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Polymorphs of clopidogrel hydrogensulfate

A technology of clopidogrel bisulfate and map, applied in the polymorphic field of clopidogrel bisulfate

Inactive Publication Date: 2007-03-07
TEVA PHARMA IND LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Dry wet samples preferably

Method used

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  • Polymorphs of clopidogrel hydrogensulfate
  • Polymorphs of clopidogrel hydrogensulfate
  • Polymorphs of clopidogrel hydrogensulfate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0185] Example 1 - Preparation of Clopidogrel Bisulfate Form II

[0186] Clopidogrel base (5.01 g, 1 eq) was dissolved in methyl ethyl ketone (MEK) (39.5 mL). To this solution was added 80% aqueous sulfuric acid (0.74 mL, 0.66 equiv) at 20°C. The reaction mixture was heated to reflux temperature for 2 hours. Then, the solution was cooled to room temperature, and half the amount of solvent was evaporated off under reduced pressure, during which time a precipitate formed. The white solid was collected by filtration, washed with MEK (2 x 10 ml), and dried in a vacuum oven at 50°C for 24 hours to yield 3.55 g (54%) of crystalline form II clopidogrel bisulfate.

Embodiment 2

[0187] Example 2 - Preparation of Clopidogrel Bisulfate Form II

[0188] Clopidogrel base (4.27 g, 1 eq) was dissolved in methyl ethyl ketone (MEK) (33.7 ml). To this solution was added 80% aqueous sulfuric acid (1.03ml, 1.1eq) at 20°C. The reaction mixture was heated to reflux temperature for 2 hours. The solution was then cooled to room temperature and stirring was continued at this temperature for 67 hours during which time a precipitate formed. The white solid was collected by filtration, washed with MEK (2 x 10 mL), and dried in a vacuum oven at 50 °C for 24 hours to yield 4.59 g (82%) of Form II crystalline clopidogrel bisulfate.

Embodiment 3

[0189] Example 3 - Preparation of Clopidogrel Bisulfate Form II

[0190] Clopidogrel base (3.73 g, 1 eq) was dissolved in dichloromethane (29.4 mL). To this solution was added 80% aqueous sulfuric acid (0.55ml, 0.66eq) at 20°C. The reaction mixture was heated to reflux temperature for 2 hours, during which time a precipitate formed. Then, the solution was cooled to room temperature, and half the amount of solvent was evaporated off under reduced pressure. The white solid was collected by filtration, washed with dichloromethane (2 x 10 ml) and dried in a vacuum oven at 50°C for 24 hours to afford 1.42 g (30%) of crystalline form II clopidogrel hydrogen sulfate.

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Abstract

Provided are new crystalline Forms III, IV, V and VI of clopidogrel hydrogensulfate and the amorphous form of clopidogrel hydrogensulfate, as well as their pharmaceutical compositions, and method of treatments with such compositions. Also provided are novel processes for preparation of clopidogrel hydrogensulfate Form I, Form II, Form III, Form IV, Form V, Form VI and amorphous form.

Description

[0001] This application is a divisional application of the invention patent application with the application number 02828204.3 (PCT / US02 / 40679) and the application date on December 18, 2002. [0002] Related application reference [0003] This application requests provisional application series: 60 / 342,440 filed December 18, 2001, 60 / 342,351 filed December 21, 2001, 60 / 348,182 filed January 11, 2002, February 12, 2002 10 / 074,409 and 60 / 359,157 filed February 21, 2002, which are incorporated herein by reference. field of invention [0004] The present invention relates to the solid state chemistry of clopidogrel bisulfate. Background of the invention [0005] Atherosclerosis is the buildup of plaque in the walls of the arteries, which causes the arteries to thicken and become less elastic. Atherosclerosis is caused by damage to the lining of arteries. This damage is caused by ordinary activities and diseases such as high cholesterol and high blood pressure, as well as smok...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D515/02A61K31/44A61P7/02A61P9/10A61KC07D
Inventor R·利夫施茨-利伦E·科瓦勒夫斯基-伊赛S·维泽尔S·阿瓦-麦丹R·利多尔-哈达斯
Owner TEVA PHARMA IND LTD
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