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1. (WO2016020324) MULTI-COMPONENT CRYSTALS OF VISMODEGIB AND SELECTED CO-CRYSTAL FORMERS OR SOLVENTS
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Claims

1 . Multi-component crystals comprising a compound of formula 1 , also known as Vismodegib,


formula 1

and

a second compound selected from the group consisting of co-crystal formers and solvents.

2. Multi-component crystals according to claim 1 , characterized in that the co-crystal former is selected from the group consisting of maleic acid, N-cyclohexyl-sulfamic acid, sorbitol and xylitol.

3. Multi-component crystals according to claim 1 , characterized in that the solvent is selected from the group consisting of benzylamine and triethanolamine.

4. Multi-component crystals according to any of claims 1 to 3, characterized in that the molar ratio of Vismodegib to the second compound is in the range of from 3 : 1 to 1 : 3.

5. Multi-component crystals according to any of claims 1 , 2 or 4, characterized in that 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 CuKa 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.

6. Multi-component crystals according to any of claims 1 , 2 or 4, characterized in that 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 CuKa radiation, selected from the following peaks located at 7.9, 1 1 .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.

7. Multi-component crystals according to any of claims 1 , 2 or 4, characterized in that the second compound is N-cyclohexyl-sulfamic acid and the multi-component crys-tal has a PXRD pattern with at least one characteristic peak, expressed in °2Θ ± 0.2 °2Θ using CuKa radiation, selected from the following peaks located 6.4, 12.8, 18.5, 19.2, 21 .6, 26.0.

8. Multi-component crystals according to any of claims 1 , 2 or 4, characterized in that 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 CuKa radiation, selected from the following peaks located at 9.8, 1 1.4, 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.

9. Multi-component crystals according to any of claims 1 , 2 or 4, characterized in that 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 CuKa radiation, selected from the following peaks located at 9.7, 1 1 .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.

10. Multi-component crystals according to any of claims 1 , 3 or 4, characterized in that 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 CuKa radiation, selected from the following peaks located at 9.8, 1 1 .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.

1 1. Multi-component crystals according to any of claims 1 , 3 or 4, characterized in that 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 CuKa radiation, selected from the following peaks located at 9.4, 10.7, 1 1 .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.

12. Pharmaceutical composition comprising, as active ingredient, multi-component crystals according to any of claims 1 to 1 1 , and preferably further comprising one, two, three, or more pharmaceutically acceptable carriers, and/or diluents, and/or further ingredients, in particular one, two, three, or more pharmaceutical excipients.

13. Pharmaceutical composition according to claim 12, wherein the total amount of Vismodegib in the multi-component crystals in the composition is in the range from 0.1 to 500 mg, preferably from 20 to 250 mg, in particular from 50 to 200 mg.

14. Multi-component crystals according to any of claims 1 to 1 1 , or pharmaceutical com-position according to any of claims 12 to 13, for use as a medicament, preferably for use in the treatment of cancer, in particular for use in the treatment of basal-cell carcinoma.

15. A process for obtaining multi-component crystals according to at least one of claims 1 to 1 1 comprising the steps of:

a) providing a compound of formula 1 , also known as Vismodegib,


formula

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.