Multi-component crystals of vismodegib and selected co-crystal formers or solvents

Patent metadata

Field	Value
Publication number	US-10105355-B2
Application number	US-201515501908-A
Country	US
Kind code	B2
Filing date	Aug 3, 2015
Priority date	Aug 7, 2014
Publication date	Oct 23, 2018
Grant date	Oct 23, 2018

Abstract

The present invention primarily relates to multi-component crystals comprising a compound of formula 1

and a second compound selected from the group consisting of co-crystal formers and solvents. The invention is further related to pharmaceutical compositions comprising such multi-component crystals. Furthermore, the invention relates to processes for preparing said multi-component crystals. The invention also relates to several aspects of using said multi-component crystals or pharmaceutical compositions to treat a disease.

First claim

The invention claimed is:

1. A multi-component crystal comprising Vismodegib, which is a compound of formula 1,

and
a second compound which is a compound in the solid state and is a co-crystal former selected from the group consisting of maleic acid, N-cyclohexyl-sulfamic acid, sorbitol and xylitol and
a solvent which is selected from the group consisting of benzylamine and triethanolamine.

2. The multi-component crystal according to claim 1 , wherein the molar ratio of Vismodegib to the second compound is in the range of from 3:1 to 1:3.

3. The multi-component crystal according to claim 1 , wherein the second compound is maleic acid and the multi-component crystal 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 6.7, 10.7, 13.1, 15.8, 18.0, 19.5, 20.1, 20.4, 21.8, 22.3, 25.4, 26.1, 27.0, 27.4, 27.9, 28.3, 29.0, 29.3.

4. The multi-component crystal according to claim 1 , wherein the second compound is N-cyclohexyl-sulfamic acid and the multi-component crystal 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 7.9, 11.3, 12.1, 13.4, 15.8, 16.0, 16.8, 17.6, 18.6, 19.0, 19.9, 21.3, 21.7, 22.0, 24.6, 24.8, 26.1, 26.7.

5. The multi-component crystal according to claim 1 , wherein the second compound is N-cyclohexyl-sulfamic acid and the multi-component crystal 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 6.4, 12.8, 18.5, 19.2, 21.6, 26.0.

6. The multi-component crystal according to claim 1 , wherein the second compound is sorbitol and the multi-component crystal 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 9.8, 11.4, 12.1, 13.4, 16.0, 16.9, 17.4, 17.7, 18.1, 19.1, 19.5, 20.0, 21.5, 22.0, 24.7, 24.9, 26.1, 26.7.

7. The multi-component crystal according to claim 1 , wherein the second compound is xylitol and the multi-component crystal 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, 11.4, 12.1, 13.4, 16.0, 16.8, 17.4, 17.6, 18.0, 19.0, 19.8, 21.5, 22.0, 22.5, 23.7, 24.6, 24.8, 26.1, 26.7, 27.0, 31.5, 32.9.

8. The multi-component crystal according to claim 1 , wherein the second compound is benzylamine and the multi-component crystal 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 9.8, 11.3, 12.0, 13.5, 16.0, 16.7, 17.3, 17.6, 17.9, 18.9, 20.7, 21.5, 21.9, 22.7, 24.3, 24.7, 26.1, 26.8, 27.1, 28.3, 28.6.

9. The multi-component crystal according to claim 1 , wherein the second compound is triethanolamine and the multi-component crystal 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 9.4, 10.7, 11.5, 12.1, 13.7, 14.3, 15.7, 16.0, 16.6, 17.3, 18.0, 18.9, 21.4, 22.2, 23.1, 23.9, 24.4, 25.6, 25.9, 27.3, 27.7, 28.4.

10. A pharmaceutical composition comprising, as active ingredient, the multi-component crystal according to claim 1 , and further comprising one, two, three, or more pharmaceutically acceptable carriers, and/or diluents, and/or further ingredients.

11. A pharmaceutical composition comprising, as active ingredient, the multi-component crystal according to claim 1 , and further comprising one, two, three, or more pharmaceutically acceptable carriers, and/or diluents, and/or one, two, three, or more pharmaceutical excipients.

12. The pharmaceutical composition according to claim 10 , wherein the total amount of Vismodegib in the multi-component crystal in the composition is in the range from 0.1 to 500 mg.

13. The pharmaceutical composition according to claim 10 , wherein the total amount of Vismodegib in the multi-component crystal in the composition is in the range from 20 to 250 mg.

14. The pharmaceutical composition according to claim 10 , wherein the total amount of Vismodegib in the multi-component crystal in the composition is in the range from 50 to 200 mg.

15. A medicament comprising the multi-component crystal according to claim 1 .

16. A process for obtaining the multi-component crystal according to claim 1 comprising the steps of:
a) providing Vismodegib which is a compound of formula 1,

as a solid or in solution;
b) adding maleic acid, N-cyclohexyl-sulfamic acid, sorbitol, xylitol, benzylamine or triethanolamine to the compound/composition of step a);
c) optionally concentrating the composition of step b) or adding an antisolvent to 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.

Assignees

• Basf Se

Inventors

• Viertelhaus Martin
• Chiodo Tiziana
• Salvador Beate
• Vossen Marcus
• Hafner Andreas
• Hintermann Tobias
• Weishaar Walter
• Hellmann Rolf

Classifications

• C07D213/40 Primary

  Acylated substituent nitrogen atom · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/4402 Primary

  only substituted in position 2, e.g. pheniramine, bisacodyl · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title