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Pharmaceutical composition containing spherical clopidogrel bisulfate I crystal form and preparation method of pharmaceutical composition

A technology of clopidogrel bisulfate and clopidogrel free base, which is applied in the direction of drug combinations, medical preparations containing active ingredients, and pharmaceutical formulas, and can solve problems such as darkening of crystal color, crystal transformation, and affecting crystal quality

Active Publication Date: 2015-11-04
SHENZHEN SALUBRIS PHARMA CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, one of the key technical factors of this process is that the sulfuric acid-cyclohexane solution needs to be slowly added to the solvent system under cooling conditions. Since the concentrated sulfuric acid and cyclohexane are not miscible, it is easy to cause partial localization of the system during the addition of the solvent system. If the concentration of sulfuric acid is too high, the color of the obtained crystals will become darker, which will affect the quality of the crystals; in addition, due to the long time required for the process, the excessively long reaction time on the one hand has the risk of crystal transformation; Irregular growth and reduced crystal bulk density
The above technical defects lead to darker color of the obtained preparation, and because the crystal bulk density is too low, it is still impossible to avoid the phenomenon of sticking

Method used

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  • Pharmaceutical composition containing spherical clopidogrel bisulfate I crystal form and preparation method of pharmaceutical composition
  • Pharmaceutical composition containing spherical clopidogrel bisulfate I crystal form and preparation method of pharmaceutical composition
  • Pharmaceutical composition containing spherical clopidogrel bisulfate I crystal form and preparation method of pharmaceutical composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Take 760g of clopidogrel bisulfate (purity greater than 99.0%) and disperse it in a mixture of 10L of dichloromethane and 5L of water, and add solid sodium bicarbonate until the pH of the aqueous phase>7. Stand still for liquid separation, take the organic phase and wash with water (1L×2), and remove water with anhydrous magnesium sulfate until the solution is clear.

[0045] The organic phase was filtered and vacuum rotary evaporated until the quality did not change, the residue was dissolved in 10.5 L of 2-butanol, and the solution was kept at 25°C. Disperse 100 mL of concentrated sulfuric acid (181 g) in 2.5 L of 2-butanol and add it to the system within 1 hour, and disperse 10 g of Form I seed crystals in 1 L of 2-butanol and pour them in together. Keep warm at 25°C for 2.5h, cool down to 15°C and keep warm for 4h, filter with suction, wash the filter cake with ethyl acetate, and dry in vacuum at 40°C for 1.0h to obtain 610g of product (2-butanol residue <0.2%).

...

Embodiment 2

[0048] Take 760g of clopidogrel bisulfate (purity greater than 99.0%) and disperse it in a mixture of 10L of dichloromethane and 5L of water, and add solid sodium bicarbonate until the pH of the aqueous phase>7. Stand still for liquid separation, take the organic phase and wash with water (1L×2), and remove water with anhydrous magnesium sulfate until the solution is clear.

[0049] The organic phase was filtered and vacuum rotary evaporated until the quality did not change, the residue was dissolved in 10.5 L of 2-butanol, and the solution was kept at 25°C. Disperse 100 mL of concentrated sulfuric acid (181 g) in 2.5 L of 2-butanol and add it to the system within 1 hour, and disperse 10 g of Form I seed crystals in 1 L of 2-butanol and pour them in together. Keep warm at 25°C for 2.5h, cool down to 15°C and keep warm for 2h, filter with suction, wash the filter cake with ethyl acetate, and dry in vacuum at 40°C for 1.0h to obtain 560g of product (2-butanol residue <0.2%).

Embodiment 3

[0055] Adopt Malvern-3000 particle size analyzer to detect the morphology of the spherical clopidogrel bisulfate I crystal form obtained in Examples 1 to 2 and Comparative Example 1, use the graduated cylinder method to detect the bulk density, and adopt the graduated cylinder knocking method to vibrate The density is tested (from Ph.Eur 2.9.34Bulk density and Tapped density), and the test results are shown in the table below:

[0056] Example

D50(μm)

D90(μm)

Bulk density (g / mL)

Tap density (g / mL)

Example 1

78.67

109.10

0.78

0.86

Example 2

73.18

114.06

0.73

0.82

Comparative Example 1

77.41

117.61

0.62

0.72

[0057] As can be seen from the table above, the particle size of the powders in Examples 1, 2 and Comparative Example 1 is similar, but because the crystallization time of Comparative Example 1 is too long, the spherical crystals are covered by tiny burrs, showing bulk densi...

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Abstract

The invention provides pharmaceutical composition containing spherical clopidogrel bisulfate I crystal form and a preparation method of the pharmaceutical composition. Direct powder compressing can be achieved favorably by the powder property of the pharmaceutical composition, and sticking during tablet compressing is avoided. The invention further provides a clopidogrel bisulfate tablet using direct powder compressing and a preparation method of the tablet. The tablet meets the requirements of clinical medication.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, in particular, the invention relates to a pharmaceutical composition containing spherical clopidogrel bisulfate I crystal form and a preparation method thereof. Background technique [0002] Clopidogrel hydrogen sulfate (CAS: 135046-48-9), is the sulfate salt of clopidogrel, English name Clopidogrel Hydrogen Sulfate, chemical name: (s)-α-(2-chlorophenyl)-6,7 - Methyl dihydrothieno[3,2-c]pyridine-5(4H)acetate hydrogensulfate. Clopidogrel bisulfate is an antiplatelet agent. The product was developed by the French pharmaceutical company Sanofi-Aventis and was first launched in the UK and the US in 1998. Clopidogrel bisulfate entered China in 2001 and is clinically used to prevent atherosclerotic thrombosis events . At present, domestic clopidogrel bisulfate preparation products mainly include Plavix of Sanofi-Aventis and Taijia of Shenzhen Xinlitai Pharmaceutical Co., Ltd. [0003] ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4365A61K9/20A61K9/36A61K9/28A61P7/02C07D495/04
Inventor 徐文进王平
Owner SHENZHEN SALUBRIS PHARMA CO LTD
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