Details for Patent: 6,504,030

Title:	Polymorphic form of clopidogrel hydrogen sulphate
Abstract:	Novel orthorombic polymorph of clopidogrel hydrogen sulfate or hydrogen sulfate of methyl (+)-(S)-.alpha.-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5 -acetate and a process for its preparation
Inventor(s):	Bousquet; Andre (Sisteron, FR), Castro; Bertrand (Kremlin-Bicetre, FR), Saint-Germain; Jean (Sisteron, FR)
Assignee:	Sanofi-Synthelabo (Paris, FR)
Filing Date:	Jun 21, 2002
Application Number:	10/177,092
Claims:	1. A process for the preparation of (+)-(S) clopidogrel hydrogen sulfate polymorph Form 2, the x-ray powder diffractogram of which shows characteristic peaks expressed as interplanar distance at approximately 4.11, 6.86, 3.60, 5.01, 3.74, 6.49, and 5.66 .ANG., which comprises allowing the acetone mother liquors of crystallization of (+)-(S) clopidogrel hydrogen sulfate polymorph Form 1 to stand for a period of 3 to 6 months to yield crystals of (+)-(S) clopidogrel hydrogen sulfate polymorph Form 2. 2. A process according to claim 1 wherein said mother liquors are obtained by reacting an acetone solution of (+)-(S) clopidogrel with 80% sulfuric acid and removing the crystallized (+)-(S) clopidogrel hydrogen sulfate polymorph Form 1. 3. A process for the preparation of (+)-(S) clopidogrel hydrogen sulfate polymorph Form 2, the infrared spectrum of which exhibits characteristic absorptions, expressed in cm.sup.-1 at 2251, 1497, 1189, and 1029 with respective transmittance percentages of approximately 43, 63.7, 18, and 33.2, which comprises allowing the acetone mother liquors of crystallization of (+)-(S) clopidogrel hydrogen sulfate polymorph Form 1 to stand for a period of 3 to 6 months to yield crystals of (+)-(S) clopidogrel hydrogen sulfate polymorph Form 2. 4. A process according to claim 3 wherein the mother liquors resulting from the crystallization of the polymorph Form 1 of (+)-(S) clopidogrel hydrogen sulfate contain from 0.3 to 1% water. 5. A process according to claim 3 wherein the mother liquors resulting from the crystallization of the polymorph Form 1 of (+)-(S) clopidogrel hydrogen sulfate contain up to about 10% of clopidogrel hydrogen sulfate, this amount being calculated on the basis of the amount of methyl (+)-(S)-.alpha.-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5 -acetate camphorsulfonate used for the preparation of the hydrogen sulfate. 6. A process according to claim 3 wherein the mother liquors resulting from the crystallization of the polymorph Form 1 of (+)-(S) clopidogrel hydrogen sulfate are allowed to stand for a period of 3 to 6 months at a temperature below 40.degree. C., to yield clopidogrel hydrogen sulfate Form 2. 7. A process according to claim 3 wherein said mother liquors are obtained by reacting an acetone solution of (+)-(S) clopidogrel with 80% sulfuric acid and removing the crystallized (+)-(S) clopidogrel hydrogen sulfate polymorph Form 1. 8. A process for the preparation of (+)-(S) clopidogrel hydrogen sulfate polymorph Form 2, having a melting point of 176.+-.3.degree. C., which comprises allowing the acetone mother liquors of crystallization of (+)-(S) clopidogrel hydrogen sulfate polymorph Form 1 to stand for a period of 3 to 6 months to yield crystals of (+)-(S) clopidogrel hydrogen sulfate polymorph Form 2. 9. A process according to claim 8 wherein the mother liquors resulting from the crystallization of the polymorph Form 1 of (+)-(S) clopidogrel hydrogen sulfate contain from 0.3 to 1% water. 10. A process according to claim 8 wherein the mother liquors resulting from the crystallization of the polymorph Form 1 of (+)-(S) clopidogrel hydrogen sulfate contain up to about 10% of clopidogrel hydrogen sulfate, this amount being calculated on the basis of the amount of methyl (+)-(S)-.alpha.