minutes to accomplish crystallization. The contents were filtered and air dried at ambient temperature for about 5 hours to obtain febuxostat-urea co- crystals (3.7699 g).
1.75 g of febuxostat-urea co-crystals were dissolved in acetone (17.5 mL) at about 55°C. The solution was kept in freezer at about -18°C to -20°C for about 20 minutes. The contents were filtered and air dried at ambient temperature for about 5 hours to obtain febuxostat-urea co-crystals.
Yield: 69%
Ή NMR (DMSO, 400 MHz): 513.51 (br, s, 1H), 58.23 (d, 1H), 5 8.17 (dd, 1H), 57.33 (d, 1H), 55.48 (s, 4H), 5 3.98 (d, 2H), 5 2.52 (s, 3H), 5 2.10 (m, 1H), 51.02 (d, 6H)
Example 2: Preparation of Febuxostat-Nicotinamide Co-Crystal
a) Febuxostat (1.584 g) and nicotinamide (0.6023 g) were dissolved in acetone (25 mL) at about 55°C. The solution was filtered and kept in freezer at about -18 to - 20°C for about 15 minutes to accomplish crystallization. The contents were filtered and air dried at ambient temperature for about 5 hours to obtain febuxostat- nicotinamide co-crystals.
Yield: 35.76%
b) Febuxostat (0.3171 g) and nicotinamide (0.1231 g) were suspended in acetone (2 mL). The reaction mixture was slurried for about 1 week at ambient temperature and kept overnight at ambient temperature for solvent evaporation to obtain febuxostat-nicotinamide co-crystals.
Yield: 91.66% c) Febuxostat (3.1515 g) and nicotinamide ( 1.2001 g) were dissolved in acetone (25 mL) at about 55°C. The solution was filtered and kept in freezer at about -18°C to -20°C for about 15 minutes to accomplish crystallization. The contents were filtered and air dried at ambient temperature for about 5 hours to obtain febuxostat- nicotinamide co-crystals (3.7549 g).
1.75 g of febuxostat-nicotinamide co-crystals were dissolved in acetone (17.5 mL) at about 55°C. The solution was kept in freezer at about -18°C to -20°C for about 15 minutes. The contents were filtered and air dried at ambient temperature for about 5 hours to obtain febuxostat-nicotinamide co-crystals.
Yield: 40.87%
Ή NMR (CDC , 400 MHz): 510.76 (br, s, IH), 59.13 (d, IH), 58.81 (d, IH), 58.29 (m, IH), 58.21 (d, IH), 58.10 (dd, IH), 57.51 (m, IH), 57.05 (d, IH), 56.81 (br, d, 2H), 53.90 (d, 2H), 52.79 (s, 3H), 52.20 (m, IH), 51.16 (d, 6H)
Example 3: Preparation of Febuxostat-Caffeine Co-Crystal
a) Febuxostat (0.9483 g) and caffeine (1.2007 g) were dissolved in acetone (50 mL) at about 55°C. The solution was kept aside at ambient temperature for complete evaporation of the solvent for about 3 days to obtain febuxostat-caffeine co- crystals (1.6054 g).
Febuxostat-caffeine co-crystals (1.500 g) were dissolved in acetone (25 mL) at about 55°C. The solution was kept in a freezer at about -18°C to -20°C for about 15 minutes. The contents were filtered and air dried at ambient temperature for about 5 hours to obtain febuxostat-caffeine co-crystals. Yield: 55.64% b) Febuxostat (0.9800 g) and caffeine (1.2050 g) were dissolved in 2-propanol (250 mL) at about 65°C. The solution was kept aside at ambient temperature for about 18 days for slow solvent evaporation. Co-crystals formation was observed. The residue was re-dissolved in acetone (50 mL) at about 55°C and kept aside at ambient temperature for about 4 days for complete evaporation of the solvent. Febuxostat-caffeine co-crystals (1.670 g) were obtained.
Febuxostat-caffeine co-crystals (1.500 g) were dissolved in acetone (25 mL) at about 55°C. The solution was kept in a freezer at about -18°C to -20°C for about 15 minutes to accomplish crystallization. The contents were filtered and air dried at ambient temperature for about 5 hours to obtain febuxostat-caffeine co-crystals (0.8565 g).
Yield: 57.10% c) Febuxostat (1.7385 g) and caffeine (2.2013 g) were dissolved in acetone (35 mL) at about 55°C. The solution was kept in freezer at about -18°C to -20°C for about 15 minutes to accomplish crystallization. The contents were filtered and air dried at ambient temperature for about 5 hours to obtain febuxostat- caffeine co-crystals
Yield: 88.75%
Ή NMR (CDC13, 400 MHz): 68.20 (d, IH), 68.10 (dd, IH), 67.58 (s, IH), 67.02 (d, IH), 64.01 (s, 3H), 63.91 (d, 2H), 63.60 (s, 3H), 63.42 (s, 3H), 62.79 (s, 3H), 62.21 (m, IH), 61.10 (d, 6H)

