WO2017008773A1 - Crystalline forms of obeticholic acid - Google Patents

Crystalline forms of obeticholic acid Download PDF

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Publication number
WO2017008773A1
WO2017008773A1 PCT/CZ2016/000078 CZ2016000078W WO2017008773A1 WO 2017008773 A1 WO2017008773 A1 WO 2017008773A1 CZ 2016000078 W CZ2016000078 W CZ 2016000078W WO 2017008773 A1 WO2017008773 A1 WO 2017008773A1
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Prior art keywords
obeticholic acid
crystalline form
acid according
preparation
obeticholic
Prior art date
Application number
PCT/CZ2016/000078
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English (en)
French (fr)
Inventor
Iva OBADALOVA
Ondrej Dammer
Lukas KREJCIK
Jakub Hert
Original Assignee
Zentiva, K.S.
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Application filed by Zentiva, K.S. filed Critical Zentiva, K.S.
Publication of WO2017008773A1 publication Critical patent/WO2017008773A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to crystalline forms of obeticholic acid of formula I, with the systematic name (3a,5 ,6a,7a)-6-ethyl-3,7-dihydroxycholan-24-oic acid, a method of their preparation and use for the production of a dosage form.
  • These crystalline forms can be advantageously used to increase purity of obeticholic acid and also for the preparation of its amorphous form.
  • Obeticholic acid is a semi-synthetic bile acid analogue with an agonist effect upon the farnesoid X receptor (FXR). It is designed for the treatment of liver diseases, e.g. primary biliary cirrhosis (PBC), non-alcoholic steatohepatitis (NASH) or primary sclerosing cholangitis (PSC).
  • FXR farnesoid X receptor
  • Obeticholic acid was first mentioned in the patent application WO2002072598. It describes its isolation by means of column chromatography, which generally produced amorphous substances; however, the patent application does not disclose any more detailed data about the character of the product.
  • solid compounds can exist in various crystalline forms that are considered as polymorphs and hydrates/solvates, having different crystal units and thus different physicochemical properties such as the melting point, solubility, dissolution rate, as well as bioavailability.
  • solid- state analytic methods can be used, e.g. X-ray powder diffraction, solid-state NMR and Raman spectroscopy, as well as thermoanalytic methods.
  • This object of the present invention is crystalline forms of obeticholic acid.
  • the first of the forms, identified as 1-2, is a monohydrate and is characterized by an easy preparation process, high crystallinity and purification capability. Its significant advantage consists in the possibility of its re-drying to an amorphous form. Thus, there is no need to transform the crystalline form of obeticholic acid to a salt (e.g. sodium or ammonium) and subsequently prepare the amorphous form by precipitation.
  • a salt e.g. sodium or ammonium
  • the other form, identified as 1-3 exhibits high stability; the melting point of Form 1-3 is significantly higher than the melting points of Forms 1-2 or C.
  • Crystalline Form 1-2 of obeticholic acid exhibiting the following characteristic reflections in the X-ray powder pattern measured by CuKa radiation: 3.1; 6.2; 9.9; 12.4 and 16.7 ⁇ 0.2° 2-theta.
  • Crystalline Form 1-2 of obeticholic acid is characterized by the following further reflections in the X-ray powder pattern: 4.9; 8.9; 10.9 and 15.8 ⁇ 0.2° 2-theta.
  • Crystalline Form 1-2 of obeticholic acid is further characterized by the differential scanning calorimetry curve with the melting point at 80.9°C. In some embodiments, Crystalline Form 1-2 of obeticholic acid is in the form of monohydrate.
  • the invention further provides Crystalline Form 1-3 of obeticholic acid, exhibiting the following characteristic reflections in the X-ray powder pattern measured by CuKa radiation: 8.0; 10.6; 16.0 and 17.6 ⁇ 0.2° 2-theta. In some embodiments, Crystalline Form 1-3 of obeticholic acid is characterized by the following further reflections in the X-ray powder pattern: 10.0; 13.2 and 15.2 ⁇ 0.2° 2-theta.
  • the invention further provides the use of Crystalline Form 1-2 and/or Crystalline Form 1-3 of obeticholic acid for the preparation of an amorphous form of obeticholic acid.
