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
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • 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 is based on crystalline forms of obeticholic acids (I), chemical name
• Obeticholic acid is a semi-synthetic bile acid analog with an agonistic effect on the farnesoid X receptor (FXR). It is designed for the treatment of liver diseases, e.g. primary biliary cirrhosis (PBC), nonalcoholic steatohepatitis (NASH) or primary sclerosing cholangitis (PSC).
• PBC primary biliary cirrhosis
• NASH nonalcoholic steatohepatitis
• PSC primary sclerosing cholangitis
• Obeticholic acid was first mentioned in the patent application WO2002072598. ft was isolated via column chromatography, and no physicochemical characterization of the solid form was mentioned here. Two patent applications WO2006122977 and US20090062526 followed, dealing with a synthesis of obeticholic acid.
• Crystalline form A of obeticholic acid was described in patent application WO2016107575. Crystalline forms 1-2 and 1-3 were described in patent application WO2017008773.
• Solid forms I and II of obeticholic acid are also described in patent application CN105777836.
• XRPD X-ray powder diffraction
• NMR solid-state nuclear magnetic resonance
• DSC thermoanalytical techniques
• the subject of the invention comprises crystalline forms of obeticholic acid marked as J-l and J-2.
• the subject of the invention comprises crystalline form J-l of obeticholic acid, showing characteristic reflections in a radiographic (X-ray) powder record using CuKa radiation: 6.3; 9.4; 12.2; 14.4; 16.5 and 19.0 ⁇ 0.2° 2-theta.
• obeticholic acid crystalline form J-l is characterized with the following other reflections in an X-ray powder record: 4.3; 5.1; 7.5; 8.8; 10.3 and 11.8; ⁇ 0.2° 2-theta.
• Another subject of the invention comprises crystalline form J-2 of obeticholic acid, showing characteristic reflections in a (X-ray) powder record using CuKa radiation: 6.3; 8.9; 10.8; 15.8; 16.5; 18.4 and 20.3 ⁇ 0.2° 2-theta.
• obeticholic acid crystalline form J-2 is characterized with the following other reflections in an X-ray powder record: 3.1; 4.1; 12.4 and 18.4 ⁇ 0.2° 2-theta.
• Fig. 1 XRPD record of crystalline form J-l of obeticholic acid
• Fig. 2 DSC record of crystalline form J-l of obeticholic acid
• Fig. 3 XRPD record of crystalline form J-2 of obeticholic acid
• Fig. 4 DSC record of crystalline form J-2 of obeticholic acid
• Form J-l crystallized surprisingly well from methylisobutylketone (MIBK), as well as from a mixture of «-butyl acetate (H-BUOAC) and acetonitrile (MeCN), whereas form J-2 was obtained from acetone and combinations of cyclopentylmethylether (CPME) or isopropyl acetate (i-PrOAc) with cyclohexane.
• MIBK methylisobutylketone
• H-BUOAC «-butyl acetate
• MeCN acetonitrile
• CPME cyclopentylmethylether
• i-PrOAc isopropyl acetate
• X-ray powder record of crystalline form J-1 of obeticholic acid is presented in Figure 1.
• Characteristic diffractions using radiation CuKa are 6.3; 9.4; 12.2; 14.4; 16.5 and 19.0 ⁇ 0.2° 2-theta.
• Form J-1 also shows the following characteristic reflections: 4.3; 5.1; 7.5; 8.8; 10.3 and 11.8; ⁇ 0.2° 2-theta.
• Diffraction peaks with relative intensity higher than 1% are presented in Table 3.
• DSC Differential scanning calorimetry
• X-ray powder record of crystalline form J-2 of obeticholic acid is presented in Figure 3. Characteristic diffractions using radiation CuKa are 6.3; 8.9; 10.8; 15.8; 16.5 and 18.4 ⁇ 20.3° 0.2 2-theta. Form J-2 also shows the following characteristic reflections: 3.1; 4.1; 12.4 and 18.4 ⁇ 0.2° 2-theta. Diffraction peaks with relative intensity higher than 1% are presented in Table 4. Table 4: XRPD - characteristic diffraction peaks of form J-2
• Crystalline form J-1 of obeticholic acid is prepared by dissolving obeticholic acid in a solvent which is methyl isobutyl ketone or a mixture of solvents which are n-butyl acetate and acetonitrile at an increased temperature from 50 °C to the boiling point of the solvent or the mixture of solvents and following cooling of fhe produced solution to a temperature ranging from -10 °C to 40 °C. Crystallized form J-1 is then isolated using known techniques.
• Crystalline form J-2 of obeticholic acid is prepared by dissolving of obeticholic acid in a solvent which is cyclopentyl methyl ether, isopropyl acetate or acetone at an increased temperature from 60 °C to the boiling point of the solvent, or another solvent is added as an antisolvent, e.g. cyclohexane or n-heptane.
• a solvent which is cyclopentyl methyl ether, isopropyl acetate or acetone
• the produced solution is cooled to a temperature ranging from -10 °C to 40 °C. Crystallized form J-2 is then isolated using known techniques.
• the amorphous form of obeticholic acid can be prepared from both forms, J-1 as well as J-2, through a procedure comprising the following steps:
• the crystalline form of obeticholic acid can be advantageously converted in step a/ to ammonium or sodium salt.
• step b/ hydrochloric acid or phosphoric acid is advantageously added.
• Crystalline forms of obeticholic acid J-1 and J-2 according to the submitted invention can be used for preparation of obeticholic acid with chemical purity higher than 99.80% according to HPLC (High Performance Liquid Chromatography). Crystalline forms of obeticholic acid J-l and 3-2 according to the submitted invention can be subsequently used for preparation of a pharmaceutical composition.