Claims

We claim:
1. Febuxostat-urea co-crystal comprising X-ray diffraction peaks having d-spacing values at about 1 1.73, 7.78, 5.87, 5.1 1 and 3.55 A.
2. The febuxostat-urea co-crystal of claim 1 , further comprising X-ray diffraction peaks having d-spacing values at about 6.86, 4.96, 3.90, 3.68 and 3.16 A.
3. The febuxostat-urea co-crystal of claim 1 , comprising a DSC having an endotherm at about 170°C.
4. The febuxostat-urea co-crystal of claim 1 , wherein the febuxostat and the urea are in a 1 : 1 stoichiometric ratio.
5. Febuxostat-nicotinamide co-crystal comprising X-ray diffraction peaks having d- spacing values at about 17.14, 7.18, 5.68, 3.54 and 3.32 A.
6. The febuxostat-nicotinamide co-crystal of claim 5, further comprising X-ray
diffraction peaks having d-spacing values at about 4.21, 3.87, 3.76, 3.50 and 3.19 A.
7. The febuxostat-nicotinamide co-crystal of claim 5, comprising a DSC having an endotherm at about 143.45°C.
8. The febuxostat-nicotinamide co-crystal of claim 5, wherein the febuxostat and the nicotinamide are in a 1 : 1 stoichiometric ratio.
9. Febuxostat-caffeine co-crystal comprising X-ray diffraction peaks having d- spacing values at about 8.76, 7.63, 7.10, 3.40 and 3.36 A.
10. The febuxostat-caffeine co-crystal of claim 9, further comprising X-ray diffraction peaks having d-spacing values at about 5.15, 4.85, 4.30, 3.82, 3.48 and 3.27 A.
1 1 . The febuxostat-caffeine co-crystal of claim 9, comprising a DSC having an
endotherm at about 193.54°C.
12. The febuxostat-caffeine co-crystal of claim 9, wherein the febuxostat and the
caffeine are in a 1 :2 stoichiometric ratio.
13. A process for the preparation of co-crystals of febuxostat with a co-crystal forms selected from urea, nicotinamide or caffeine comprising contacting febuxostat of Formula I
Figure imgf000017_0001
Formula I
with the co-crystal former.
14. The process according to claim 13, wherein the febuxostat is contacted with the co- crystal former in a solvent selected from the group comprising of water, alcohols, ketones, carboxylic acids, chlorinated hydrocarbons, ethers, amides, sulphoxides, alkyl acetates, or mixtures thereof.
15. The process according to claim 14, wherein the febuxostat is contacted with the co- crystal former in acetone.
16. The process according to claim 14, wherein the febuxostat is contacted with the co- crystal former in ethanol.
17. The process according to claim 14, wherein the febuxostat is contacted with the co- crystal former in 2-propanol.
18. The process according to claim 13, wherein the febuxostat is contacted with the co- crystal former at ambient temperature to reflux temperature of solvent(s).
19. The process according to claim 13, wherein the reaction mixture containing
febuxostat and the co-crystal former in solvent(s) is kept at a temperature of about -18°C to about -20°C.
20. The process according to claim 13, wherein the co-crystals of febuxostat are
purified by crystallization from a solvent selected from the group comprising of alcohols, ketones, water, carboxylic acids, chlorinated hydrocarbons, amides, sulphoxides, ethers, or mixtures thereof.
21. A pharmaceutical composition comprising co-crystals of febuxostat selected from febuxostat-urea, febuxostat-nicotinamide or febuxostat-caffeine and one or more pharmaceutically acceptable carriers, diluents or excipients.
22. Use of co-crystals of febuxostat selected from febuxostat-urea, febuxostat- nicotinamide or febuxostat-caffeine for chronic management of hyperuricemia in patients with gout.
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104177308A (en) * 2014-07-31 2014-12-03 浙江中医药大学 Three novel febuxostat medicament eutectic crystals and preparation method thereof
KR20170002104A (en) 2015-06-29 2017-01-06 순천향대학교 산학협력단 Co-crystals of Febuxostat and methods of preparing therof
CN106565627A (en) * 2016-10-10 2017-04-19 扬子江药业集团有限公司 Preparation method for pharmaceutical crystal form of febuxostat
CN108530382A (en) * 2018-03-20 2018-09-14 华南理工大学 A kind of Febuxostat ligustrazine eutectic and its preparation method and application
EP3001814B1 (en) * 2013-03-15 2021-05-19 Allen, Davidoff Xanthine oxidase inhibitor formulations