  • the invention further provides a method for preparation of the amorphous form of obeticholic acid, comprising drying of Crystalline Form 1-2 in a vacuum drier at the temperature of 40°C or higher, preferably at a temperature in the range of 40 to 80°C.
  • Crystalline Form 1-2 of obeticholic acid is dried at the temperature of 40°C for at least 20 hours.
  • the invention further provides a method for preparation of the amorphous form of obeticholic acid, comprising:
  • step a) Crystalline Form 1-2 and/or Crystalline Form 1-3 of obeticholic acid is advantageously converted to the ammonium or sodium salt.
  • step b) an organic or inorganic acid is added, preferably hydrochloric or phosphoric acid.
  • the invention further provides the use of Crystalline Form 1-2 and or Crystalline Form 1-3 of obeticholic acid for the preparation of obeticholic acid with a chemical purity higher than 99.80% in accordance with HPLC.
  • the invention further provides the use of Crystalline Form 1-2 and/or Crystalline Form 1-3 for the preparation of a pharmaceutical composition.
  • the invention further provides a pharmaceutical composition containing Crystalline Form 1-2 and/or Crystalline Form 1-3 of obeticholic acid and at least one pharmaceutically acceptable excipient.
  • at least one pharmaceutically acceptable excipient is selected from the group comprising lactose, microcrystalline cellulose, sodium croscarmellose and magnesium stearate and their combinations.
  • the pharmaceutical composition has the form of a tablet.
  • Fig. 1 XRPD pattern of Form 1-2 of obeticholic acid
  • Fig. 2 DSC record of Form 1-2 of obeticholic acid
  • Fig. 3 TGA record of Form 1-2 of obeticholic acid
  • Fig. 4 XRPD pattern of Form 1-3 of obeticholic acid
  • This invention provides two novel crystalline forms of obeticholic acid.
  • Form 1-2 exhibits a distinctly crystalline character.
  • the X-ray powder pattern of this salt is shown in Fig. 1. Its characteristic diffractions measured by CuKa radiation are 3.1; 6.2; 9.9; 12.4 and 16.7 ⁇ 0.2 °2-theta. Form 1-2 further exhibits the following characteristic reflections: 4.9; 8.9; 10.9 and 15.8 ⁇ 0.2 °2-theta. Diffraction peaks with a higher relative intensity than 15% are shown in Table 1.
  • DSC Differential scanning calorimetry
  • TGA thermogravimetric analysis
  • Form 1-2 of obeticholic acid contains 4.3 % of water, which corresponds to one molar equivalent (Fig. 3). Due to its high crystallinity, Form 1-2 is suitable not only for purification of crude obeticholic acid or for preparation of an amorphous form of obeticholic acid, but it is also directly usable in the dosage form.
  • Form 1-3 also exhibits a strongly crystalline character.
  • the X-ray powder pattern of this salt is shown in Fig. 4. Its characteristic diffractions measured by CuKa radiation are 8.0; 10.6; 16.0; and 17.6 ⁇ 0.2 °2-theta.
  • Form 1-3 further exhibits the following characteristic reflections: 10.0; 13.2 and 15.2 ⁇ 0.2 °2-theta. Diffraction peaks with a higher relative intensity than 15% are shown in Table 2.
  • Forms 1-2 and 1-3 can be advantageously used to increase the chemical purity of obeticholic acid. These forms crystallize well and remove impurities from obeticholic acid. Conversion of Form C to Form 1-2 increased the chemical purity from 99.10% (starting Form C) to 99.61% (final Form 1-2). The recrystallization of Form 1-2 alone also increases the chemical purity from the initial 99.61% to the final 99.98% (HPLC). Purification of crude obeticholic acid (HPLC purity 97.59%) can be advantageously achieved by conducting recrystallization through Form 1-2 and in such a case the chemical purity of the final product rises to 99.83% (HPLC) during a single crystallization.
  • Form 1-3 does not exhibit such a high tendency to crystallize as Form 1-2.
  • conversion of Form C to Form 1-3 increased the chemical purity from 99.10% (starting Form C) to 99.48% (final Form 1-3).
