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Crystal form A brexpiprazole hydrochloride and preparation method thereof

A technology of epirazole and hydrochloride, applied in the field of medicine, can solve the problems of cumbersome preparation process of epirazole dihydrate, low solubility of epirazole anhydrous, etc., and achieves strong operability and solubility. Good properties and stable crystal form

Inactive Publication Date: 2015-08-12
HANGZHOU XINBOSI BIOMEDICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The patented Epirazole anhydrous has low solubility, and the preparation process of Epirazole Dihydrate is relatively cumbersome
There is no report of any epizole hydrochloride crystal form at present

Method used

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  • Crystal form A brexpiprazole hydrochloride and preparation method thereof
  • Crystal form A brexpiprazole hydrochloride and preparation method thereof
  • Crystal form A brexpiprazole hydrochloride and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] In a 250ml three-necked flask, add 7.1g of the epizole solid, add the mixture of 160ml of ethanol and 10ml of acetic acid, and heat to reflux and stir. After all the solids were dissolved, concentrated hydrochloric acid was added dropwise until the pH was 2-3. After the dropwise addition, the temperature was naturally lowered to the temperature in the system ≤ 20°C. Filter to obtain a white filter cake. Blast-dried at 70°C to obtain 7.6 g of crystalline form A epirazole hydrochloride with a molar yield of 95%. Determination of its XRPD, DSC and DSC-TGA, its spectra are as follows Figure 1-Figure 3 shown.

Embodiment 2

[0030] In the 3L four-neck flask, add 90g of the epizole solid, add the mixture of 2050ml of ethanol and 150ml of acetic acid, and heat to reflux and stir. After all the solids were dissolved, concentrated hydrochloric acid was added dropwise until the pH was 2-3. After the dropwise addition, the temperature was naturally lowered to the temperature in the system ≤ 20°C. Filter to obtain a white filter cake. Blow drying at 70°C to obtain 96 g of crystalline form A epirazole hydrochloride with a molar yield of 95%.

[0031] The chemical formula of the crystal form A epizopine hydrochloride obtained in Examples 1 and 2 is: , and compared it with the solubility of epirazole anhydrate, the results showed that: at 37°C, the saturated solubility of epirazole anhydrate in an aqueous solution with a pH value of 4.5 was 0.1 mg / ml; crystal form A Epirazole hydrochloride has a saturated solubility of 0.6 mg / ml in an aqueous solution with a pH value of 4.5. The type A crystalline e...

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Abstract

The invention relates to a crystal form A brexpiprazole hydrochloride shown in the formula (I) and a preparation method thereof. The crystal form A brexpiprazole hydrochloride is a monohydrate of brexpiprazole hydrochlorides and the powder x-ray diffraction pattern of the crystal form A brexpiprazole hydrochloride has characteristic peaks at least at the angle 2 theta of 9.2 degrees+ / -0.2 degree, 16.0 degrees+ / -0.2 degree, 17.6 degrees+ / -0.2 degree, 20.2 degrees+ / -0.2 degree, 23.8 degrees+ / -0.2 degree and 25.1 degrees+ / -0.2 degree. The preparation method comprises the following steps: (1) adding solid brexpiprazole into a mixes solvent of alcohol and organic carboxylic acid and heating for dissolving the solid brexpiprazole; (2) adjusting concentrated hydrochloric acid to adjust pH to 2-4 and cooling for crystallizing; and (3) filtering and separating the solid obtained in the step (2) and drying to obtain the crystal form A brexpiprazole hydrochloride. The crystal form A brexpiprazole hydrochloride has good solubleness and is beneficial to medicine absorption and the preparation process is simple and safe. (The formula (I) is shown in the specification).

Description

technical field [0001] The invention relates to crystal form A epirazole hydrochloride and a method for preparing crystal form epirazole hydrochloride, belonging to the technical field of medicine. technical background [0002] Brexpiprazole, jointly developed by Lundbeck Pharmaceuticals and Otsuka Pharmaceuticals, is a serotonin-dopamine activity modulator (SDAM) for the adjuvant treatment of schizophrenia and major depression. [0003] On July 14, 2014, Lundbeck Pharmaceuticals of Denmark and Otsuka Pharmaceuticals of Japan submitted a new drug application (NDA) for epizopa to the US Food and Drug Administration (FDA). In terms of schizophrenia, the efficacy of epizopa is comparable to that of aripiprazole, but it is more superior in improving negative symptoms, cognitive function and depression. [0004] Ipizopa has unique pharmacological targeting, is effective for the treatment of a wide range of mental disorders, and is safe and well tolerated. Compared with the tra...

Claims

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Application Information

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IPC IPC(8): C07D409/12A61P25/28A61P25/18
CPCC07D409/12
Inventor 杜焕达叶鑫杰王振宇丁建圣陈宇王万青刘艳华韩璐
Owner HANGZHOU XINBOSI BIOMEDICAL CO LTD
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