WO2012020272A2 - Nouveaux sels, polymorphes et solvates d'un ingrédient pharmaceutiquement actif - Google Patents

Nouveaux sels, polymorphes et solvates d'un ingrédient pharmaceutiquement actif Download PDF

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Publication number
WO2012020272A2
WO2012020272A2 PCT/HU2011/000086 HU2011000086W WO2012020272A2 WO 2012020272 A2 WO2012020272 A2 WO 2012020272A2 HU 2011000086 W HU2011000086 W HU 2011000086W WO 2012020272 A2 WO2012020272 A2 WO 2012020272A2
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WO
WIPO (PCT)
Prior art keywords
febuxostat
salt
formula
ray powder
diffraction pattern
Prior art date
Application number
PCT/HU2011/000086
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English (en)
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WO2012020272A3 (fr
Inventor
László Pongó
Balázs VOLK
József Barkóczy
András DANCSÓ
Gyula LUKÁCS
Gyula István SIMIG
László SZÁZDI
Péter TÖMPE
György RUZSICS
Zsuzsanna SZENT-KIRÁLLYI
Original Assignee
EGIS GYÓGYSZERGYÁR Nyilvánosan Müködö Részvénytársaság
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.)
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Publication date
Priority claimed from HU1000429A external-priority patent/HU230879B1/hu
Priority claimed from HU1000430A external-priority patent/HUP1000430A2/hu
Priority claimed from HU1000431A external-priority patent/HUP1000431A2/hu
Application filed by EGIS GYÓGYSZERGYÁR Nyilvánosan Müködö Részvénytársaság filed Critical EGIS GYÓGYSZERGYÁR Nyilvánosan Müködö Részvénytársaság
Publication of WO2012020272A2 publication Critical patent/WO2012020272A2/fr
Publication of WO2012020272A3 publication Critical patent/WO2012020272A3/fr