Citations (5)

* 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
WO2004078163A2 (en) * 2003-02-28 2004-09-16 Transform Pharmaceuticals, Inc. Pharmaceutical co-crystal compositions of drugs such as carbamazepine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen
EP2039691A1 (en) * 2006-06-23 2009-03-25 Teijin Pharma Limited Process for production of a polymorph of 2-(3-cyano-4- isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid
US7541475B2 (en) 2003-07-30 2009-06-02 Abbott Laboratories Substituted thiazoles
US20100317702A1 (en) * 2009-06-10 2010-12-16 Teva Pharmaceutical Industries Ltd. Crystalline form of febuxostat

Patent Citations (6)

* 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
WO2004078163A2 (en) * 2003-02-28 2004-09-16 Transform Pharmaceuticals, Inc. Pharmaceutical co-crystal compositions of drugs such as carbamazepine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen
US7541475B2 (en) 2003-07-30 2009-06-02 Abbott Laboratories Substituted thiazoles
EP2039691A1 (en) * 2006-06-23 2009-03-25 Teijin Pharma Limited Process for production of a polymorph of 2-(3-cyano-4- isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid
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
US20100317702A1 (en) * 2009-06-10 2010-12-16 Teva Pharmaceutical Industries Ltd. Crystalline form of febuxostat

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ALMARSSON ET AL: "Crystal engineering of the composition of pharmaceutical phases. Do pharmaceutical co-crystals reprepsent a new path to improved medicines", CHEMICAL COMMUNICATIONS - CHEMCOM; [6015D], ROYAL SOCIETY OF CHEMISTRY, GB, 1 January 2004 (2004-01-01), pages 1889 - 1896, XP002415977, ISSN: 1359-7345, DOI: 10.1039/B402150A *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3001814B1 (en) * 2013-03-15 2021-05-19 Allen, Davidoff Xanthine oxidase inhibitor formulations
US11406713B2 (en) 2013-03-15 2022-08-09 Xortx Therapeutics, Inc. Xanthine oxidase inhibitor formulations
CN104177308A (en) * 2014-07-31 2014-12-03 浙江中医药大学 Three novel febuxostat medicament eutectic crystals and preparation method thereof
KR20170002104A (en) 2015-06-29 2017-01-06 순천향대학교 산학협력단 Co-crystals of Febuxostat and methods of preparing therof
KR101821855B1 (en) * 2015-06-29 2018-01-24 순천향대학교 산학협력단 Co-crystals of Febuxostat and methods of preparing therof
CN106565627A (en) * 2016-10-10 2017-04-19 扬子江药业集团有限公司 Preparation method for pharmaceutical crystal form of febuxostat
CN108530382A (en) * 2018-03-20 2018-09-14 华南理工大学 A kind of Febuxostat ligustrazine eutectic and its preparation method and application

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