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NOVEL POLYMORPH OF CLOPIDOGREL HYDROGEN SULPHATE

IP.com Disclosure Number: IPCOM000200441D
Publication Date: 2010-Oct-13
Document File: 8 page(s) / 176K

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Abstract

The present disclosure relates to a novel crystalline polymorph of clopidogrel hydrogen sulphate and processes for its preparation. The novel polymorphic form is designated as Form R. The disclosure further relates to pharmaceutical compositions comprising Form R of clopidogrel hydrogen sulphate.

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NOVEL POLYMORPH OF CLOPIDOGREL HYDROGEN SULPHATE

Abstract

The present disclosure relates to a novel crystalline polymorph of clopidogrel hydrogen sulphate and processes for its preparation.  The novel polymorphic form is designated as Form R.  The disclosure further relates to pharmaceutical compositions comprising Form R of clopidogrel hydrogen sulphate.

Clopidogrel, an inhibitor of induced platelet aggregation, is the dextro-rotatory enantiomer of methyl-alpha-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl)-(2-chlorophenyl)-acetate, having the absolute configuration S and is represented by Formula I.

FORMULA I

            U.S. Patent No. 4,529,596 provides methyl alpha-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl)(2-chlorophenyl)-acetate.

U.S. Patent No. 4,847,265 (herein after “the ‘265 patent”) provides the dextro-rotatory enantiomer of methyl alpha-5-(4,5,6,7-tetrahydro(3,2-c)thienopyridyl)(2-chlorophenyl)-acetate and a pharmaceutically acceptable salts thereof.  The hydrochloride, hydrogen sulfate, hydrobromide and taurocholate salts are specifically disclosed.  It further provides a process for the preparation of clopidogrel hydrogen sulfate, however does not suggest or teach any polymorphs of clopidogrel or its salts.

WO 99/65915 (hereinafter referred as “WO ‘915”) provides two polymorphs of clopidogrel hydrogen sulphate, referred to as Form 1 and Form 2, though Form 1 is originally disclosed in the ‘265 patent.  According to WO ‘915, Form 1 has a XRD pattern with d-spacing (Å) values at 9.60, 3.49, 3.83, 3.80, 4.31, 8.13, 4.80, 3.86, 5.80, and 4.95 and Form 2 has a XRD pattern with pattern with d-spacing (Å) values at 4.11, 6.86, 3.87, 3.60, 4.80, 5.01, 3.74, 6.49, and 5.66.  Both Form 1 and Form 2 are crystallized from acetone under different conditions.

U.S. Patent No. 6,767,913 discloses crystalline forms III, IV and V, an amorphous form of clopidogrel hydrogen sulfate and processes for their preparation the same.  Clopidogrel hydrogen sulfate Form III is a solvate of 1-butanol, and contains about 7 to about 8% 1-butanol by weight.  Form IV is considered a solvate of isopropanol, and contains about 3% to about 9% isopropanol by weight.  Form V is a solvate of 2-butanol and contains about 9% to about 10% 2-butanol by weight.  Form VI is a solvate of 1-propanol, and contains about 6% propanol by weight.  It also provides a process for the preparation of polymorphs Form 1 and Form 2.

Several processes have been reported for the preparation of clopidogrel or its salt and various polymorphic forms, for example, in U.S. Patent No. 5,204,469; Chinese Patent Applications CN 1850827 A; CN 1840533 A; CN 1775782 A; PCT Publications WO 98/51681; WO 98/51682; WO 98/39322; WO 99/18110; WO 03/000636; WO 03/093276; WO 98/51689; WO 00/27840; WO 02/59128; WO 02/18357; WO 03/035652; WO 03/004502; WO 2004/013147; WO 2004/074215; WO 2004/072085; WO 2004/072084; WO 2004/108665; WO 2004/094374; WO 2004/081015; WO 2004/081...