Patent EA-002386-B1 (EA)
Title: Polymorphic clopidogrel hydrogenesulphate form
Inventor: BOUSQUET ANDRE
IPC: C07D495/04
Filed: 1999-06-10
Abstract: 1. Crystalline (+)-(S) polymorph of clopidogrel hydrogen sulphate (Form 2) whose powder  X-ray diffractogram shows the following characteristic peaks expressed as interplanar distances at approximately 4.11; 6.86; 3.60; 5.01; 3.74; 6.49;  5.66  A. 2. Crystalline (+)-(S) polymorph of clopidogrel hydrogen sulphate (Form 2) whose infrared spectrum exhibits characteristic absorptions expressed in cm-1 at: 2551, 1697, 1189 and 1029, with respective percentages of transmittance of about: 43; 63.7; 18;  33.2. 3. Crystalline (+)-(S) polymorph of clopidogrel hydrogen sulphate (Form 2) having a melting point of 176 +- 3 degree C.  4. Crystalline polymorph of clopidogrel hydrogen sulphate (Form 2) characterized by the powder  X-ray diffractogram according to Figure 2. 5. Crystalline polymorph of clopidogrel hydrogen sulphate (Form 2) characterized by an infrared spectrum according to Figure 3. 6. Crystalline polymorph of clopidogrel hydrogen sulphate (Form 2) characterized by the powder  X-ray diffractogram. according to Claim 1 and an infrared spectrum according to Claim 2.  7. Method for the preparation of  (+)-(S)-clopidogrel hydrogen sulphate (Form 2), according to Claims 1, 2 and 3, characterized in that the aqueous-acetone' mother liquors resulting from the crystallization of (+)-(S)-clopidogrel hydrogen sulphate (Form 1) undergo salting out in order to obtain, after 3 to 6 months, crystals of clopidogrel hydrogen sulphate (Form 2). 8. Method according to Claim 7, characterized in that the aqueous-acetone mother liquors resulting from the crystallization of  (+)-(S)-clopidogrel hydrogen sulphate (Form 1) contain 0.3 to 1% of water. 9. Method according to Claim 7, characterized in that the aqueous-acetone mother liquors resulting from the crystallization of (+)-(S)-clopidogrel hydrogen sulphate Form 1 contain up to about 10% of clopidogrel hydrogen sulphate, this quantity being calculated from the quantity of methyl (+)-(S)-.alpha.-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl-5-acetate camphorsulphonate used during the conversion to hydrogen sulphate. 10. Method according to any one of Claims 7 to 9, characterized in that the aqueous-acetone mother liquors resulting from the crystallization of (+)-(S)-clopidogrel hydrogen sulphate Form 1 release slowly, after a period of three to six months, at a temperature of less than 40 degree C, clopidogrel hydrogen sulphate (Form 2).  11. Method for the preparation of clopidogrel hydrogen sulphate (Form 2) in which: (a) methyl (+)-(S)-.alpha.-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl-5-acetate camphorsulphonate is dissolved in an organic solvent, (b) camphorsulphonic acid is extracted with an aqueous alkaline solution of potassium carbonate and washed with water,  (c) the organic phase is concentrated under reduced pressure and the concentration residue is taken up in acetone,  (d) 94-96% sulphuric acid is added and the mixture is seeded with clopidogrel hydrogen sulphate (Form 2), the product is crystallized, the mixture is cooled, filtered and the crystals are washed and then dried under reduced pressure to give clopidogrel hydrogen sulphate (Form 2). 12. Pharmaceutical composition containing, as active ingredient, the (Form 2) polymorph of clopidogrel hydrogen sulphate according to Claim 1 in combination with at least one pharmaceutical excipient.