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Spherical clopidogrel hydrogen sulfate II crystal form and preparation method thereof

A technology of clopidogrel hydrogen sulfate and crystal form, applied in the field of spherical clopidogrel hydrogen sulfate II crystal form and preparation, can solve problems such as sticking and flushing, and achieve the effects of simple process flow, uniform particle size and fast separation speed

Inactive Publication Date: 2018-12-28
TIANJIN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In order to overcome the defects of existing products and fill the technical gap, the invention provides a method for changing the crystal form of clopidogrel hydrogen sulfate II crystal form, and prepares the crystal product of spherical clopidogrel hydrogen sulfate II crystal form, which solves the problem Product sticking problems caused by static electricity and viscosity

Method used

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  • Spherical clopidogrel hydrogen sulfate II crystal form and preparation method thereof
  • Spherical clopidogrel hydrogen sulfate II crystal form and preparation method thereof
  • Spherical clopidogrel hydrogen sulfate II crystal form and preparation method thereof

Examples

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Effect test

Embodiment 1

[0020] Step (1), dissolve 10g of clopidogrel free base in 100ml of acetone, set the temperature to -20°C, add 62ml of a mixed solvent of sulfuric acid with a sulfuric acid concentration of 0.5mol / L sulfuric acid-acetone, that is, add sulfuric acid and clopidogrel free base The molar ratio of alkali is about 1:1, and the rate of addition is 0.5% / min;

[0021] In step (2), keep the temperature, continue to stir until the crystals emerge, and keep stirring for 10 hours to make the crystals coalesce into compact spheres;

[0022] Step (3), filtering, washing, and drying to obtain clopidogrel bisulfate II crystalline spherical crystals.

[0023] The XRD pattern of the product is shown in figure 1 , it can be seen that the product is a stable pure II crystal form; the particle size distribution comparison between spherical particles and ordinary products is shown in figure 2 , it can be seen that the main particle size of the product is increased from 20 microns to 100 microns, a...

Embodiment 2

[0025] Step (1), dissolve 10g of clopidogrel free base in 200ml of acetone, set the temperature to 0°C, add 37ml of a mixed solvent of sulfuric acid-acetone with a sulfuric acid concentration of 1.0mol / L, that is, add sulfuric acid and clopidogrel free base The molar ratio is about 1.2:1, and the dropping rate is 2.5% / min;

[0026] In step (2), keep the temperature, continue to stir until the crystals emerge, and keep stirring for 6 hours to make the crystals coalesce into compact spheres;

[0027] Step (3), filtering, washing, and drying to obtain clopidogrel bisulfate II crystalline spherical crystals.

[0028] The XRD pattern of the product is shown in figure 1 , it can be seen that the product is a stable pure II crystal form; the main particle size is 93 microns; the product is smooth spherical, and the circularity is 0.862.

Embodiment 3

[0030] Step (1), dissolve 10g of clopidogrel free base in 350ml of butanone, set the temperature to 20°C, add 33ml of sulfuric acid-butanone mixed solvent with a sulfuric acid concentration of 1.5mol / L, that is, add sulfuric acid and clopidogrel The molar ratio of Gray free base is about 1.6:1, and the dropping rate is 4.0% / min;

[0031] In step (2), keep the temperature, continue to stir until the crystals emerge, and keep stirring for 3 hours to make the crystals coalesce into a compact sphere;

[0032] Step (3), filtering, washing, and drying to obtain clopidogrel bisulfate II crystalline spherical crystals.

[0033] The XRD pattern of the product is shown in figure 1 , it can be seen that the product is a stable pure II crystal form; the main particle size is 105 microns; the product is smooth spherical, and the circularity is 0.926.

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Abstract

The invention discloses a spherical clopidogrel hydrogen sulfate II crystal form and a preparation method thereof. The method includes dissolving clopidogrel free base in a ketone solvent to obtain afree alkali solution with the concentration of 0.02-0.1 g / mL, setting the temperature to be -20-40 DEG C, adding a mixed solvent of sulfuric acid and ketone, wherein the molar ratio of the sulfuric acid to the clopidogrel free base is 1-1.8:1; maintaining the temperature, continue stirring until the crystal is formed, stirring for 1-10 hours to form the crystal into a compact sphere; conducting filtration, washing and drying to obtain a clopidogrel hydrogen sulfate II crystal form spherical crystals. The spherical crystals have the primary particle diameter of 20-300 micrometers, are mellow and full, have no static electricity, are low in viscosity, have no sticking problem, and can be directly pressed by eliminating the granulating process and the drying process after granulation. No additional additive is required to control the crystal size and form. No need to add seed crystal exists, the process links are reduced, and the implementation of commercial and industrial scale is facilitated.

Description

technical field [0001] The invention belongs to the technical field of crystallization in the chemical engineering industry, and in particular relates to a spherical clopidogrel bisulfate II crystal form and a preparation method thereof. Background technique [0002] Clopidogrel hydrogen sulfate (CAS: 135046-48-9), English name clopidogrel hydrogen sulfate), chemical name: (S)α-(2-chlorophenyl)-6,7-dihydrothieno[3, 2-c]pyridine-5(4H)acetate methyl bisulfate, the chemical formula is C 16 h 16 ClNO 2 SH 2 SO 4 , usually white or off-white crystal, odorless, soluble in water, methanol, ethanol, etc., very slightly soluble in acetone, ethyl acetate, chloroform, specific rotation is +52° to +56°. Clopidogrel bisulfate is a platelet inhibitor, which selectively inhibits the binding of ADP to platelet receptors, and then inhibits the activation of ADP and glycoprotein GPⅡb / Ⅲa complex, thereby inhibiting platelet aggregation. Clopidogrel has strong curative effect , low cost, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04
CPCC07B2200/07C07B2200/13C07D495/04
Inventor 龚俊波陈明洋王琦侯宝红
Owner TIANJIN UNIV