  • the recrystallization of Form 1-3 alone increased the chemical purity from the initial 99.48% to the final 99.87% (HPLC).
  • Purification of crude obeticholic acid (HPLC purity 97.59%) can be advantageously achieved by conducting recrystallization through Form 1-3 and in such a case the chemical purity of the final product rose to 98.99% (HPLC) during a single crystallization.
  • Crystalline Form 1-2 can be advantageously used to prepare the amorphous form by mere drying in a vacuum drier, wherein at the temperature of 40°C already the content of the amorphous form starts to increase. Vacuum drying for at least 20 hours at 40°C provides a nearly complete amorphous form. If vacuum drying is carried out at a higher temperature, the drying time is reduced proportionally.
  • the amorphous form of obeticholic acid can also be prepared directly during the formulation process, e.g. by spray drying or in a fluid bed reactor.
  • All the prepared forms of obeticholic acid according to this invention can be used for the preparation of pharmaceutical compositions, especially solid dosage forms, e.g. tablets.
  • Such pharmaceutical compositions can contain at least one excipient from the group of fillers (e.g. lactose), binders (e.g. microcrystalline cellulose), disintegrants (e.g. sodium salt of croscarmellose), lubricants (e.g. magnesium stearate), surfactants, etc.
  • These tablets can be coated with common coatings, e.g. polyvinyl alcohol or polyethylene glycol.
  • the preparation of the novel Crystalline Forms 1-2 and 1-3 comprises the following steps: a) dissolution and/or dispersion of obeticholic acid in a solvent/s;
  • the dissolution or dispersion in the solvent or mixture of solvents can be carried out at a temperature in the range from 20°C to the boiling point of the solvents. Subsequently, the mixture is usually cooled down to a temperature of 0°C to 30°C, preferably to the range of 20°C to 25°C, and left to crystallize. The mixture can be seeded.
  • the solid product can be isolated either directly by filtration, or concentration of the mixture, or evaporation of the solvents may follow.
  • the solvents can be selected from a group of solvents of general formula ROH, RCN, RCOR or RCOOR wherein R can be a CI to C4 carbon chain, preferably ethyl acetate, isopropyl acetate, butyl acetate, acetonitrile or 2-butanone.
  • room temperature refers, for the purposes of the text below and above, to the temperature range from 22 to 26°C. Overview of analytic methods
  • the primary optical equipment programmable divergence slits with the irradiated area of the sample of 10 mm, 0.02 rad Soller slits and a 1 ⁇ 4° anti-diffusion slit were used.
  • an X'Celerator detector with maximum opening of the detection slot 0.02 rad, Soller slits and a 5.0 mm anti-diffusion slit were used.
  • the records of differential scanning calorimetr were measured using a Discovery DSC device made by TA Instruments.
  • the sample charge in a standard Al pot (40 ⁇ ) was between 4 and 5 mg and the heating rate was 5°C/min.
  • As the carrier gas 5.0 N 2 was used at the flow of 50 ml/min.
  • thermogravimetric analysis TGA 6 device made by the company Perkin Elmer.
  • the sample charge in a corundum pot was 10-21 mg and the heating rate was 10°C/min.
  • the temperature program that was used consists of 1 minute's stabilization at the temperature of 20°C and then of heating up to 300°C at the heating rate of 10°C/min.
  • As the carrier gas 4.0 N 2 was used at the flow of 20 ml/min.
  • Chemical purity was measured with the use of liquid chromatography (HPLC):
  • Obeticholic acid was prepared according to the procedure disclosed in the patent application WO2002072598.
  • the chemical purity of crude obeticholic acid prepared this way was 97.59 % (HPLC).
  • the 1H and I3 C NMR spectra confirmed the structure of obeticholic acid.
