Crystalline salts of quinoline compounds and methods for preparing them

• US 8,314,124 B2
• Filed: 03/17/2009
• Issued: 11/20/2012
• Est. Priority Date: 02/06/2004
• Status: Active Grant

• Current Assignee: Active Biotech AB
• Original Assignee: Active Biotech AB
• Inventors: Jansson, Karl, Fristedt, Tomas, Wännman, Hans, Björk, Anders
• Primary Examiner(s): Andres, Janet
• Assistant Examiner(s): Rozof, Timothy R
• Application Number:
  US12/405,413
• Publication Number:
  US 20090232889A1
• Time in Patent Office: 1,344 Days
• Field of Search: None
• US Class Current: 514/312
• CPC Class Codes: A61K 31/4704 2-Quinolinones, e.g. carbostyril
• CPC Class Codes: A61K 31/4706 4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
• CPC Class Codes: C07D 215/56 with oxygen atoms in position 4

Abstract

A stable solid pharmaceutical composition consisting essentially of an effective amount of a crystalline salt of formula (II)

together with an alkaline-reacting component maintaining the pH preferably above 8, or a salt with a divalent metal cation; and
at least one pharmaceutical excipient;
said salt of formula (II) being essentially stable during storage at room temperature for a period of at least 3 years. A process for stabilizing the salt of formula (II).

A crystalline salt of formula (II) and a process for preparing said salt.

Claims

1. A process for the preparation of a crystalline salt of formula (II)

2. The process according to claim 1, wherein the monovalent metal salt is a sodium or potassium salt.

3. A process for the preparation of a crystalline salt of formula (II)

4. The process according to claim 3, wherein the first organic solvent is chloroform.

5. The process according to claim 3, wherein the second organic solvent is methanol.

6. The process according to claim 3, wherein the monovalent metal salt is a sodium or potassium salt.

7. A crystalline salt of formula (II)

8. The crystalline salt of claim 7, which a salt of N-ethyl-N-phenyl-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide, or of N-ethyl-N-phenyl-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide.

9. A stable solid pharmaceutical composition comprising a therapeutically effective amount of a crystalline salt of formula (II)

10. The solid pharmaceutical composition of claim 9 wherein the salt of formula (II) is a salt of N-ethyl-N-phenyl-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide, or of N-ethyl-N-phenyl-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide.

11. The solid pharmaceutical composition of claim 9 wherein n is 2 and Aⁿ⁺ is Ca²⁺ or Zn²⁺.

12. The solid pharmaceutical composition of claim 11 wherein Aⁿ⁺ is Ca²⁺.

13. The solid pharmaceutical composition of claim 9 wherein the salt of formula (II) is a calcium salt of N-ethyl-N-phenyl-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide or a calcium or zinc salt of N-ethyl-N-phenyl-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide.

14. The solid pharmaceutical composition of claim 9 which is in the form of a tablet or a capsule.

15. A method of preparing the solid pharmaceutical composition of claim 9, comprising:

spraying a solution of an alkaline-reacting component onto a mixture of pharmaceutical excipients;

granulating the mixture;

drying the granulated mixture, to obtain a dry granulate;

mixing the dry granulate with a crystalline salt of formula (II) as defined in claim 9, to obtain a blend of the granulate and the salt.

16. The method of claim 15, comprising compressing the blend into a tablet core and optionally adding a tablet coating to said tablet core.

17. The method of claim 15, comprising filling the blend into a hard gelatin capsule.

18. A method of preparing the solid pharmaceutical composition of claim 9, comprising:

mixing a crystalline salt of formula (II) as defined in claim 9, and at least one pharmaceutically acceptable excipient, so as to obtain a preblend;

wet granulating the preblend with an aqueous solution of a divalent metal salt, to obtain a granulate; and

drying the granulate.

19. The solid pharmaceutical composition of claim 9 wherein the crystalline salt of formula (II) is present in an amount of 0.01 to 10% by weight of the composition.

20. The solid pharmaceutical composition of claim 9 wherein the crystalline salt of formula (II) is present in an amount of 0.1 to 2% by weight of the composition.

21. The solid pharmaceutical composition of claim 9 wherein the alkaline-reacting component is selected from sodium, potassium, calcium and aluminum salts of acetic acid, carbonic acid, citric acid and phosphoric acid.

22. The solid pharmaceutical composition of claim 9 wherein the alkaline-reacting component is present in an amount of 0.1 to 99% by weight of the composition.

23. The solid pharmaceutical composition of claim 9 wherein the alkaline-reacting component is present in an amount of 1 to 20% by weight of the composition.