MULTICOMPONENT CRYSTALS OF DASATINIB WITH MENTHOL OR VANILLIN

Abstract

The present invention primarily relates to multicomponent crystals comprising a compound of formula 1 and a second compound selected from the group consisting of menthol and vanillin. The invention is further related to pharmaceutical compositions comprising such multicomponent crystals. Furthermore, the invention relates to processes for preparing said multicomponent crystals. The invention also relates to several aspects of using said multicomponent crystals or pharmaceutical compositions to treat a disease.

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Claims

1. A process for obtaining a multicomponent crystals crystal comprising Dasatinib, which is a compound of formula 1 ##STR00008## and a second compound selected from the group consisting of menthol and vanillin, the process comprising: (a) providing the compound of formula 1; and (b) adding at least a stoichiometric amount of menthol or vanillin to the compound of formula 1 such that the menthol or vanillin is used as a co-crystal former and as a solvent to form a mixture that can be stirred, or adding at least a stoichiometric amount of menthol or vanillin as a co-crystal former and an additional solvent to the compound of formula 1 such that a mixture is formed, wherein the additional solvent is selected from the group consisting of a C2 to C5 alcohol, a C3 to C6 ketone, a C2 to C6 ester, an ether, an alkane, and a mixture thereof.

2. A process according to claim 1, wherein the adding in (b) further comprises heating the mixture to a temperature of at least a melting temperature of the co-crystal former.

3. A process according to claim 1, wherein the multicomponent crystal is formed in a suspension or a concentrated solution of the menthol or vanillin in the additional solvent, or in a suspension or a concentrated solution of menthol in the absence of the additional solvent.

4. A process according to claim 1, further comprising: (c) heating the mixture obtained in (b) to a temperature of from 40 to 150 C.; (d) optionally cooling the mixture heated in (c) to a temperature from 10 C. to less than 30 C.; (e) isolating a crystalline material; and optionally washing the crystalline material using the menthol or vanillin or the additional solvent, drying the crystalline material, or both.

5. A process according to claim 1, wherein an amount of the menthol or vanillin added in (b) is at least 2 molar parts per 1 molar part of the compound of formula 1.

6. A process according to claim 1, wherein any solvent used in addition to the menthol or vanillin is selected from the group consisting of ethanol, propanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, ethyl formate, ethyl ether, isopropyl ether, methyl tert-butyl ether, pentane and heptane, and a mixture thereof.

7. A process according to claim 1, wherein the menthol is selected from the group consisting of (1R,2S,5R)-()-menthol, (1S,2R,5S)-(+)-menthol, DL-menthol, a stereoisomer of menthol, and a mixture thereof.

8. A multicomponent crystal, comprising: a compound of formula 1 (INN: Dasatinib) ##STR00009## and a second compound selected from the group consisting of menthol and vanillin, wherein the multicomponent crystal is obtained or obtainable by the process according to claim 1.

9. A multicomponent crystal according to claim 8, wherein a molar ratio of the compound of formula 1 to the second compound is in a range of from 1.1:1 to 0.9:1 if the second compound is vanillin, and a molar ratio of the compound of formula 1 to the second compound is in a range of from 2.2:1 to 1.8:1 if the second compound is menthol.

10. A multicomponent crystal according to claim 8, wherein the second compound is menthol and the multicomponent crystal has a PXRD pattern comprising characteristic peaks, expressed in 20.2 2, CuK radiation, located at 5.8, 9.1, 10.4, 11.7, 11.9. 12.7, 14.9, 15.7 16.5. 18.2, 21.1, 21.3, 21.8, 22.8, 23.9, and 24.4.

11. A multicomponent crystal according to claim 8, wherein the second compound is vanillin and the multicomponent crystal has a PXRD pattern comprising characteristic peaks, expressed in 20.2 2, CuK radiation, located at 5.9, 8.9, 11.2, 11.8, 12.9, 15.4, 16.0, 17.7, 17.9, 18.6, 19.0, 19.8 20.7, 22.4, 24.0, 24.6, 25.4, and 26.3.

12. A composition, essentially consisting of: the multicomponent crystal according to claim 8; menthol or vanillin; and up to 0.5% by weight, relative to a total weight of the composition, of the additional solvent.

13. A pharmaceutical composition, comprising: an active ingredient comprising the multicomponent crystal according to claim 8; and a pharmaceutically acceptable carrier, a diluent, a pharmaceutical excipient, or a mixture thereof.

14. A pharmaceutical composition according to claim 13, wherein a total amount of the multicomponent crystal per dosage unit is in a range of from 0.1 to 300 mg.

15. A method for treating cancer, comprising: administering to a subject the multicomponent crystal according to claim 8, wherein the cancer is at least one of chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

16. A method according to claim 1, wherein an amount of the menthol or vanillin added to the compound of formula 1 is substantially greater than an amount of menthol or vanillin in the multicomponent crystal.

17. The method according to claim 1, wherein the additional solvent comprises an ICH class 3 solvent.

18. A method according to claim 1, wherein the additional solvent is added in (b) such that suspension equilibration and filtration are carried out at a temperature lower than a melting temperature of the co-crystal former.

19. A process according to claim 1, wherein an amount of the menthol or vanillin added in (b) is about 1 to 20 parts by weight per one part by weight of the compound of formula 1.

20. A composition according to claim 12, wherein the composition contains less than 0.5% by weight of a component other than the multicomponent crystal, the menthol or vanillin, and the additional solvent.

Description

BRIEF DESCRIPTION OF FIGURES

[0147] FIG. 1: PXRD pattern of Dasatinib-menthol co-crystal 2:1 (CuK radiation)

[0148] FIG. 2: PXRD pattern of Dasatinib-vanillin co-crystal 1:1 (CuK radiation)