  • Obeticholic acid (1 g, 2.38 mmol, 99.10% HPLC) was dissolved in 3 ml of butyl acetate under moderate reflux. The clear solution was left to slowly cool down to the room temperature and subsequently left to crystallize at the room temperature for approximately 3 hours. The produced crystals were aspirated and dried in a vacuum drier at 25°C for 6 hours. 850 mg of Crystalline Form 1-2 of obeticholic acid was obtained at the chemical purity of 99.61% (HPLC)
  • Obeticholic acid (0.5 g, 1.19 mmol, 97.59% HPLC) was dissolved in 2 ml of acetonitrile under moderate reflux. The clear solution was left to slowly cool down to the room temperature, seeded and subsequently left to crystallize at the room temperature for 24 hours. The produced crystals were aspirated and dried in a vacuum drier at 40°C for 6 hours. 380 mg of Crystalline Form 1-3 of obeticholic acid was obtained at the chemical purity of 98.99% (HPLC).
  • Obeticholic acid (1.5 g, 3.56 mmol, 99.61% HPLC) was dissolved in 4.5 ml of butyl acetate under moderate reflux. The clear solution was left to slowly cool down to the room temperature and subsequently left to crystallize at the room temperature for approximately 3 hours. The produced crystals were aspirated and dried in a vacuum drier at 25°C for 6 hours. 1.38 g of Crystalline Form 1-2 of obeticholic acid was obtained at the chemical purity of 99.98% (HPLC).
  • Obeticholic acid (3.8 g, 9.03 mmol, 97.59% HPLC) was dissolved in 20 ml of butyl acetate under moderate reflux. The clear solution was left to slowly cool down to the room temperature and subsequently left to crystallize at the room temperature for approximately 3 hours. The produced crystals were aspirated and dried in a vacuum drier at 25°C for 25 hours. 2.2 g of Crystalline Form 1-2 of obeticholic acid was obtained at the chemical purity of 99.83% (HPLC). This Form 1-2 was further dried in a vacuum drier at 40°C for 48 hours, providing amorphous obeticholic acid.
  • Obeticholic acid (580 mg) was dissolved in a solution of 8.7 ml of water and 8.7 ml of a 50% solution of sodium hydroxide at 40°C. The obtained solution was slowly added to diluted hydrochloric acid (37%, 9.6 ml) with water (8.7 ml) at 40°C. The produced suspension was stirred at 40°C for 30 minutes and then cooled down to 10°C. The solid fraction was filtered and washed with water. After drying in a vacuum drier (40°C), 526 mg of amorphous obeticholic acid was obtained.
  • Obeticholic acid 500 mg was dissolved in a solution of 5 ml of water and 0.11 g of 30% ammonia. The obtained solution was maintained at the temperature of 30 - 40°C and 150 mg of phosphoric acid was slowly added. The produced suspension was stirred at 30 - 40°C and then cooled down to 20°C and filtered. The solid fraction was washed with water (3 x 1 ml) and dried in a vacuum drier (40°C). 440 mg of amorphous obeticholic acid was obtained.

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Cited By (15)

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WO2017137931A1 (en) 2016-02-10 2017-08-17 Dr. Reddy’S Laboratories Limited Amine salt of obeticholic acid
WO2017167233A1 (zh) * 2016-03-31 2017-10-05 江苏恒瑞医药股份有限公司 一种奥贝胆酸的新结晶形式及其制备方法
WO2017170858A1 (ja) * 2016-03-31 2017-10-05 大日本住友製薬株式会社 溶出性に優れた経口製剤
