Crystals of laquinimod sodium, and process for the manufacture thereof

• US 8,647,646 B2
• Filed: 01/21/2011
• Issued: 02/11/2014
• Est. Priority Date: 10/19/2005
• Status: Expired due to Fees

• 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:
  US13/011,233
• Publication Number:
  US 20110112141A1
• Time in Patent Office: 1,117 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 laguinimod 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 process of recrystallization of laquinimod sodium comprising:

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

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

c) adding acetone to the concentrated solution to form laquinimod sodium crystals; and

d) isolating the laquinimod sodium crystals,

wherein step a) is performed by heating the aqueous solution to a temperature of 40-80°

C. and wherein the concentrated solution in step b) comprises 1-4 milliliters of water per gram of laquinimod sodium.

2. The process of claim 1, further comprising step aa) after step a) and before step b), said step aa) comprising filtering the aqueous solution to remove solid impurities.

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

4. The process of claim 1 wherein the anti-solvent is added in an amount between 3 and 15 milliliters per gram of laquinimod sodium.

5. The process of claim 1 wherein step b) is followed by cooling the concentrated solution to a temperature of below 10°

C.

6. The process of claims 2 wherein step aa) is followed by seeding the concentrated solution with laquinimod sodium.

7. A mixture of laquinimod sodium prepared by the process of claim 1, wherein the mixture comprises no more than 2 ppm of a heavy metal calculated based on total amount of laquinimod sodium in the mixture, 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.

8. A process for making a pharmaceutical composition comprising laquinimod sodium comprising recrystallizing laquinimod sodium by:

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

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

c) adding acetone to the concentrated solution to form laquinimod sodium crystals; and

d) isolating the laquinimod sodium crystals,

wherein step a) is performed by heating the aqueous solution to a temperature of 40-80°

C. and wherein the concentrated solution in step b) comprises 1-4 milliliters of water per gram of laquinimod sodium.

9. The process of claim 8, further comprising step aa) after step a) and before step b), said step aa) comprising filtering the aqueous solution to remove solid impurities.

10. The process of claim 8 wherein the acetone is added in an amount between 3 and 15 milliliters per gram of laquinimod sodium.

11. The process of claim 8 wherein step b) is followed by cooling the concentrated solution to a temperature of below 10°

C.

12. The process of claims 9 wherein step aa) is followed by seeding the concentrated solution with laquinimod sodium.

13. The pharmaceutical composition comprising laquinimod sodium prepared by the process of claim 8 having 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.

14. The process of claim 8, wherein the resulting laquinimod sodium crystals have reduced levels of polar impurities.

15. The process of claim 8, wherein the resulting laquinimod sodium crystals have reduced levels 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%).

16. The process of claim 8, wherein the resulting laquinimod sodium crystals have reduced levels 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%).

17. The process of claim 8, wherein the resulting laquinimod sodium crystals have reduced levels 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%).

18. The process of claim 8,

i) wherein step a) is performed by dissolving an amount of laquinimod sodium in water by stirring and heating a mixture of laquinimod sodium and approximately 11 mL of water per gram of laquinimod sodium to 50°

C. until complete dissolution of laquinimod sodium and filtering the resulting solution through filter paper, washing the filter paper with water, and combining the wash with the filtrate to form an aqueous solution;

ii) wherein step b) is performed by concentrating the aqueous solution of step a) by evaporation under vacuum of 35-38 mbar to form a concentrated solution having approximately 2.4 mL of water per gram of laquinimod sodium;

iii) wherein step c) is performed by allowing the concentrated solution of step b) to equilibrate to atmospheric pressure, heating the concentrated solution to 50°

C., adding acetone in an amount approximately 6.3 times the amount of laquinimod sodium to the concentrated solution over 2 hours, cooling the resulting mixture to 2°

C. and stirring for 12 hours to produce laquinimod sodium crystals;

iv) wherein step d) is performed by isolating the laquinimod sodium crystals of step c) by filtration, washing the resulting filtered laquinimod sodium crystals twice with acetone and drying under vacuum at 35-40°

C. to constant weight of the laquinimod sodium crystals.

19. The process of claim 8,

i) wherein step a) is performed by dissolving an amount of laquinimod sodium in water by stirring and heating a mixture of laquinimod sodium and approximately 11 mL of water per gram of laquinimod sodium to 60°

C. until complete dissolution of laquinimod sodium and filtering the resulting solution through filter paper, washing the filter paper with water, and combining the wash with the filtrate to form an aqueous solution;

ii) wherein step b) is performed by concentrating the aqueous solution of step a) by evaporation under vacuum of 37-38 mbar to form a concentrated solution having approximately 2.1 mL of water per gram of laquinimod sodium;

iii) wherein step c) is performed by allowing the concentrated solution of step b) to equilibrate to atmospheric pressure, heating the concentrated solution to 50°

