(WO/2006/008636) PROCESSES FOR THE PREPARATION OF ZOLPIDEM AND ITS HEMITARTRATE

(WO/2006/008636) PROCESSES FOR THE PREPARATION OF ZOLPIDEM AND ITS HEMITARTRATE

We Claim: 1. A process for the preparation of Zolpidem of Formula I,

FORMULA I or a salt thereof, the process comprising: a) condensing a bromo amide of Formula IV,

FORMULA IV with 2-amino-5-methylpyridine in one or more polar aprotic solvents at a reaction temperature above 8O0C; and

b) isolating Zolpidem of Formula I or a salt thereof, by the removal of the solvent.

2. The process of claim 1, wherein the solvent used in step a) has a boiling point above 8O0C.

3. The process of claim 1, wherein the solvent comprises one or more of methyl isobutyl ketone, ethyl methyl ketone, diisobutyl ketone, 1,4-dioxane, sulpholane, dimethylformamide, dimethylacetamide, acetone, acetonitrile, N-methylpyrrolidone, and mixtures thereof.

4. The process of claim 3, wherein the solvent is methyl isobutyl ketone.

5. The process of claim 1, wherein the reaction temperature is from about 8O0C to about 12O0C.

6. The process of claim 5, wherein the reaction temperature is from about 8O0C to about 1000C. 7. The process of claim 1, wherein removing the solvent comprises one or more of distillation, distillation under vacuum, evaporation, filtration, filtration under vacuum, decantation and centrifugation.

8. The process of claim 1, further comprising additional drying of the product obtained.

9. The process of claim 1, further comprising forming the product obtained into a finished dosage form.

10. The process of claim 1, wherein the salt is Zolpidem hemitartrate.

11. The process of claim 10, wherein the Zolpidem hemitartrate is prepared from Zolpidem by treating it with L-(+)-tartaric acid.

12. A non-hygroscopic polymorphic Form I of Zolpidem hemitartrate.

13. The Form I of Zolpidem hemitartrate of claim 12 having characteristic X-ray diffraction peaks at two-theta values of 7.0, 7.8, 8.6, 8.9, 12.2, 15.6, 16.5, 17.3, 24.3 and 26.0.

14. The Form I of Zolpidem hemitartrate of claim 12 having X-ray diffraction pattern of Figure I.

15. The Form I of Zolpidem hemitartrate of claim 12 having characteristic differential scanning calorimetry endothermic peaks at about 7O0C, 1090C, 1890C and 2040C.

16. The Form I of Zolpidem hemitartrate of claim 15 having exothermic peaks at about 1190C and 1570C.

17. The Form I of Zolpidem hemitartrate of claim 12 having differential scanning calorimetry profile of Figure II.

18. The Form I of Zolpidem hemitartrate of claim 12 having characteristic thermogravimetric weight loss from about 1.0% w/w up to about 1.75% w/w.

19. The Form I of Zolpidem hemitartrate of claim 12 having moisture content of about 1.25% w/w to 2.5% w/w as determined by Karl Fischer method.

20. The Form I of Zolpidem hemitartrate of claim 12 having infrared spectrum of Figure III. 21. A process for the preparation of Form I of Zolpidem hemitartrate, the process comprising: a) obtaining a solution of Zolpidem base in one or more alcoholic solvents; b) contacting the solution with L-(+)-tartaric acid; c) adding an anti-solvent to the reaction mixture; and

d) isolating Form I of Zolpidem hemitartrate from the mixture thereof.

22. The process of claim 21, wherein temperature of the reaction mixture is from about

-5O0C to about 250C.

23. The process of claim 21, wherein the alcoholic solvent comprises one or more of methanol, ethanol, isopropanol, n-butanol, and mixtures thereof.

24. The process of claim 23, wherein the alcoholic solvent is methanol.

25. The process of claim 21 , wherein the anti-solvent comprises one or more of acetone, methyl isobutyl ketone, ethyl methyl ketone, diisobutyl ketone, and mixtures thereof.

26. The process of claim 25, wherein the anti-solvent is methyl isobutyl ketone.

27. A pharmaceutical composition comprising:

a therapeutically effective amount of Form I of Zolpidem hemitartrate; and

one or more pharmaceutically acceptable carriers, excipients or diluents.

28. A method of treating anxiety, insomnia, sleep disorders, and convulsions in a warm-blooded animal, the method comprising providing a pharmaceutical composition to the warm-blooded animal, the pharmaceutical composition comprising Form I of Zolpidem hemitartrate.

PATENTSCOPE®

Related Links

E-Newsletters