Salts of Dasatinib in crystalline form

Patent metadata

Field	Value
Publication number	US-9556164-B2
Application number	US-201414907148-A
Country	US
Kind code	B2
Filing date	Jul 22, 2014
Priority date	Jul 25, 2013
Publication date	Jan 31, 2017
Grant date	Jan 31, 2017

Abstract

The present invention primarily relates to molecular crystalline substances, preferably salts of Dasatinib in crystalline form, comprising a compound of formula 1, preferably a cation of a compound of formula 1,

and a second compound selected from the group consisting of glutaric acid, nicotinic acid and saccharin, preferably an anion thereof. The invention is further related to pharmaceutical compositions comprising such a substance. Furthermore, the invention relates to processes for preparing said substances. The invention also relates to several aspects of using said substances or pharmaceutical compositions to treat a disease.

First claim

The invention claimed is:

1. A molecular crystalline substance in crystalline form, comprising a compound of formula 1 also known as Dasatinib,

and
a second compound selected from the group consisting of
a) saccharin which crystalline substance has a PXRD pattern with at least one characteristic peak, expressed in 2θ±0.2° 2θ using CuKα radiation, selected from the following peaks located at 9.7, 13.4, 15.1, 20.4, 20.7, 21.6, 22.6, 23.5, 24.4 and 25.2° or a PXRD pattern with at least one characteristic peak, expressed in 2θ±0.2° 2θ using CuKα radiation, selected from the following peaks located 4.3, 8.0, 14.9. 20.8, 23.7 and 25.5°,
b) glutaric acid which crystalline substance has a PXRD pattern with at least one characteristic peak, expressed in 2θ±0.2° 2θ using CuKα radiation, selected from the following peaks located at 5.6, 5.8, 11.1, 15.8, 16.7, 23.3, 23.5 and 25.2°, and
c) nicotinic acid which crystalline substance has a PXRD pattern with at least one characteristic peak, expressed in 2θ±0.2° 2θ using CuKα radiation, selected from the following peaks located at 5.9, 11.0, 14.7, 19.9, 24.3, 25.8 and 27.3°.

2. The substance according to claim 1 , wherein the substance is a saccharinate salt.

3. The substance according to claim 1 , wherein the substance is a salt selected from the group consisting of saccharinate hydrate, saccharinate isopropanol solvate, glutarate and nicotinate.

4. The substance as claimed in claim 1 , wherein the molar ratio of Dasatinib and the organic acid is in the range of from 2:1 to 1:2.

5. A pharmaceutical composition comprising, as active ingredient, the substance according to claim 1 , and further comprising one, two, three, or more pharmaceutically acceptable carriers, diluents, or further ingredients.

6. The pharmaceutical composition according to claim 5 , wherein the total amount of the substance in the composition is in the range of from 0.1 to 300 mg.

7. The pharmaceutical composition according to claim 5 , wherein the total amount of the substance in the composition is in the range of from 5.0 to 200 mg.

8. A method for treating cancer which comprises administering to a patient in need of treatment an effective amount of the substance as claimed in claim 1 .

9. A process for obtaining the substance according to claim 1 comprising the steps of:
a) providing a compound of formula 1, which is also known as Dasatinib,

in a solvent or a mixture of solvents
b) adding glutaric acid, or nicotinic acid, or saccharin to the mixture of step a);
c) optionally concentrating the composition of step b);
d) crystallizing;
e) optionally evaporating to dryness or equilibrating the obtained suspension of step d); and
f) isolating the obtained precipitate.

10. A process for the purification of Dasatinib, which is a compound of formula 1,

which process comprises the steps of providing a solution or dispersion containing the compound of formula 1 and a second compound selected from the group consisting of glutaric acid, nicotinic acid and saccharin in a suitable solvent, and
isolating the crystalline substance according to claim 1 .

11. A process for the purification of Dasatinib, which is a compound of formula 1,

which process comprises the steps of
providing a solution or dispersion containing the compound of formula 1 and a second compound selected from the group consisting of glutaric acid, nicotinic acid and saccharin in a suitable solvent, and
isolating a crystalline substance comprising a compound of formula 1,

and
a second compound selected from the group consisting of saccharin, glutaric acid, and nicotinic acid, and
said process following the steps (a) to (f) according to claim 9 .

12. The process according to claim 11 , wherein the second compound is saccharin, and the molar ratio of the compound of formula 1 and saccharin provided is in the range from 1:0.5 to 1:3.

13. The process according to claim 11 , wherein the solvent is selected from the group consisting of C 1 -C 4 alcohols, water, or mixtures thereof, and/or wherein seed crystals are added before crystallizing.

14. The pharmaceutical composition according to claim 1 , wherein the further ingredients-are one, two, three, or more pharmaceutical excipients.

15. The method for treating cancer as claimed in claim 8 , wherein the cancer is chronic myelogenous leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia.

16. A method for treating cancer which comprises administering to a patient in need of treatment an effective amount of the pharmaceutical composition according to claim 5 to a patient.

17. The method for treating cancer as claimed in claim 15 , wherein the cancer is chronic myelogenous leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia.

18. The method according to claim 8 , wherein the total amount of the substance is in the range of from 0.1 to 300 mg.

19. The method according to claim 16 , wherein the total amount of the pharmaceutical composition is in the range of from 0.1 to 300 mg.

Assignees

• Basf Se

Inventors

• Hafner Andreas
• Blatter Fritz
• Szelagiewicz Martin
• Siebenhaar Bernd
• Chiodo Tiziana
• Hintermann Tobias
• Salvador Beate
• Vossen Marcus

Classifications

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07D417/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D275/06

  with hetero atoms directly attached to the ring sulfur atom · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title