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Obeticholic acid crystal form I, preparation method, pharmaceutical composition, and application thereof

A technology of obeticholic acid and crystal form, which is applied in the field of medicinal chemical crystallization, can solve the problems of polluted environment and poor stability, and achieves the effects of simple steps, good stability and easy operation.

Active Publication Date: 2015-12-23
LIVZON PHARM GRP INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Patent document WO2013192097A1 discloses crystalline form 1 (amorphous), crystalline form A, crystalline form C, crystalline form D, crystalline form F and crystalline form G of obeticholic acid, wherein crystalline forms A, C, and D are mixed types containing water and a certain range of organic solvents The crystal form of hydrate / solvate, the above-mentioned crystal form still has the problem of poor stability, and solvents such as nitromethane and acetonitrile are used in the preparation process of crystal form F and G, polluting the environment

Method used

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  • Obeticholic acid crystal form I, preparation method, pharmaceutical composition, and application thereof
  • Obeticholic acid crystal form I, preparation method, pharmaceutical composition, and application thereof
  • Obeticholic acid crystal form I, preparation method, pharmaceutical composition, and application thereof

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Experimental program
Comparison scheme
Effect test

preparation example 1

[0056] Obeticholic acid Form C was prepared according to Example 1, Reaction 6 of the patent document WO2013192097A1, and the specific operations were as follows:

[0057] 3α-Hydroxy-6α-ethyl-7-keto-5β-cholan-24-oic acid (86 g, 205.4 mmol), water (688 mL) and 50% (w / w) sodium hydroxide solution (56.4 mL) The mixture of was reacted with sodium borohydride (7.77 g, 205.4 mmol) in a mixture of 50% (w / w) sodium hydroxide solution (1.5 mL) and water (20 mL) at 90°C to 105°C. Heating to reflux under stirring for at least 3 hours, after the reaction, the reaction solution was cooled to 80°C. A mixture of citric acid (320.2 g, anhydrous), n-butyl acetate (860 mL) and water (491 mL) was added at 30° C. to 50° C. to ensure an acidic pH, and the aqueous phase was separated. The organic phase was distilled, and the distilled residue was diluted with n-butyl acetate, cooled slowly to 15°C to 20°C, and centrifugally filtered. The crude product was crystallized from n-butyl acetate. Obeti...

Embodiment 1

[0060] Take 50 mg of obeticholic acid form C, add 1 mL of n-butyl acetate to dissolve, and evaporate to dryness at 50°C to obtain obeticholic acid crystal form I.

[0061] The XRPD pattern of crystal form I is as follows figure 2 shown. Appears as crystalline material.

[0062] The DSC spectrum of crystal form I is as follows image 3 shown. It shows a melting point of 77°C.

[0063] The TGA spectrum of crystal form I is as follows Figure 4 shown. It showed 7.07% weight loss before 100°C and 11.79% weight loss before 150°C.

[0064] The DVS spectrum and isotherm adsorption curve of crystal form I are as follows: Figure 5 and Image 6 shown. It shows that the weight change is 0.57% in the range of 20%-80% relative humidity, and the weight change is 0.69% in the whole process.

[0065] The infrared spectrum of crystal form I is as follows Figure 7 shown. Display: at wave numbers of 2930, 1707, 1450, 1364, 1262, 1242, 1161, 1121, 1062, 1045, 973, 954 and 808cm -1 ...

Embodiment 2

[0067] Take 50 mg of obeticholic acid form C, add 0.25 mL of n-butyl acetate to dissolve, and volatilize at room temperature to obtain obeticholic acid crystal form I single crystal.

[0068] The single crystal unit cell parameters are shown in Table 1.

[0069] Table 1 Single Crystal Unit Cell Parameters of Form I

[0070]

[0071]

[0072] In Table 1, a, b, c represent the unit cell axis length, α, β, γ represent the dihedral angle, Z represents the number of molecules in each unit cell, V represents the unit cell volume, D calc represents the unit cell density.

[0073] Single crystal analysis related parameters: residual factor R1=0.0568, weighted R value wR2=0.1453, goodness of fit GooF(S)=0.917. The R1 value is less than 0.06, the wR2 value is less than 0.15, and the S value is close to 1, indicating that the single crystal data is reasonable.

[0074] The results proved that the crystal form I was composed of obeticholic acid molecules and was an anhydrous subs...

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Abstract

The invention relates to obeticholic acid crystal form I, which is represented in the description, and a preparation method. The preparation method comprises the following steps: dissolving obeticholic acid in an organic solvent to form a solution, wherein the organic solvent is halogenated alkane or ester, and volatilizing the solution until all solvent is completely volatilized so as to obtain the obeticholic acid crystal form I. Compared with the known solid forms of obeticholic acid, the novel crystal form is more stable and is more suitable for being applied to industrial production. The invention also relates to a pharmaceutical composition of the novel crystal form and an application thereof in the preparation of drugs for treating and / or preventing FXR mediated impaired adjustment, cardiovascular disease, cholestatic liver disease, high HDL cholesterol, high triglyceride, and fibrosis diseases.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemical crystallization. Specifically, it relates to a crystal form I of obeticholic acid, and also relates to a preparation method of the crystal form I, a pharmaceutical composition and an application thereof. Background technique [0002] Obeticholic acid, a potent farnesoid X receptor agonist, plays a role in regulating bile acid levels. Animal experiments have demonstrated its effect on improving insulin resistance (IR) and reducing liver fat content. Late-stage clinical trials have shown that obeticholic acid can significantly improve the signs of a rare liver disease that mainly occurs in middle-aged women, reduce the need for liver transplantation and the risk of death in patients, and it is also used to treat non-alcoholic Steatohepatitis. [0003] Obeticholic acid is a chenodeoxycholic acid derivative, its chemical name is 6-ethylchenodeoxycholic acid, its English name is Obetichol...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J9/00A61K31/575A61P9/00A61P1/16A61P3/06A61P9/10A61P31/14
Inventor 周月广李光州黄滔罗清锋马小玲汪华吴起娟王秀杰
Owner LIVZON PHARM GRP INC
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