Multicomponent crystalline system comprising nilotinib and selected co-crystal formers

Patent metadata

Field	Value
Publication number	US-9567317-B2
Application number	US-201314433147-A
Country	US
Kind code	B2
Filing date	Oct 16, 2013
Priority date	Oct 19, 2012
Publication date	Feb 14, 2017
Grant date	Feb 14, 2017

Abstract

The present invention relates to crystalline materials comprising nilotinib and a carboxylic acid, carboxylic acid ester, carboxylic acid amide or sulfonic acid as a co-crystal former, and to pharmaceutical compositions comprising said materials. The invention also relates to processes for preparing said crystalline materials and to methods of using said crystalline materials to treat a disease condition in which tyrosine kinase inhibition is beneficial.

First claim

The invention claimed is:

1. A crystalline material, comprising a co-crystal of component (a) and component (b), wherein:
(a) a hydrohalogenide salt of nilotinib, or a mixture of nilotinib and a hydrohalogenide salt of nilotinib; and
(b) a carboxylic acid, carboxylic acid ester, carboxylic acid amide, or sulfonic acid.

2. A crystalline material comprising a co-crystal of component (a) and component (b), wherein:
(a) a hydrohalogenide salt of nilotinib; and
(b) a carboxylic acid.

3. The crystalline material according to claim 1 , wherein component (a) is a hydrochloride salt of nilotinib.

4. The crystalline material according to claim 1 , wherein component (b) is a carboxylic acid.

5. The crystalline material according to claim 1 , wherein a molar ratio of component (a) and component (b) is from about 2:1 to about 1:2.

6. The crystalline material according to claim 1 , wherein (b) is fumaric acid, and the crystalline material has a powder X-ray diffraction pattern with the characteristic peaks expressed in d-values(Å): 13.6, 7.1, 5.68, 4.84, 4.67, 4.57, 3.87, 3.69, 3.39, 3.36, 3.31, and 3.16.

7. The crystalline material according to claim 1 , wherein (b) is maleic acid, and the crystalline material has a powder X-ray diffraction pattern with the following characteristic peaks expressed in d-values (Å):
a) 17.2, 15.8, 10.8, 9.1, 7.3, 5.89, 3.66, and 3.60, or
b) 16.6, 15.7, 13.0, 10.7, 9.2, 8.7, 7.3, 6.0, 5.83, 5.39, 5.22, 3.92, 3.65, 3.53, 3.51, 3.44 and 3.40, or
c) 10.8, 9.2, 3.93 and 3.66.

8. The crystalline material according to claim 1 , wherein (b) is succinic acid, and the crystalline material has a powder X--ray diffraction pattern with the characteristic peaks expressed in d-values (Å): 21.1, 3.56, 3.45, and 3.36, or 10.3, 4.58, 3.52 and 3.35.

9. The crystalline material according to claim 1 , wherein the carboxylic acid is gentisic acid, and the crystalline material has a powder X-ray diffraction pattern with the characteristic peaks expressed in d-values (Å):
A) 16.2, 10.1, 3.45, 3.33, and 3.31, herein designated as nilotinib hydrochloride gentisic acid co-crystal form A;
B) 16.1, 10.1, 7.3, 6.0, 5.60, 3.58, 3.42, 3.31, 3.28 and 3.25, herein designated as nilotinib hydrochloride gentisic acid co-crystal form B;
C) 10.1, 7.7, 5.93, 5.02, 3.60, and 3.55, herein designated as nilotinib hydrochloride gentisic acid co-crystal form C;
D) 16.3, 10.2, 6.1, 5.68, 3.62, 3.58, 3.46, 3.35, 3.32 and 3.29, herein designated as nilotinib hydrochloride gentisic acid co-crystal form D; or
E) 16.2, 15.8, 9.9, 3.41, and 3.29, herein designated as nilotinib hydrochloride gentisic acid co-crystal form E.

10. The crystalline material according to claim 1 , wherein the carboxylic acid is izentisic acid, and the crystalline material has a powder X-ray diffraction pattern with the characteristic peaks expressed in d-values (Å):
16.2, 10.1, 7.4, 6.1, 5.59, 4.61, 3.61, 3.45, 3.33, 3.31 and 3.27, herein designated as nilotinib hydrochloride gentisic acid co-crystal form A; or
16.2, 15.8, 9.9, 7.1, 5.97, 5.53, 4.76, 3.58, 3.53, 3.41, 3.29 and 3.23, herein designated as nilotinib hydrochloride gentisic acid co-crystal form E.

11. The crystalline material according to claim 1 , wherein component (b) is a carboxylic acid amide or carboxylic acid ester, and wherein a molar ratio of component (a) and component (b) is from about 2:1 to about 1:1.

