Crystals of laquinimod sodium, and process for the manufacture thereof

• US 8,673,322 B2
• Filed: 01/21/2011
• Issued: 03/18/2014
• Est. Priority Date: 10/19/2005
• Status: Active Grant

• Current Assignee: Teva Pharmaceutical Industries Limited
• Original Assignee: Teva Pharmaceutical Industries Limited
• Inventors: Frenkel, Anton, Gurevich, Eduard, Laxer, Avital
• Primary Examiner(s): Lundgren, Jeffrey S.
• Assistant Examiner(s): SIMMONS, CHRIS E
• Application Number:
  US13/011,187
• Publication Number:
  US 20110118308A1
• Time in Patent Office: 1,152 Days
• Field of Search: 514/312, 546/156
• US Class Current: 424/400
• CPC Class Codes: A61K 31/4704 2-Quinolinones, e.g. carbostyril
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 215/54 attached in position 3
• CPC Class Codes: C07D 215/56 with oxygen atoms in position 4

Abstract

Disclosed is a process for the preparation of laquinimod sodium which removes the impurities after the salt formation step, thus resulting in crystals of higher purity as well as crystals having improved crystalline characteristics.

Claims

1. A mixture of crystalline laquinimod sodium particles wherein 10% or more of the total amount by volume of the laquinimod sodium particles have a size of greater than 40 microns, having a bulk density of at least 0.2 g/mL or a tapped density of at least 0.4 g/mL.

2. The mixture of claim 1, having a tapped density of at least 0.4 g/mL and a bulk density of at least 0.2 g/mL.

3. The mixture of claim 1, having a tapped density of at least 0.5 g/mL.

4. The mixture of claim 1, having a tapped density of less than 0.7 g/mL.

5. The mixture of claim 1, having a tapped density of at least 0.5 g/mL and less than 0.7 g/mL.

6. The mixture of claim 5, having a tapped density of at least 0.6 g/mL and less than 0.7 g/mL.

7. The mixture of claim 1, having a bulk density of at least 0.3 g/mL.

8. The mixture of claim 7, having a tapped density of at least 0.4 g/mL.

11. The mixture of claim 7, having a tapped density of at least 0.5 g/mL and less than 0.7 g/mL.

12. The mixture of claim 11, having a tapped density of at least 0.6 g/mL and less than 0.7 g/mL.

13. The mixture of claim 1, comprising no more than 2 ppm of a heavy metal, wherein the heavy metal is iron, nickel, chromium or a mixture thereof, and the iron content is no more than 2 ppm, the nickel is no more than 0.2 ppm and the chromium content is no than 0.3 ppm.

14. The mixture of claim 5, comprising no more than 2 ppm of a heavy metal, wherein the heavy metal is iron, nickel, chromium or a mixture thereof, and the iron content is no more than 2 ppm, the nickel content is no more than 0.2 ppm and the chromium content is no more than 0.3 ppm.

15. The mixture of claim 6, comprising no more than 2 ppm of a heavy metal, wherein the heavy metal is iron, nickel, chromium or a mixture thereof, and the iron content is no more than 2 ppm, the nickel content is no more than 0.2 ppm and the chromium content is no more than 0.3 ppm.

16. The mixture of claim 7, comprising no more than 2 ppm of a heavy metal, wherein the heavy metal is iron, nickel, chromium or a mixture thereof, and the iron content is no more than 2 ppm, the nickel content is no more than 0.2 ppm and the ins content no more than 0.3 ppm.

17. The mixture of claim 11, comprising no more than 2 ppm of a heavy metal, wherein the heavy metal is Iron, nickel, chromium or a mixture thereof, and the iron content is no more than 2 ppm, the nickel content is no more than 0.2 ppm and the chromium content is no more than 0.3 ppm.

18. The mixture of claim 12, comprising no more than 2 ppm of a heavy metal, wherein the heavy metal is iron, nickel, chromium or a mixture thereof, and the iron content is no more than 2 ppm, the nickel content is no more than 0.2 ppm and the chromium content is no more than 0.3 ppm.

19. A pharmaceutical composition comprising the mixture of claim 1 and a pharmaceutically acceptable carrier.

20. The pharmaceutical composition of claim 19, wherein the mixture has a tapped density of at least 0.5 g/mL and less than 0.7 g/mL.