C., stirring the concentrated solution for 25 minutes, adding acetone in amount approximately 6.3 times the amount of laquinimod sodium to the concentrated solution over 2 hours, cooling the resulting mixture to 2°

C. and stirring for 12 hours to produce laquinimod sodium crystals;

iv) wherein step d) is performed by isolating the laquinimod sodium crystals of step c) by filtration, washing the filtered laquinimod sodium crystals twice with acetone and drying under vacuum at 35-40°

C. to constant weight of the laquinimod sodium crystals.

20. The process of claim 8,

i) wherein step a) performed by dissolving an amount of laquinimod sodium in water by stirring and heating a mixture of laquinimod sodium and approximately 10 mL of water per gram of laquinimod sodium to 60°

C. until complete dissolution of laquinimod sodium and filtering the resulting solution through filter paper, washing the filter paper with water, and combining the wash with the filtrate to form an aqueous solution;

ii) wherein step b) is performed by concentrating the aqueous solution of step a) by evaporation under vacuum of 20-25 mbar to form a concentrated solution having a residual weight of approximately 2.4 times the amount of laquinimod sodium;

iii) wherein step c) is performed by transferring the concentrated solution of step b) to a vessel pre-heated to 50°

C. and seeding the transferred solution with solid laquinimod sodium, stirring for one hour, adding acetone in an amount approximately 6.3 times the amount of laquinimod sodium to the concentrated solution over 2 hours, cooling the resulting mixture to 2°

C. and stirring for 12 hours to produce laquinimod sodium crystals;

iv) wherein step d) is performed by isolating the laquinimod sodium crystals of step c) by filtration, washing the filtered laquinimod sodium crystals twice with acetone and drying under vacuum at 35-40°

C. to constant weight of the laquinimod sodium crystals.

21. The process of claim 8,

i) wherein step a) is performed by dissolving an amount of laquinimod sodium in water by heating a mixture of laquinimod sodium in approximately 10 mL of water per gram of laquinimod sodium to 70-73°

C. to form a clear solution, then cooling the clear solution to 50°

C., filtering the cooled solution through a 0.2 micron filter, washing the filter with water, and combining the wash with the filtrate to form an aqueous solution;

ii) wherein step b) is performed by concentrating the aqueous solution of step a) by evaporation in a jacketed reactor under vacuum of 30-50 mbar while maintaining the temperature of the jacket at 60°

C. and maintaining the temperature of the reactor at about 35-40°

C. to form a concentrated solution having approximately 2.1 mL of water per gram of laquinimod sodium;

iii) wherein step c) is performed by allowing the concentrated solution of step b) to equilibrate to atmospheric pressure, adding acetone in an amount approximately 8 times the amount of laquinimod sodium to the concentrated residue over 2 hours while maintaining the jacket temperature at 50°

C., cooling the resulting mixture to 2°

C. over 2 hours and keeping the mixture at this temperature for 5-10 hours to produce laquinimod sodium crystals;

iv) wherein step d) is performed by isolating the laquinimod sodium crystals of step c) by filtration, washing the filtered laquinimod sodium crystals twice with acetone and drying under vacuum at 30-40°

C.

22. The process of claim 8,

i) wherein step a) is performed by dissolving an amount of laquinimod sodium in water by heating a mixture of laquinimod sodium and approximately 10 mL of water per gram of laquinimod sodium to 75°

C., cooling the resulting solution to 50°

C., filtering the cooled solution through a filter, washing the filter with water, and combining the wash with the filtrate in a jacketed reactor to form an aqueous solution;

ii) wherein step b) is performed by cooling the aqueous solution of step a) by lowering the jacket temperature to 25°

C., concentrating said aqueous solution of step a) by evaporation in the jacketed reactor under vacuum of less than 45 mmHg while heating for 30 minutes by raising the jacket temperature to 65°

C. to form a concentrated solution having approximately 2.1 mL of water per gram of laquinimod sodium;

iii) wherein step c) is performed by cooling the concentrated solution of step b) by lowering the jacket temperature to 50°

C. and agitating for 10 minutes, seeding the resulting solution with solid laquinimod sodium and stirring while maintaining the jacket temperature at 50°

C. for 1 hour, adding acetone in an amount approximately 8 times the amount of laquinimod sodium to the resulting mixture over 2 hours at 50°

C., cooling the resulting mixture to 2°

C. over 4 hours and maintaining the temperature of the mixture at 2°

C. for 11 additional hours to form laquinimod sodium crystals;

iv) wherein step d) is performed by isolating the laquinimod sodium crystals of step c) by filtration, washing the filtered laquinimod sodium crystals twice with acetone and drying under vacuum at 30-40°

C.

23. The process of claim 8, further comprising step e) after step d), wherein said step e) comprising preparing a powder or granules from the isolated laquinimod sodium crystals of step d).