• Another subject of the invention is a pharmaceutical composition containing crystalline form J-l or crystalline form J-2 of obeticholic acid and at least one pharmaceutically acceptable excipient.
• at least one pharmaceutically acceptable excipient is selected out of the group including lactose, microcrystalline cellulose, carboxymethyl starch sodium salt and magnesium stearate.
• the pharmaceutical composition is in the form of tablet.
• Obeticholic acid (1.5 g) was dissolved while boiling in methyl isobutyl ketone (10 ml), and the produced solution, while being stirred, was gradually cooled to a laboratory temperature of approx. 23 °C. Suspension was then stirred at that temperature for 24 hours. The crystalline product was isolated through filtration and dried via sucking of air on a frit for 24 hours. 0.75 g (50% yield) of crystalline form J-l of obeticholic acid was obhtained. XRPD in Fig. 1, melting point 92.5 °C, content of methyl isobutyl ketone 8.0% (determined by gas chromatography (GC)).
• GC gas chromatography
• Obeticholic acid (0.227 g) was dissolved while boiling in acetone (0.6 ml), and the produced solution, while being stirred, was gradually cooled to a laboratory temperature of approx. 23 °C. Thick suspension was then stirred at that temperature for 24 hours. The crystalline product was isolated through filtration and dried via sucking of air on a frit for 24 hours. 0.124 g (55% yield) of crystalline form J-2 was obtained.
• Obeticholic acid (1.67 g) was, while boiling, dissolved in cyclopentyl methyl ether (10 ml), cooled to approx. 80 C, then cyclohexane was slowly added (10 ml) while the mixture was stirred. The produced solution was gradually cooled to the laboratory temperature of approx. 23 °C and the suspension was stirred at this temperature for 22 hours. The crystalline product was isolated through filtration and dried via sucking of air on a frit. 1.29 g of crystalline form J-2 of obeticholic acid was obtained (yield 77%). XRPD in Fig. 3, melting point 78.6 °C, content of cyclopentyl methylether 5.56%, cyclohexane 3.8% (GC).
• Obeticholic acid (1.5 g) was, while boiling, dissolved in isopropyl acetate (5 ml), then cyclohexane was slowly added (10 ml) while the mixture was stirred. The produced solution was gradually cooled to the laboratory temperature of approx. 23 °C and the suspension was stirred at this temperature for 22 hours. The crystalline product was isolated through filtration and dried via sucking of air on a frit for 24 hours, and then in a vacuum drier at 50 °C/180 mbar for 3 days. 1.24 g (83% yield) of crystalline form J-2 of obeticholic acid was obtained. Content of isopropyl acetate 0.05%, cyclohexane 3.3% (GC).
• Obeticholic acid (300 mg, HPLC 95.83%) was dissolved at 80 °C in methyl isobutyl ketone (0.5 ml), and the solution, while being stirred and slightly cooled to a temperature of approx. 60 °C, was inoculated with crystals of form J-l (approx. 5 mg) and left stirred to cool to a laboratory temperature of approx. 23 °C. Suspension was then stirred at that temperature for 16 hours. The crystalline product was isolated through filtration and dried via sucking of air on a frit for 2 hours, and then in a vacuum drier at 40 °C/200 mbar for 16 hours. Crystalline form J-l of obeticholic acid was obtained (246 mg, yield 82%) of HPLC purity 99.38%. XRPD in Fig. 1 , content of methyl isobutyl ketone 8.5% (GC).
• Obeticholic acid (30 g, HPLC 99.54%, content of chenoxydeoxycholic acid 0.32%) was dissolved at 53 °C in a mixture of butyl acetate (45 ml) and acetonitrile (45 ml), and the solution was stirred at that temperature for 30 minutes. Then the solution was cooled to the temperature of 40 °C and stirred at that temperature for 1 hour. The produced suspension was then cooled slowly along 5 hours to the temperature of -10 °C, ant at that temperature it was stirred for 16 hours. The crystalline product was isolated through filtration and the obtained white crystals were dried in a vacuum drier at 40 °C/200 mbar for 16 hours. Crystalline form J-1 of obeticholic acid (27.35 g, yield 91.2%) of HPLC purity 99.74%, content of chenoxydeoxycholic acid 0.17%.
• Obeticholic acid (form J-1, 3.0 g; 7.14 mmol; HPLC 99.48%) was stirred up in demineralized water (60 ml) and the suspension was heated to 40 °C. At that temperature, 25% aqueous solution of ammonium hydroxide (1.35 ml) was added and the produced solution was stirred for 40 minutes and filtered. The solution was cooled to a temperature of 5 °C and at that temperature diluted phosphoric acid was dripped in during 30 minutes (1 ml of 85% of phosphoric acid + 1.5 ml of demineralized water). The suspension was stirred for 2 hours while being cooled, than it was filtered and washed through with water (approx. 60 ml).
• amorphous obeticholic acid was dried for 16 hours in a vacuum drier at 40 °C/180 mbar.
• Amorphous obeticholic acid was obtained (2.874 g, yield 95.8%)of HPLC purity 99.91%, content of methyl isobutyl ketone 790 ppm (GC), content of water 4%.
• Mobile phase A 1.0 ml of 70% wt perchloric acid dissolved in 1000 ml of water
• mobile phase B acetonitrile, linear gradient according to the table below, flow-rate 0.7 ml/min,
• Residual solvents were determined through gas chromatography (GC) according to the method Ph. Eur. 2.2.28.

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• 2017
  • 2017-09-05 CZ CZ2017-34072U patent/CZ31099U1/cs not_active IP Right Cessation
• 2018
  • 2018-08-31 WO PCT/CZ2018/000040 patent/WO2019047989A2/en not_active Ceased

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