Polymorphic clopidogrel hydrogenesulphate form

Details Polymorphic clopidogrel hydrogenesulphate form Polymorphic clopidogrel hydrogenesulphate form

2001-04-05

2002-08-06

Aulakh, Charanjit S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S114000

Reexamination Certificate

active

06429210

ABSTRACT:

The present invention relates to a novel polymorph of clopidogrel hydrogen sulfate or the hydrogen sulfate of methyl (+)-(S)-&agr;-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-acetate and a process for its preparation. More particularly, the invention relates to the preparation of this polymorph called Form 2 and to the isolation of this compound in this novel crystalline form, as well as to pharmaceutical compositions containing it.
Clopidogrel hydrogen sulfate is a platelet aggregation inhibitor which was described for the first time in EP 281459. The synthetic process claimed in this patent leads to the preparation of clopidogrel hydrogen sulfate which is called Form 1. It has now been discovered that clopidogrel hydrogen sulfate can exist in different polymorphic crystalline forms which differ from each other by their stability, their physical properties, their spectral characteristics and the process for their preparation.
Thus, one of these novel polymorphic forms is the object of the present invention, it is described in the present application and will be named Form 2.
The present invention also relates to a process for the preparation of clopidogrel hydrogen sulfate in its polymorphic Form 2.
Patent EP 281459 describes enantiomers of tetrahydrothienopyridine derivatives and their pharmaceutically acceptable salts. EP 281459 specifically claims clopidogrel hydrogen sulfate, i.e. the dextrorotatory isomer which possesses an excellent platelet aggregation inhibiting activity whereas the levorotatory isomer is less active and less well tolerated. Patent EP 281459, filed ten years ago, makes no reference to the existence of specific polymorphic forms of clopidogrel hydrogen sulfate. The synthesis described in EP 281459 leads to the preparation of the hydrogen sulfate of the polymorph of clopidogrel Form 1. Nor does EP 281459 suggest the existence of different polymorphic forms of clopidogrel or of clopidogrel hydrogen sulfate.
According to all of the teachings of the above documents, the dextrorotatory isomer of clopidogrel is prepared by salt formation from the racemic compound using an optically active acid such as 10-L-camphorsulfonic acid in acetone, followed by successive recrystallisations of the salt until a product with constant rotatory power was obtained, followed by release of the dextrorotatory isomer from its salt by a base. Clopidogrel hydrogen sulfate is then obtained in a standard manner by the dissolution of said base in acetone cooled in ice and addition of concentrated sulfuric acid to precipitation. The precipitate thus obtained is then isolated by filtration, washed and dried to give clopidogrel hydrogen sulfate in the form of white crystals whose melting point is 184° C. and optical rotation +55.1° (c=1.891/CH
3
OH).
The process described in the prior art leads only to the form 1 of clopidogrel hydrogen sulfate.
Thus, the present invention relates to the polymorphic form called Form 2 of clopidogrel hydrogen sulfate which, like Form 1 of this compound, is useful as a medicine for prophylaxis and the treatment of thrombosis by acting as a platelet aggregation inhibitor. As far as the use of clopidogrel and its salts is concerned, reference may be made to Drugs of the Future, 1993, 18, 2, 107-112. Polymorphic Form 2 of clopidogrel hydrogen sulfate is thus used as active ingredient for the preparation of a medicine, in combination with at least one pharmaceutically acceptable excipient, in the same indications as Form 1.
It has now been found that if clopidogrel hydrogen sulfate is crystallised from a solvent, either the crystalline form, Form 1, corresponding to that of the product obtained according EP 281459 mentioned above may be produced or a new, very stable crystalline form having a well-defined structure designated Form 2 below. More particularly, it has been found that the novel crystalline form of clopidogrel hydrogen sulfate, Form 2, is at least as stable as the Form 1 described and that it does not convert spontaneously into the previously known Form 1. Furthermore, Form 2 bulk solid is more compact and much less electrostatic than Form 1 and may hence be more readily subjected to any treatment under the usual conditions of pharmaceutical technology and, in particular, of formulation on an industrial scale.
It has moreover been observed that Form 2 exhibits a lower solubility than Form 1 as a result of its greater thermodynamic stability.
The difference between the new crystalline form of clopidogrel hydrogen sulfate according to the present invention, Form 2, and Form 1 is apparent on examination of the
FIGS. 1
to
4
, whereas the
FIGS. 5
to
7
demonstrate the structure in the crystals of Form 2.


REFERENCES:
patent: 4847265 (1989-07-01), Badore et al.
patent: 5132435 (1992-07-01), Bousquet et al.
patent: 281 459 (1987-02-01), None
patent: 465 358 (1990-07-01), None

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