CRYSTALLINE SALTS OF QUINOLINE COMPOUNDS AND METHODS FOR PREPARING THEM

• US 20090232889A1
• Filed: 03/17/2009
• Published: 09/17/2009
• Est. Priority Date: 02/06/2004
• Status: Active Grant

• Current Assignee: Active Biotech AB
• Original Assignee: Active Biotech AB
• Inventors: Wannman, Hans, Fristedt, Tomas, Bjork, Anders, Jansson, Karl
• Granted Patent: US 8,314,124 B2
• Time in Patent Office: Days
• US Class Current: 424/465
• 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)

wherein

n is an integer of 2 or 3;

Aⁿ⁺ is a multivalent metal cation selected from Mg²⁺, Ca²⁺, Mn²⁺, Cu²⁺, Zn²⁺, Al³⁺, and Fe³⁺;

R is a straight or branched C₁-C₄-alkyl or -alkenyl or a cyclic C₃-C₄-alkyl;

R5 is a straight or branched, saturated or unsaturated C₁-C₄-alkyl or -alkenyl, a cyclic C₃-C₄-alkyl, a straight or branched C₁-C₄-alkylthio, a cyclic C₃-C₄-alkylthio, a straight or branched C₁-C₄-alkylsulfinyl, a cyclic C₃-C₄-alkylsulfinyl, fluoro, chloro, bromo, trifluoromethyl or trifluoromethoxy; and

R6 is hydrogen;

or

R5 and R6 taken together are methylenedioxy;

R′

is hydrogen, a straight or branched, saturated or unsaturated C₁-C₄-alkyl or -alkenyl, a cyclic C₃-C₄-alkyl, a straight or branched C₁-C₄-alkoxy, a cyclic C₃-C₄-alkoxy, fluoro, chloro, bromo or trifluoromethyl; and

R″

is hydrogen, fluoro or chloro, with the proviso that R″

is fluoro or chloro only when R′

is fluoro or chloro;

by reacting a 3-quinolinecarboxamide derivative in neutral form or as a monovalent metal salt, with a salt containing the multivalent metal cation in a liquid phase consisting of water and at least one water miscible organic solvent, in which liquid phase the salt of formula (II) is sparingly soluble.

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)

wherein

n is an integer of 2 or 3;

Aⁿ⁺ is a multivalent metal cation selected from Mg²⁺, Ca²⁺, Mn²⁺, Cu²⁺, Zn²⁺, Al³⁺, and Fe³⁺;

R is a straight or branched C₁-C₄-alkyl or -alkenyl or a cyclic C₃-C₄-alkyl;

R5 is a straight or branched, saturated or unsaturated C₁-C₄-alkyl or -alkenyl, a cyclic C₃-C₄-alkyl, a straight or branched C₁-C₄-alkylthio, a cyclic C₃-C₄-alkylthio, a straight or branched C₁-C₄-alkylsulfinyl, a cyclic C₃-C₄-alkylsulfinyl, fluoro, chloro, bromo, trifluoromethyl or trifluoromethoxy; and

R6 is hydrogen;

or

R5 and R6 taken together are methylenedioxy;

R′

is hydrogen, a straight or branched, saturated or unsaturated C₁-C₄-alkyl or -alkenyl, a cyclic C₃-C₄-alkyl, a straight or branched C₁-C₄-alkoxy, a cyclic C₃-C₄-alkoxy, fluoro, chloro, bromo or trifluoromethyl; and

R″

is hydrogen, fluoro or chloro, with the proviso that R″

is fluoro or chloro only when R′

is fluoro or chloro;

by

reacting a 3-quinolinecarboxamide derivative in neutral form or as a monovalent metal salt, with a salt containing the multivalent metal cation in a mixture of water and a first organic solvent wherein the multivalent salt of formula (II) is soluble, so as to obtain an organic solvent solution of the multivalent salt of formula (II);

separating the first organic solvent, containing the multivalent salt of formula (II), from the aqueous phase;

precipitating the multivalent salt of formula (II) from the first organic solvent as an amorphous solid salt;

redissolving the multivalent salt of formula (II) in a second liquid organic solvent wherein the salt has a lower solubility than in the first organic solvent; and

allowing crystals of the salt of formula (II) to form in said second liquid organic solvent.

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)

wherein

n is an integer of 2 or 3;

Aⁿ⁺ is a multivalent metal cation selected from Mg²⁺, Ca²⁺, Mn²⁺, Cu²⁺, Zn, Al³⁺, and Fe³⁺;

R is a straight or branched C₁-C₄-alkyl or -alkenyl or a cyclic C₃-C₄-alkyl;

R5 is a straight or branched, saturated or unsaturated C₁-C₄-alkyl or -alkenyl, a cyclic C₃-C₄-alkyl, a straight or branched C₁-C₄-alkylthio, a cyclic C₃-C₄-alkylthio, a straight or branched C₁-C₄-alkylsulfinyl, a cyclic C₃-C₄-alkylsulfinyl, fluoro, chloro, bromo, trifluoromethyl or trifluoromethoxy; and

R6 is hydrogen;

or

R5 and R6 taken together are methylenedioxy;

R′

is hydrogen, a straight or branched, saturated or unsaturated C₁-C₄-alkyl or -alkenyl, a cyclic C₃-C₄-alkyl, a straight or branched C₁-C₄-alkoxy, a cyclic C₃-C₄-alkoxy, fluoro, chloro, bromo or trifluoromethyl; and

R″

is hydrogen, fluoro or chloro, with the proviso that R″

is fluoro or chloro only when R′

is fluoro or chloro.

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)

wherein

n is an integer of 2 or 3;

Aⁿ⁺ is a multivalent metal cation selected from Mg²⁺, Ca²⁺, Mn²⁺, Cu²⁺, Zn²⁺, Al³⁺, and Fe³⁺;

R is a straight or branched C₁-C₄-alkyl or -alkenyl or a cyclic C₃-C₄-alkyl;

R5 is a straight or branched, saturated or unsaturated C₁-C₄-alkyl or -alkenyl, a cyclic C₃-C₄-alkyl, a straight or branched C₁-C₄-alkylthio, a cyclic C₃-C₄-alkylthio, a straight or branched C₁-C₄-alkylsulfinyl, a cyclic C₃-C₄-alkylsulfinyl, fluoro, chloro, bromo, trifluoromethyl or trifluoromethoxy; and

R6 is hydrogen;

or

R5 and R6 taken together are methylenedioxy;

R′

is hydrogen, a straight or branched, saturated or unsaturated C₁-C₄-alkyl or -alkenyl, a cyclic C₃-C₄-alkyl, a straight or branched C₁-C₄-alkoxy, a cyclic C₃-C₄-alkoxy, fluoro, chloro, bromo or trifluoromethyl; and

R″

is hydrogen, fluoro or chloro, with the proviso that R″

is fluoro or chloro only when R′

is fluoro or chloro;

an alkaline-reacting component or a salt with a divalent metal cation; and

at least one pharmaceutical excipient.

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, by

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 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, by

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.