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Classifications

    • 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

  • 2-(3-cyano-4-isobutyloxyphenyI)-4-methyl-5-thiazol-carboxilyc acid (INN: febuxostat) of formula (II) is a pharmaceutically active ingredient which is a non-purinselective xhantine oxidase inhibitor.
  • febuxostat salts are not disclosed in the patent or scientific literature and only febuxostat free acid is mentioned as pharmaceutical active ingredient. Therefore a person skilled in the art held that only the febuxostat free acid was suitable for the production of a pharmaceutical preparation suitable for therapeutic needs.
  • Figures 1 to 23 show the intensity (cps) vs 2Theta (°).
  • Figure 5 X-ray powder diffraction pattern of benzenesulfonic acid salt of febuxostat.
  • Figure 6 X-ray powder diffraction pattern of -toluenesulfonic acid salt of febuxostat.
  • Figure 16 X-ray powder diffraction pattern of calcium salt of febuxostat.
  • Figure 17 X-ray powder diffraction pattern of strontium salt of febuxostat.
  • Figure 25 An atomic cell of febuxostat ethanolate solvate (1 : 1)
  • the present invention concerns compounds according to formula (I)
  • R 1 , R 2 and R 3 is independently from each other
  • ethanolamine implies 2-aminoethanolamine
  • diethanolamine implies 2-(2-hydroxyethylamino)ethanol
  • dimethylaminoethanol implies 2-dimethylamino-ethanolt
  • ethanolammonium ion implies 2-hydroxyethylammonium
  • diethanolammonium ion implies bis-(2- hydroxyethyl)ammonium ion
  • tris-(hydroxymethyl) methylammonium ion implies 2-aminoethanolamine
  • diethanolamine implies 2-(2-hydroxyethylamino)ethanol
  • dimethylaminoethanol implies 2-dimethylamino-ethanolt
  • ethanolammonium ion implies 2-hydroxyethylammonium
  • diethanolammonium ion implies bis-(2- hydroxyethyl)ammonium ion
  • tris-(hydroxymethyl) methylammonium ion implies
  • the invention further relates to crystalline febuxostat ethanolammonium salt according to general formula (III), wherein Q n+ is ethanolammonium cation, n is 1, z is 0 which compound shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 3.340; 8.780; 14.180; 16.600; 19.500; 25840, and in more detail can be described by the following characteristic peaks at reflection angle 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 3.340; 8.780; 9.900; 14.180; 16.600; 16.920; 18.880; 19.500; 21.420; 25.160; 25.840.
  • the X-ray powder diffraction pattern of febuxostat ethanolammonium salt can be seen on figure 1 1 and the peaks showing greater than 3% intensity are summarized in table 11 below:
  • the pattern can be described by the following characteristic peaks at reflection angle 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 4.320; 4.920; 8.200; 8.700; 11.580; 15.620; 17.560; 19.360; 20.040; 20.400; 23.480.
  • the X-ray powder diffraction pattern of febuxostat piperazine salt can be seen on figure 15 and the peaks showing greater than 2% intensity are summarized in table 15 below:
  • the invention further relates to crystalline febuxostat calcium salt dihydrate according to general formula (III), wherein Q n+ is calcium cation, n is 2, z is 2 which compound shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 5.880; 9.360; 16.900; 19.100; 21.520; 23.520; 26.640, and in more detail can be described by the following characteristic peaks at reflection angle 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 5.880; 6.940; 9.360; 11.700; 16.900; 19.100; 21.520; 22.760; 23.520; 24.920; 26.640; 28.740; 32.120.
  • the X-ray powder diffraction pattern of febuxostat calcium salt can be seen on figure 16 and the peaks showing greater than 2% intensity are summarized in table 16 below:
  • salt formation preferably as inorganic acid hydrochloric acid, hydrogen bromide or sulfuric acid, as organic acid methanesulfonic acid, benzenesulfonic acid or 7-toIuenesulfonic acid can be used, more preferably hydrochloric acid can be used.
  • the febuxostat />-toluenesulfonate (1 :1) salt can be produced preferably by stirring febuxostat free acid in an ether type solvent, most preferably in THF, then to the mixture p- toluenesulfonic acid is added at a temperature between room temperature and 60°C, most preferably at room temperature.
  • the obtained reaction mixture is if needed cooled to a temperature between 5 and 25°C, the precipitated crystals are filtered, optionally washed, dried.
  • the base used for salt formation is preferably used in an amount that is from 0.4 to 3.0 molar equivalent to the amount of the febuxostat.
  • the febuxostat magnesium, calcium and zinc salt of general formula (III) preferably can be produced by reacting a febuxostat alkali salt of general formula (III) by an organic or inorganic magnesium, calcium or zinc salt and the thus formed product is then isolated.
  • the febuxostat methylammonium (1 : 1) salt form II can be produced preferably by stirring febuxostat free acid in an ether type solvent, most preferably in THF, then to the mixture methylamine in ethanol is added at a temperature between room temperature and 60°C, most preferably at room temperature.
  • the obtained reaction mixture is if needed cooled to a temperature between 5 and 25°C, the precipitated crystals are filtered, optionally washed, dried then recrystallized from 2-propanol.
  • the methylamine can be added to the reaction mixture as a gas or as an organic solvent saturated with methylamine or as methylamine dissolved in water. Most preferably a solution of 33% methylamine in ethanol is used.
  • the febuxostat dietanolammonium (1 : 1) salt can be produced preferably by stirring febuxostat free acid in an ether type solvent, most preferably in THF, then to the mixture dietanolamine is added at a temperature between room temperature and 60°C, most preferably at room temperature.
