Alpha crystal form of obeticholic acid as well as preparation method, medicine composition and application thereof

A technology of obeticholic acid and crystal form, which is applied in the field of α crystal form of obeticholic acid and its preparation, can solve problems such as low melting temperature, unsuitability, and potential safety hazards, and achieve simple process operation and good stability , low-cost effect

Inactive Publication Date: 2016-08-17
SICHUAN RUIXIKANG BIOLOGICAL MEDICINE CO LTD
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

However, the above crystal forms lose both crystal water and solvent when heated, and are not suitable for further drug development due to their low melting temperature and high solvent content
However, although crystalline forms G and F have higher melting points and may have application prospects, crystalline form G cannot be scaled up and reproduced. The recrystallization process of crystalline form F uses relatively toxic nitromethane, and the industry There are potential safety hazards in the chemicalization process, so Form F is not suitable for drug development
[0005] The crystal form I of obeticholic acid disclosed in CN104781272A is actually a non-crystalline form, and the water content of six different batches of the crystal form I of obeticholic acid disclosed by it ranges from 0.6% to 1.7%, and the water content of the products varies. Stable, the obeticholic acid crystal form I prepared by this process is inconvenient to measure when the preparation is fed as raw material

Method used

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  • Alpha crystal form of obeticholic acid as well as preparation method, medicine composition and application thereof
  • Alpha crystal form of obeticholic acid as well as preparation method, medicine composition and application thereof
  • Alpha crystal form of obeticholic acid as well as preparation method, medicine composition and application thereof

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Experimental program
Comparison scheme
Effect test

preparation example Construction

[0064] Preparation of α-crystal form of obeticholic acid

[0065] Testing instruments and methods:

[0066] X-ray powder diffraction (XRPD)

[0067] Instrument: DX-2700B X-ray diffractometer

[0068] Sample preparation: Use the original sample for detection, that is, without grinding the sample, directly take about 50 mg of sample and gently flatten it on a glass slide to obtain a flat surface.

[0069] Sample determination: put the sample into a sample holder for X-ray powder diffraction determination, use a DX-2700B X-ray diffractometer equipped with Cu-Kα radiation (α=1.54059nm), and the effective 2θ range is 5° -50°, the step angle is 0.03 seconds (0.01-0.03), the software used to collect data is X-ray diffractometer 2.1 software, and MDJJade9.0 analysis software is used to present the data.

[0070] Differential thermal-thermogravimetric analysis

[0071] Equipment: Japan Shimadzu DTG-60(H)

[0072] TGA (Thermogravimetric Analysis) data was collected on a Mettler TGA...

Embodiment 1

[0076] Add 10g of obeticholic acid and 120ml of toluene into a three-necked reaction flask with a reflux condenser, heat to reflux with stirring, stop heating after obeticholic acid is completely dissolved, and lower the crystallization system to 60°C within half an hour while stirring. ℃. After the crystallization system was stably lowered to 60° C., the crystallization system was lowered to room temperature within half an hour under stirring. Then, the temperature of the crystallization system was lowered to 0° C. under stirring, and the crystallization was stirred at 0° C. for 12 hours. After filtering and washing with 5 ml of toluene, the obtained crystals were placed in an oven at 70° C. and dried under normal pressure for 12 hours to obtain 9.3 g of fine needle crystals, yield: 93%. mp: 106.0-108.0°C; HPLC purity: 99.83%; water content (Karl Fischer method): 0.92%.

Embodiment 2

[0078] Add 10g of obeticholic acid and 150ml of toluene to a three-neck reaction flask with a reflux condenser, heat to reflux under stirring, after obeticholic acid is completely dissolved, add 0.3g of activated carbon, decolorize under reflux for 30 minutes, filter, Collect the filtrate. The filtrate was transferred to a three-port reaction and continued heating to reflux. Make sure that the solution heated to reflux is completely clear, stop heating and stir. The crystallization system was naturally lowered to room temperature, and after crystallization at room temperature for 6 hours, it was frozen and crystallized at -5°C for 10 hours. After suction filtration and washing with 5 ml of toluene, the obtained crystals were placed in an oven at 60° C., dried under reduced pressure at 150 mmHg for 8 hours, and then 9.0 g of fine needle crystals were obtained. Yield: 90%. mp: 107.0-108.0°C; HPLC purity: 99.66%; water content (Karl Fischer method): 0.78%.

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Abstract

The invention relates to an alpha crystal form of obeticholic acid and a preparation method thereof. The preparation method comprises the following steps: (a) fully dissolving obeticholic acid under a backflow state in a mixed solvent of toluene or toluene and another kind of solvent forming a homogeneous system; (b) cooling the obtained obeticholic acid solution, so the alpha crystal form of the obeticholic acid precipitates out from the solution; (c) separating the alpha crystal form of the obeticholic acid out from the solution; and (d) placing the alpha crystal form of the obeticholic acid under 30-70 DEG C and drying for 3-30 hours at reduced pressure or ordinary pressure. The prepared alpha crystal form of obeticholic acid has the characteristics of better stability, higher purity, stable moisture content and the like. Furthermore, the invention also relates to a medicine composition of the alpha crystal form and the application of the alpha crystal form in preparing medicines for treating hepatic diseases such as biliary atresia, cholestatic liver disease, chronic liver disease, primary biliary cirrhosis, alcoholic fatty liver, non-alcoholic fatty liver disease and the like.

Description

field of invention [0001] The present invention relates to an α-crystal form of obeticholic acid and a preparation method thereof, and its preparation method for treating biliary atresia, cholestatic liver disease, chronic liver disease, primary biliary cirrhosis, alcoholic fatty liver, non-alcoholic Application in liver disease drugs such as chronic fatty liver disease. In addition, the present invention also provides a pharmaceutical composition containing this specific crystal form of obeticholic acid. Background of the invention [0002] The chemical name of obeticholic acid (Ⅰ) is: 3α, 7α-dihydroxy-6α-ethyl-5β-cholan-24 acid, also known as: 6α-ethylchenodeoxycholic acid. The CAS registration number of obeticholic acid is: 459789-99-2. Obeticholic acid is a farnesoid X receptor agonist, which indirectly inhibits the gene expression of cytochrome 7A1 (CYP7A1) by activating farnesoid X receptor. Since CYP7A1 is the rate-limiting enzyme of bile acid biosynthesis, obetich...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J9/00A61K31/575A61P1/16
CPCC07B2200/13C07J9/005
Inventor 王娜蔡泽贵
Owner SICHUAN RUIXIKANG BIOLOGICAL MEDICINE CO LTD
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