Crystals of laquinimod sodium, and process for the manufacture thereof

• US 20070088050A1
• Filed: 10/18/2006
• Published: 04/19/2007
• Est. Priority Date: 10/19/2005
• Status: Active Grant

• Current Assignee: Teva Pharmaceutical Industries Limited
• Original Assignee: Teva Pharmaceutical Industries Limited
• Inventors: Frenkel, Anton, Laxer, Avital, Gurevich, Eduard
• Granted Patent: US 7,884,208 B2
• Time in Patent Office: Days
• US Class Current: 514/312
• 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.

2. The mixture of claim 1, wherein 50% or more of the total amount by volume of the laquinimod sodium particles have a size of greater than 15 microns.

3. The mixture of claim 1, having a tapped density of at least 0.6 g/mL.

4. The mixture of claim 1, having a bulk density of at least 0.4 g/mL.

5. The mixture of claim 1, having a tapped density of less than 0.8 g/mL.

6. The mixture of claim 1, comprising no more than 2 ppm of a heavy metal.

7. The mixture of claim 6, wherein the heavy metal is iron, nickel or chromium.

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

20. The pharmaceutical composition of claim 19 in the form of a tablet or capsule.

8-10. -10. (canceled)

11. A mixture of crystalline laquinimod sodium particles, having a tapped density of at least 0.6 g/mL.

12-18. -18. (canceled)

21. A composition comprising laquinimod sodium and no more than 2 ppm of a heavy metal calculated based on the total amount of laquinimod sodium in the composition.

22-28. -28. (canceled)

29. A process of recrystallization of laquinimod sodium comprising:

a) dissolving laquinimod sodium in water to form an aqueous solution;

b) filtering the aqueous solution to remove solid impurities;

c) concentrating the aqueous solution to form a concentrated solution;

d) adding a water-miscible anti-solvent to the concentrated solution to form laquinimod sodium crystals; and

e) isolating the laquinimod sodium crystals.

30. The process of claim 29 wherein step a) is performed by heating the aqueous solution to a temperature of 40-80°

C.

31. The process of claim 29 wherein the concentrated solution comprises 1-4 milliliters of water per gram of laquinimod sodium.

32. The process of claim 31 wherein the concentrated solution comprises 1-2 milliliters of water per gram of laquinimod sodium.

33. The process of claim 29 wherein the anti-solvent is one, or a mixture of more than one, of the group consisting of ethanol, isopropanol, and acetone.

34. The process of claim 33 wherein the anti-solvent is acetone.

35. The process of claim 29 wherein the anti-solvent is added in an amount between 3 and 15 milliliters per gram of laquinimod sodium.

36. The process of claim 29 wherein step c) is followed by cooling the solution to a temperature of below 10°

C.

37. The process of claim 29 wherein step b) is followed by seeding the concentrated solution with laquinimod sodium.

38. Laquinimod sodium prepared by claim 29.

39. A process for making a pharmaceutical composition comprising laquinimod sodium comprising:

a) obtaining a batch of laquinimod sodium;

b) determining whether insoluble matter is present in the batch of step a) by mixing a sample from the batch in deionized water at room temperature at a ratio of at least 110 mg of sample to 1.0 ml of water, and inspecting the resulting mixture for the presence of insoluble matter; and

c) mixing the batch of step a) with at least one pharmaceutically acceptable carrier if in step b) insoluble matter is determined to be present below a predetermined amount.

40. The process of claim 39, wherein if insoluble matter in the mixture of step b) is determined not to be present below a predetermined amount, the process further comprises:

d) dissolving the batch of step a) in water to form an aqueous solution;

e) filtering the aqueous solution of step d) to reduce the amount of insoluble matter to below the predetermined amount;

f) concentrating the aqueous solution of step e) to form a concentrated solution;

g) adding a water-miscible anti-solvent to the concentrated solution of step f) to form laquinimod sodium crystals; and

h) isolating the laquinimod sodium crystals of step g).