  • the obtained reaction mixture is if needed cooled to a temperature between 5 and 25°C, the precipitated crystals are filtered, optionally washed, dried.
  • the febuxostat piperazine (2:1) salt can be produced preferably by stirring febuxostat free acid in an ether type solvent, most preferably in THF, then to the mixture piperazine is added at a temperature between room temperature and 60°C, most preferably at room temperature.
  • the obtained reaction mixture is if needed cooled to a temperature between 5 and 25°C, the precipitated crystals are filtered, optionally washed, dried.
  • the febuxostat calcium (2:1) salt dihydrate can be produced preferably by stirring febuxostat sodium salt monohydrate in an alcohol type solvent, most preferably in methanol, then to the mixture calcium chloride in water is added at a temperature between room temperature and 60°C, most preferably at room temperature. The precipitated crystals are filtered, optionally washed, dried.
  • the febuxostat magnesium (2:1) salt dihydrate can be produced preferably by stirring febuxostat sodium salt monohydrate in an alcohol type solvent, most preferably in methanol, then to the mixture magnesium chloride in water is added at a temperature between room temperature and 60°C, most preferably at room temperature. The precipitated crystals are filtered, optionally washed, dried.
  • the present invention relates to a new polymorph of febuxostat of formula (II), the crystalline form of febuxostat ethanolate solvate (1 :1), to a method for their production, to pharmaceutical compositions comprising thereof and to the use of the above forms for the treatment of gout or hyperuricaemia.
  • febuxostat of formula (II) the crystalline form of febuxostat ethanolate solvate (1 :1)
  • the crystalline form L febuxostat of formula (II) shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 7.900; 8.660; 12.440; 15.040; 18.540; 23.300.
  • the used form L febuxostat can be further characterized by the following diffraction pattern having characteristic peaks at reflection angle 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 6.120; 7.900; 8.660; 9.660; 12.440; 13.740; 15.040; 18.540; 23.300; 25.060; 25.800.
  • the febuxostat Form L can be further characterized by the diffraction pattern shown on figure 23 and the peaks showing greater than 2 % intensity are summarized in table 20 below:
  • the present invention further relates to a process for the preparation of febuxostat form L of formula (II).
  • the febuxostat form L of formula (II) can be prepared by recrystallizing any polymorph or an amorphous form of febuxostat from ethanol.
  • febuxostat form L of formula (II) was produced by dissolving any polymorphic or an amorphous febuxostat in ethanol while heating, and then the solution is cooled while stirring with a specified cooling rate and the precipitated product is filtered and dried.
  • 'recrystallization' in the present application not only means the process generally known according to the state of the art whereby a crystalline product is dissolved then as a crystal it is again precipitated, but it also includes the process in which an amorphous product is dissolved and then crystallized.
  • febuxostat is dissolved in ethanol while heating, then the reaction mixture is kept at the boiling point of the solvent for 1.5 to 2.5 hours, then the mixture is cooled to 0 to 25°C by 0.5 to 1.5°C per minute while stirring at 80 to 100 min ⁇ l the precipitated product is then filtered and dried.
  • a colorless prism shaped crystal of size 1,41 x 0,18 ⁇ 0,15 mm febuxostat ethanolate solvate (1 :1) was selected for single crystal X-ray crystallography.
  • the measurement was made on Rigaku R-AXIS SPIDER and the data was evaluated by Rigaku CrystalClear and Crystal Structure software.
  • the goodness of the fit was R w - 0.1175 (I > 2 ⁇ ( ⁇ )).
  • Figure 24 depicts an ORTEP drawing of febuxostat ethanolate solvate (1 :1) of formula (IV) and figure 25 shows an atomic cell.
  • the atomic coordinates are shown in table 21, the binding lengths are shown in table 22, the binding angles are shown in table 23 and the torsion angles are shown in table 24.
  • B EQ 8/3 TU 2 (UI l(aa*) 2 + U22(bb*) 2 + U33(cc*) 2 + 2Ul2(aa*bb*)cos ⁇ + 2Ul3(aa*cc*)cos ⁇ + 2U23(bb*cc*)cos a
  • the febuxostat ethanolate solvate (1 : 1) of formula (IV) can be prepared by dissolving febuxostat ethanol while heating, the reaction mixture is kept at the boiling point of ethanol for 1.0 to 2.0 hours, then the mixture is cooled to 0 to 25°C by a cooling rate of 0.5 to 1.0°C per minute without stirring the precipitated product is then filtered and dried.
  • the febuxostat form A free acid found in the marketed composition as an active ingredient dissolves very badly in water [0,0129 mg/ml; British Journal of Clinical Pharmacology 2007, 65, 356], thus the dissolution of the active ingredient is significantly decreased.
  • the present invention further concerns pharmaceutical compositions and to the production of said pharmaceutical compositions that contain the novel febuxostat salts of formula (I) or (III) according to the invention, the febuxostat ethanolate solvate of formula (IV) or the febuxostat form L according to the invention.
  • the invention further concerns treatment methods wherein for the treatment or prophylaxis of gout or hyperuricaemia the febuxostat salt of formula (I) or (III) is administered in an effective amount to a person in need thereof.
  • the invention relates to pharmaceutical compositions comprising the salts of formula (I) or (III), the febuxostat ethanolate solvate of formula (IV) or the febuxostat form L and one or more further carriers or excipients.