EP3248983A4 (en) * 2014-12-30 2017-12-13 Crystal Pharmatech Co. Ltd. Crystal form a of obeticholic acid and preparation method therefor
EP3293196A1 (en) * 2016-09-09 2018-03-14 Hexal AG Process for purifying obeticholic acid
WO2018211413A1 (en) * 2017-05-15 2018-11-22 Dr. Reddy’S Laboratories Limited Solid forms of obeticholic acid and process for preparation
WO2018215002A1 (en) 2017-05-26 2018-11-29 Zentiva, K.S. Amorphous forms of obeticholic acid
CN109485687A (zh) * 2017-09-12 2019-03-19 成都弘达药业有限公司 奥贝胆酸的晶型j及其制备方法
CN109535216A (zh) * 2017-09-22 2019-03-29 上海汇伦生命科技有限公司 一种无定型奥贝胆酸的制备方法及无定型奥贝胆酸
CN109655571A (zh) * 2019-01-08 2019-04-19 丽珠集团新北江制药股份有限公司 一种奥贝胆酸的高效液相色谱分析方法
CN109806386A (zh) * 2017-11-20 2019-05-28 江苏恒瑞医药股份有限公司 Fxr激动剂与glp-1类似物的药物组合物和用途
WO2019047989A3 (en) * 2017-09-05 2019-06-06 Zentiva, K.S. CRYSTALLINE FORMS OF (3α,5β,6α,7α)-6-ETHYL-3,7-DIHYDROXYCHOLAN-24-IC ACID
WO2019106043A1 (en) 2017-11-29 2019-06-06 Hexal Ag Pharmaceutical composition comprising obeticholic acid
CN110831602A (zh) * 2017-03-08 2020-02-21 英特塞普特医药品公司 奥贝胆酸的结晶形式
WO2020097167A1 (en) * 2018-11-08 2020-05-14 Intercept Pharmaceuticals, Inc. Methods of using obeticholic acid

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CN109212044B (zh) * 2017-06-30 2021-11-26 南京济群医药科技股份有限公司 一种奥贝胆酸有关物质的检测方法

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Cited By (19)

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Publication number Priority date Publication date Assignee Title
EP3248983A4 (en) * 2014-12-30 2017-12-13 Crystal Pharmatech Co. Ltd. Crystal form a of obeticholic acid and preparation method therefor
WO2017137931A1 (en) 2016-02-10 2017-08-17 Dr. Reddy’S Laboratories Limited Amine salt of obeticholic acid
US11413295B2 (en) 2016-03-31 2022-08-16 Intercept Pharmaceuticals, Inc. Oral preparation of obeticholic acid
WO2017170858A1 (ja) * 2016-03-31 2017-10-05 大日本住友製薬株式会社 溶出性に優れた経口製剤
WO2017167233A1 (zh) * 2016-03-31 2017-10-05 江苏恒瑞医药股份有限公司 一种奥贝胆酸的新结晶形式及其制备方法
US11161871B2 (en) 2016-03-31 2021-11-02 Jiangsu Hengrui Medicine Co., Ltd. Crystalline form of obeticholic acid and preparation method therefor
EP3293196A1 (en) * 2016-09-09 2018-03-14 Hexal AG Process for purifying obeticholic acid
CN110831602A (zh) * 2017-03-08 2020-02-21 英特塞普特医药品公司 奥贝胆酸的结晶形式
WO2018165269A3 (en) * 2017-03-08 2020-03-26 Intercept Pharmaceuticals, Inc Crystalline forms of obeticholic acid
WO2018211413A1 (en) * 2017-05-15 2018-11-22 Dr. Reddy’S Laboratories Limited Solid forms of obeticholic acid and process for preparation
WO2018215002A1 (en) 2017-05-26 2018-11-29 Zentiva, K.S. Amorphous forms of obeticholic acid
WO2019047989A3 (en) * 2017-09-05 2019-06-06 Zentiva, K.S. CRYSTALLINE FORMS OF (3α,5β,6α,7α)-6-ETHYL-3,7-DIHYDROXYCHOLAN-24-IC ACID
CN109485687A (zh) * 2017-09-12 2019-03-19 成都弘达药业有限公司 奥贝胆酸的晶型j及其制备方法
CN109535216A (zh) * 2017-09-22 2019-03-29 上海汇伦生命科技有限公司 一种无定型奥贝胆酸的制备方法及无定型奥贝胆酸
CN109535216B (zh) * 2017-09-22 2022-09-16 上海汇伦医药股份有限公司 一种无定型奥贝胆酸的制备方法及无定型奥贝胆酸
CN109806386A (zh) * 2017-11-20 2019-05-28 江苏恒瑞医药股份有限公司 Fxr激动剂与glp-1类似物的药物组合物和用途
WO2019106043A1 (en) 2017-11-29 2019-06-06 Hexal Ag Pharmaceutical composition comprising obeticholic acid
WO2020097167A1 (en) * 2018-11-08 2020-05-14 Intercept Pharmaceuticals, Inc. Methods of using obeticholic acid
CN109655571A (zh) * 2019-01-08 2019-04-19 丽珠集团新北江制药股份有限公司 一种奥贝胆酸的高效液相色谱分析方法

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