-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5 -acetate camphorsulfonate used for the preparation of the hydrogen sulfate. 11. A process according to claim 8 wherein the mother liquors resulting from the crystallization of the polymorph Form 1 of (+)-(S) clopidogrel hydrogen sulfate are allowed to stand for a period of 3 to 6 months at a temperature below 40.degree. C., to yield clopidogrel hydrogen sulfate Form 2. 12. A process according to claim 8 wherein said mother liquors are obtained by reacting an acetone solution of (+)-(S) clopidogrel with 80% sulfuric acid and removing the crystallized (+)-(S) clopidogrel hydrogen sulfate polymorph Form 1. 13. A process for the preparation of clopidogrel hydrogen sulfate polymorph Form 2 which comprises reacting an acetone solution of (+)-(S) clopidogrel with 94-96% sulfuric acid and seeding the resulting solution with (+)-(S) clopidogrel hydrogen sulfate polymorph Form 2 to effect crystallization of (+)-(S) clopidogrel hydrogen sulfate polymorph Form 2. 14. A process according to claim 13 wherein the acetone solution of (+)-(S) clopidogrel is obtained by extracting a mixture of methyl (+)-(S)-.alpha.-(2-chlorophenyl)4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5- acetate camphorsulfonate in an organic solvent with an aqueous solution of potassium carbonate, concentrating the organic phase and taking up the resulting residue in acetone. 15. A process for the preparation of (+)-(S) clopidogrel hydrogen sulfate polymorph Form 2 which comprises reacting an acetone solution of (+)-(S) clopidogrel with 80% sulfuric acid and heating the mixture at reflux to effect crystallization of (+)-(S) clopidogrel hydrogen sulfate polymorph Form 2. 16. A process according to claim 15 wherein the mixture is heated at reflux for about two hours. 17. (+)-(S) Clopidogrel hydrogen sulfate Form 2 prepared by the process of claim 1. 18. (+)-(S) Clopidogrel hydrogen sulfate Form 2 prepared by the process of claim 3. 19. (+)-(S) Clopidogrel hydrogen sulfate Form 2 prepared by the process of claim 8. 20. (+)-(S) Clopidogrel hydrogen sulfate Form 2 prepared by the process of claim 13. 21. (+)-(S) Clopidogrel hydrogen sulfate Form 2 prepared by the process of claim 15. 22. (+)-(S) Clopidogrel hydrogen sulfate Form 2, the x-ray powder diffraction pattern of which shows characteristic peaks, expressed in terms of interplanar distance, at approximately 4.11 and 6.86 .ANG. prepared by the process of claim 1. 23. (+)-(S) Clopidogrel hydrogen sulfate Form 2, the x-ray powder diffraction pattern of which shows characteristic peaks, expressed in terms of interplanar distance, at approximately 4.11 and 6.86 .ANG. prepared by the process of claim 13. 24. (+)-(S) Clopidogrel hydrogen sulfate Form 2, the x-ray powder diffraction pattern of which shows characteristic peaks, expressed in terms of interplanar distance, at approximately 4.11 and 6.86 .ANG. prepared by the process of claim 15. 25. A process according to claim 1 wherein the mother liquors resulting from the crystallization of the polymorph Form 1 of (+)-(S) clopidogrel hydrogen sulfate contain from 0.3 to 1% water. 26. A process according to claim 1 wherein the mother liquors resulting from the crystallization of the polymorph Form 1 of (+)-(S) clopidogrel hydrogen sulfate contain up to about 10% of clopidogrel hydrogen sulfate, this amount being calculated on the basis of the amount of methyl (+)-(S)-.alpha.-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5 -acetate camphorsulfonate used for the preparation of the hydrogen sulfate. 27. A process according to claim 1 wherein the mother liquors resulting from the crystallization of the polymorph Form 1 of (+)-(S) clopidogrel hydrogen sulfate are allowed to stand for a period of 3 to 6 months at a temperature below 40.degree. C., to yield clopidogrel hydrogen sulfate Form 2.