  • the pharmaceutical composition according to the invention generally contains from 0.1 to 95 weight%, preferably from 1 to 50 weight% and most preferably from 5 to 30 weight% active ingredient.
  • compositions according to the invention can be given orally (e.g. in the form of powders, tablets, capsules, microcapsules, dragees, solutions, suspensions or emulsions) parenterally (e.g. in the form of intravenous, intramuscular, subcutan or intraperitonealis compositions or infusion compositions), rectally (e.g. in the form of suppositories), transdermally (e.g. in the form of patches), as an implant or locally (e.g. in the form of creams ointments or patches).
  • parenterally e.g. in the form of intravenous, intramuscular, subcutan or intraperitonealis compositions or infusion compositions
  • rectally e.g. in the form of suppositories
  • transdermally e.g. in the form of patches
  • the pharmaceutical compositions according to the invention in solid, soft or liquid form can be produced by methods known to a person skilled in the art.
  • the orally administrable solid pharmaceutical compositions comprising the salts of formula (I) or (III), the febuxostat ethanolate solvate of formula (IV) or the febuxostat form L as an active ingredient may contain filling or carrier materials (e.g. lactose, glucose, starch, calcium phosphate, microcrystalline cellulose), binding materials (e.g. gelatin, sorbitol, polyvinil pirrolidon), disintegrating agents (e.g. croscarmellose, Na-carboxymethyl cellulose, crospovidon), excipients (e.g. magnesium stearate, talc, polyethylene glycol, silica, silicium dioxide) and surfactants (e.g. sodium lauryl sulfate).
  • carrier materials e.g. lactose, glucose, starch, calcium phosphate, microcrystalline cellulose
  • binding materials e.g. gelatin, sorbitol, polyvinil pirrolidon
  • parenterally administrable liquid pharmaceutical compositions comprising the salts of formula (I) or (III), the febuxostat ethanolate solvate of formula (IV) or the febuxostat form L as an active ingredient may be sterile isotonic solutions that contain pH regulating agents and preservatives beside the solvent.
  • the soft pharmaceutical compositions e.g. suppositories comprising the salts of formula (I) or (III), the febuxostat ethanolate solvate of formula (IV) or the febuxostat form L as an active ingredient may contain the active ingredient uniformly dispersed in the base material of the suppository (e.g. in polyethylene glycol or cocoa butter).
  • the present invention relates to the use of the salts of formula (I) or (III), the febuxostat ethanolate solvate of formula (IV) or the febuxostat form L for the preparation of a pharmaceutical composition.
  • compositions according to the invention comprising the salts of formula (I) or (III), the febuxostat ethanolate solvate of formula (IV) or the febuxostat form L as an active ingredient may be produced by known methods of drug production.
  • the active ingredient is mixed with solid or liquid pharmaceutical carriers and excipients then it is brought to galenic form.
  • the pharmaceutically acceptable carrier materials and excipients and the useable methods are known in the state of the art (Remington's Pharmaceutical Sciences, Edition 18, Mack Publishing Co., Easton, USA, 1990).
  • compositions according to the invention comprising the salts of formula (I) or (III), the febuxostat ethanolate solvate of formula (IV) or the febuxostat form L as an active ingredient may comprise the active ingredients in a unit dose form.
  • the present invention further relates to the use of the salts of formula (I) or (III), the febuxostat ethanolate solvate of formula (IV) or the febuxostat form L for the production of a pharmaceutical composition for the treatment of gout or hyperuricaemia, characterized in that the salts of formula (I) or (III), febuxostat form L of formula (II) or febuxostat ethanolate solvate of formula (IV) is mixed with a pharmaceutically acceptable carrier and/or excipient then the mixture is brought to galenic form.
  • the present invention further relates to the treatment of gout or hyperuricaemia, characterized in that salts of formula (I) or (III), febuxostat form L of formula (II) or febuxostat ethanolate solvate of formula (IV) is provided in a pharmaceutically effective amount to a patient in need thereof.
  • the precipitated crystalline product was filtered, washed by a small amount of ethanol of 0 to 5°C then it was dried at 20 - 25 °C until constant weight.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
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  • 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)
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  • General Health & Medical Sciences (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne de nouveaux sels de febuxostat formés par des acides inorganiques ou organiques ou des bases, en un nouveau polymorphe et solvate de febuxostat, leur production et leur utilisation pour prévenir et traiter essentiellement la goutte ou l'hyperuricémie.
PCT/HU2011/000086 2010-08-13 2011-08-15 Nouveaux sels, polymorphes et solvates d'un ingrédient pharmaceutiquement actif WO2012020272A2 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
HU1000429A HU230879B1 (hu) 2010-08-13 2010-08-13 Febuxostat dietanolammónium só
HUP1000430 2010-08-13
HUP1000429 2010-08-13
HU1000430A HUP1000430A2 (en) 2010-08-13 2010-08-13 New polymorphous and solvate forms of a pharmaceutical active ingredient
HUP1000431 2010-08-13
HU1000431A HUP1000431A2 (en) 2010-08-13 2010-08-13 Acid addition salts of a pharmaceutical active ingredient