12. The crystalline material according to claim 1 , wherein component (b) is isonicotinamide, and the crystalline material has a powder X-ray diffraction pattern with the characteristic peaks expressed in d-values (Å):
13.6, 12.4, 6.2, 3.65, 3.54, 3.48 and 3.38, herein designated as the nilotinib hydrochloride isonicotinamide co-crystal.

13. The crystalline material according to claim 1 , wherein component (b) is gallic acid methyl ester, and the crystalline material has a powder X-ray diffraction pattern with the characteristic peaks expressed in d-values (Å):
17.2, 15.0, 12.3, 11.5, 8.0, 6.8, 5.66, 5.51 and 3.46, herein designated as the nilotinib hydrochloride gallic acid methyl ester co-crystal.

14. The crystalline material according to claim 1 , wherein component (b) is 1,5-naphtalene disulfonic acid, and the crystalline material has a powder X-ray diffraction pattern with the characteristic peaks expressed in d-values (Å):
a) 10.0, 9.4, 9.2, 7.7, 5.95, 4.83, 4.69, 3.53, 3.50, and 3.35, herein designated as nilotinib naphthalene disulfonic acid co-crystal form 1;
b) 18.4, 9.9, 8.3, 7.8, 6.1, 5.86, 4.85, 4.63, 4.42, 4.29, 4.10, 3.87, and 3.68, herein designated as nilotinib naphthalene disulfbnic acid co-crystal form 2;
c) 16.6, 5.78, 3.52, 3.46, and 3.40, herein designated as nilotinib naphthalene disulthnic acid co-crystal form 3;
d) 12.0, 7.9, 6.8, 6.6, 5.50, 5.20, 4.74, 4.63, 3.76, 3.68, and 3.48, herein designated as nilotinib naphthalene disulfbnic acid co-crystal form 4;
e) 12.0, 7.9, 7.7, 6.8, 6.0, 5.17, 4,72, 4.65, 3.72 and 3.51, herein designated as nilotinib naphthalene disulfonate form 5; or
f) 12.0, 6.8, 5.20, 3.76 and 3.69, herein designated as nilotinib naphthalene disulfonate form 6.

15. The crystalline material according to claim 1 , consisting essentially of
(a) nilotinib, a hydrohalogenide salt of nilotinib, or a mixture of nilotinib and a hydrohalogenide salt of nilotinib;
(b) fumaric acid, maleic acid, succinic acid, gentisic acid, isonicotinamide, gallic acid methyl ester, or 1,5-naphtalene disulfonic acid; and optionally
(c) up to 2.5 mol of water per mol of nilotinib.

16. The crystalline material according to claim 1 , wherein the crystalline material is suitable for the treatment of the human or animal body.

17. A pharmaceutical composition comprising a crystalline material according to claim 1 , and optionally further comprising comprising pharmaceutically acceptable carriers, diluents, and/or further ingredients.

18. The pharmaceutical composition according to claim 17 , wherein the pharmaceutical composition is suitable for the treatment of chronic myelogenous leukemia (CML).

19. The pharmaceutical composition according to claim 17 , wherein the carboxylic acid is fumaric acid and which has at least one characteristic peak in an x-ray powder diffractogram expressed in d-values (Å) selected from 13.6, 7.1, 5.68, 4.84, 4.67, 4.57, 3.87, 3.69, 3.39, 3.36, 3.31, and 3.16; or
wherein the carboxylic acid is maleic acid and which has at least one characteristic peak in an x-ray powder diffractogram expressed in d-values (Å) selected from 17.2, 15.8, 10.8, 9.1, 7.3, 5.89, 3.66, and 3.60; or
wherein the carboxylic acid is maleic acid and which has at least one characteristic peak in an x-ray powder diffractogram expressed in d-values (Å) selected from 16.6, 15.7, 13.0, 10.7, 9.2, 8.7, 7.3, 6.0, 5.83, 5.39, 5.22, 3.92, 3.65, 3.53, 3.51, 3.44 and 3.40; or
wherein the carboxylic acid is maleic acid and which has at least one characteristic peak in an x-ray powder diffractogram expressed in d-values (Å) selected from 10.8, 9.2, 5.4, 5.22, 3.93, 3.66, 3.54, 3.51, and 3.45; or
wherein the carboxylic acid is succinic acid and which has at least one characteristic peak in an x-ray powder diffractogram expressed in d-values (Å) selected from 21.1, 3.56, 3.45, and 3.36, or 10.3, 4.58, 3.52 and 3.35; or
wherein the carboxylic acid is gentisic acid and which has at least one characteristic peak in an x-ray powder diffractogram expressed in d-values (Å) selected from 16.2, 10.1, 3.45, 3.33, and 3.31; or
wherein the carboxylic acid is gentisic acid and which has at least

Assignees

• Basf Se

Inventors

• Chiodo Tiziana
• Hafner Andreas
• Hintermann Tobias
• Salvador Beate
• Szelagiewicz Martin
• Blatter Fritz
• Roedel Eva
• Vossen Marcus

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title