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Method for preparing crystalline form I of clopidogrel bisulfate

A technology of clopidogrel hydrogen sulfate and crystal form, applied in the field of pharmaceutical preparation, can solve the problems of low efficiency, large amount of solvent consumption, long time consumption and the like

Active Publication Date: 2013-11-27
ZHEJIANG APELOA JIAYUAN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method consumes a large amount of solvent, takes a long time and has low efficiency

Method used

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  • Method for preparing crystalline form I of clopidogrel bisulfate
  • Method for preparing crystalline form I of clopidogrel bisulfate
  • Method for preparing crystalline form I of clopidogrel bisulfate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Weigh 0.8g of clopidogrel bisulfate crystal form mixture into a flask, add 1ml of methanol dropwise, shake to dissolve, and add the mixture dropwise to the mixed solution of 0.2ml of acetic acid and 2ml of methyl tert-butyl ether at -18°C , centrifuge after stirring evenly, set the centrifugation speed to 9500rpm, and the time is 4 minutes; add 5ml of methyl tert-butyl ether to the centrifuged product for washing; then suction filter and dry to obtain a white powder. Detected by X-ray diffractometer, the product is clopidogrel bisulfate crystal form I, such as figure 1 shown. The calculated yield was 85%.

Embodiment 2

[0035] Weigh 1g of clopidogrel bisulfate crystal form mixture in a flask, add dropwise 1.5ml of methanol, shake to dissolve and add the mixture dropwise to the mixed solution of 0.3ml formic acid and 3ml methyl tert-butyl ether at 0°C , centrifuged after stirring evenly, set the centrifugal speed to 8500rpm, and the time was 5 minutes; the centrifuged product was washed with 6ml methyl tert-butyl ether; then suction filtered and dried to obtain a white powder, the calculated yield was 82%. The product has a melting point of 185.0°C tested by a differential scanning calorimeter, and the results are shown in figure 2 .

Embodiment 3

[0037] Weigh 1g of clopidogrel bisulfate crystal form mixture in a flask, add 1ml of methanol dropwise, shake to dissolve, and add the mixed solution dropwise to the mixed solution of 0.5ml propionic acid and 1.5ml methyl tert-butyl ether at 0°C , centrifuge after stirring evenly, set the centrifugation speed to 12000rpm, and the time is 4 minutes; add 7ml of methyl tert-butyl ether to the centrifuged product for washing; then suction filter and dry to obtain a white powder. The product was detected by X-ray diffractometer, and the product was crystal form I of clopidogrel hydrogen sulfate. The morphology was observed by scanning electron microscope, and it was an agglomerate of tetragonal crystals with a particle size of about 100 microns. The calculated yield was 88%.

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Abstract

The invention provides a method for preparing a crystalline form I of clopidogrel bisulfate. The method is characterized by comprising a step of dissolving raw materials of a clopidogrel bisulfate crystal form product into an organic solvent methanol or ethanol; a step of adding, in a temperature range of -30 DEG C to 30 DEG C, the dissolved and clarified solution into a mixed solution of an acid and an anti-solvent; a step of stirring uniformly and centrifuging for 3-60 min; and a step of drying the centrifugation product, after the centrifugation product is washed with the anti-solvent, to obtain the stable crystalline form I powder of the clopidogrel bisulfate. The product of the method is an aggregation of tetragonal-structured crystals, and has good stability. The method has simple operation, suitability for industrial production, capability of environmental protection, high product purity and high yield.

Description

technical field [0001] The invention belongs to the field of medicine preparation, in particular to a new method for preparing clopidogrel bisulfate crystal form I. Background technique [0002] Clopidogrel bisulfate (Clopidogrel Bisulfate), as a new type of highly effective anti-platelet drug, has the following structural formula: [0003] [0004] There are many crystal forms of clopidogrel hydrogen sulfate, because the thermodynamic stability of clopidogrel hydrogen sulfate crystal form I is worse than that of crystal form II, so the clopidogrel hydrogen sulfate crystal form I partly transforms after a long period of time, resulting in chlorine hydrogen sulfate The crystal form of pidogrel is impure, which has a certain impact on the stability of the preparation. Therefore, the development of a new preparation method for crystal form I and the synthesis of stable crystal form I products have good application value. [0005] U.S. Patent US7772398B2 discloses a kind of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04
Inventor 张国庆敖桔皋海涛吴朝刚汪金涛靳小舜
Owner ZHEJIANG APELOA JIAYUAN PHARMA
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