Publications (2)

Publication Number Publication Date
WO2012020272A2 true WO2012020272A2 (fr) 2012-02-16
WO2012020272A3 WO2012020272A3 (fr) 2012-04-05

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016104960A3 (fr) * 2014-12-22 2016-09-15 제이투에이치바이오텍 (주) Sel cristallin de pidolate de febuxostat et son procédé de préparation
CN111320589A (zh) * 2020-01-08 2020-06-23 武汉伯睿科医药科技有限公司 一种非布司他钠盐a晶型及其制备方法和用途

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EP1020454A1 (fr) 1998-06-19 2000-07-19 Teijin Limited Modifications polymorphes de 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazole-acide carboxylique et procedes de preparation associes
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CN101684107A (zh) 2008-09-26 2010-03-31 上海优拓医药科技有限公司 非布索坦的新晶型及其制备方法
CN101684108A (zh) 2009-04-15 2010-03-31 江苏正大丰海制药有限公司 2-(3-氰基-4-异丁氧基苯基)-4-甲基-5-噻唑甲酸及其组合物

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CN101386604B (zh) * 2008-10-23 2012-07-18 漆又毛 抑制黄嘌呤氧化酶活性的芳腈基噻唑衍生物及制备方法和用途

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EP1020454A1 (fr) 1998-06-19 2000-07-19 Teijin Limited Modifications polymorphes de 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazole-acide carboxylique et procedes de preparation associes
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
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CN101684107A (zh) 2008-09-26 2010-03-31 上海优拓医药科技有限公司 非布索坦的新晶型及其制备方法
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
CN101684108A (zh) 2009-04-15 2010-03-31 江苏正大丰海制药有限公司 2-(3-氰基-4-异丁氧基苯基)-4-甲基-5-噻唑甲酸及其组合物
CN101648926A (zh) 2009-07-09 2010-02-17 石药集团欧意药业有限公司 一种非布司他晶型及其制备方法
CN101671315A (zh) 2009-08-19 2010-03-17 何广卫 非布索坦的新晶型及其制备方法
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016104960A3 (fr) * 2014-12-22 2016-09-15 제이투에이치바이오텍 (주) Sel cristallin de pidolate de febuxostat et son procédé de préparation
CN111320589A (zh) * 2020-01-08 2020-06-23 武汉伯睿科医药科技有限公司 一种非布司他钠盐a晶型及其制备方法和用途

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