21. The pharmaceutical composition of claim 20, wherein the mixture has a tapped density of at least 0.6 g/mL and less than 0.7 g/mL.

22. The pharmaceutical composition of claim 19, wherein the mixture has a bulk density of at least 0.3 g/mL.

23. The pharmaceutical composition of claim 22, wherein the mixture has a tapped density of at least 0.5 g/mL and less than 0.7 g/mL.

24. The pharmaceutical composition of claim 23, wherein the mixture has a tapped density of at least 0.6 g/mL and less than 0.7 g/mL.

25. The pharmaceutical composition of claim 19 in the form of a tablet, capsule, pill, powder or granule.

26. The pharmaceutical composition of claim 25, wherein the mixture has a tapped density of at least 0.5 g/mL and less than 0.7 g/mL.

27. The pharmaceutical composition of claim 26, wherein the mixture has a tapped density of at least 0.6 g/mL and less than 0.7 g/mL.

28. The pharmaceutical composition of claim 25, wherein the mixture has a bulk density of at least 0.3 g/mL.

29. The pharmaceutical composition of claim 28, wherein the mixture has a tapped density of at least 0.5 g/mL and less than 0.7 g/mL.

30. The pharmaceutical composition of claim 29, wherein the mixture has a tapped density of at least 0.6 g/mL and less than 0.7 g/mL.

31. A composition comprising a mixture of crystalline laquinimod sodium particles according to claim 1 and no more than 2 ppm of a heavy metal calculated based on total amount of laquinimod sodium in the composition, wherein the heavy metal is iron, nickel, chromium or a mixture thereof, and the iron content is no more than 2 ppm the nickel content is no more than 0.2 ppm and the chromium content is no more than 0.3 ppm.

32. The composition of claim 31 in crystalline, powder or granule form.

33. The composition of claim 31 further comprising a pharmaceutically acceptable carrier.

34. The composition of claim 31 in the form of a tablet, or capsule or pill.

35. The mixture of claim 2, having a tapped density of at least 0.5 g/mL and less than 0.7 g/mL.

36. The mixture of claim 35, comprising no more than 2 ppm of a heavy metal, wherein the heavy metal is iron, nickel chromium or a mixture thereof, and the iron content is no more than 2 ppm, the nickel content is no more than 0.2 ppm and the chromium content is no more than 0.3 ppm.

37. The mixture of claim 35, wherein 50% or more of the total amount by volume of the laquinimod sodium particles have a size of greater than 15 microns.

38. The mixture of claim 1, wherein an amount of a polar impurity having an approximate retention time of 5.52 minutes when determined by isocratic reversed phase HPLC, using an ODS-3V column and a mobile phase comprised of a mixture of ammonium acetate buffer at pH 7.0 (80%) and acetonitrile (20%) is less than 0.01 of the total amount of laquinimod sodium as measured by ultraviolet absorption at 240 nm, or the impurity is not detectable.

39. The mixture of claim 1, wherein an amount of a polar impurity having an approximate retention time of 8.48 minutes when determined by isocratic reversed phase HPLC, using an ODS-3V column and a mobile phase comprised of a mixture of ammonium acetate buffer at pH 7.0 (80%) and acetonitrile (20%) is less than 0.01 of the total amount of laquinimod sodium as measured by ultraviolet absorption at 240 nm, or the impurity is not detectable.

40. The mixture of claim 1, wherein an amount of a polar impurity having an approximate retention time of 12.19 minutes when determined by isocratic reversed phase HPLC, using an ODS-3V column and a mobile phase comprised of a mixture of ammonium acetate buffer at pH 7.0 (80%) and acetonitrile (20%) is less than 0.01 of the total amount of laquinimod sodium as measured by ultraviolet absorption at 240 nm, or the impurity is not detectable.

41. The pharmaceutical composition of claim 19, wherein the pharmaceutically acceptable carrier is mannitol.

42. The pharmaceutical composition of claim 33, wherein the pharmaceutically acceptable carrier is mannitol.

43. The pharmaceutical composition of claim 19, further comprising an alkaline-reacting component.

44. The pharmaceutical composition of claim 33, further comprising an alkaline-reacting component.

9. The mixture of 8, having a tapped density of at least 0.5 g/mL.

10. The mixture of 7, having a tapped density of less than 0.7 g/mL.