Polymorphs of cabozantinib (S)-malate and cabozantinib free base
The present disclosure provides novel crystalline forms of cabozantinib (S)-malate, designated as form-M 1 , M 2 , M 3 and M 4 and novel crystalline forms of cabozantinib free base, form-M 1 , M 2 and M 3 and methods of their production. The present disclosure also provides processes for the preparation of crystalline cabozantinib (S)-malate form N-1.
1. Crystalline polymorph form-M 4 of cabozantinib (S)-malate, which is characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 8 or a thermogravimetric analysis pattern substantially as shown in FIG. 9 .
2. Crystalline polymorph form-M 4 of cabozantinib (S)-malate, which has an X-ray powder diffraction pattern with significant peaks at about 20 values of 9.3, 13.3, 15.0, 22.8, and 25.8(±)0.2°.
3. A process for the preparation of crystalline form-M 4 of cabozantinib (S)-malate of claim 2 comprising the steps of:
a) dissolving cabozantinib base and (S)-malic acid in a solvent to create a solution;
b) adding the solution to a non-polar solvent; and
c) isolating crystalline form-M 4 of cabozantinib (S)-malate.
4. The process according to claim 3 , wherein the solvent is selected from an ethereal solvent, an alcoholic solvent, water, or mixtures thereof.
5. The process according to claim 4 , wherein the ethereal solvent is selected from the group consisting of dimethyl ether, diethyl ether, ethyl methyl ether, methyl-tert-butyl ether, tetrahydrofuran, and 1,4-dioxane.
6. The process according to claim 4 wherein the alcoholic solvent is selected from the group consisting of methanol, ethanol, propanol, and butanol.
7. The process according to claim 4 , wherein the solvent is a mixture of tetrahydrofuran and water.
8. The process according to claim 7 , wherein the mixture of tetrahydrofuran and water are exist in a ratio of 15:1.
9. The process according to claim 3 , wherein the non-polar solvent is selected from the group consisting of C1-C10 alkanes or a mixture of C1-C10 alkanes.
10. The process according to claim 9 , wherein non-polar solvent is n-heptane.
11. A process for the preparation of crystalline form-M 4 of cabozantinib (S)-malate of claim 2 comprising the steps of:
a) dissolving cabozantinib (S)-malate in an amide solvent to create a reaction mixture;
b) adding a solvent to the reaction mixture; and
c) isolating the crystalline form-M 4 of cabozantinib (S)-malate.
12. The process according to claim 11 , wherein the amide solvent is selected from the group consisting of N, N-dimethylacetamide, N, N-dimethylformamide, and N-methylpyrrolidone.
13. The process according to claim 12 where the amid solvent is N, N-dimethylacetamide.
14. The process according to claim 11 , wherein the solvent selected from the group consisting of an ethereal solvent, an alcoholic solvent, and mixtures thereof.
15. The process according to claim 14 , wherein the ethereal solvent is selected from the group consisting of dimethyl ether, diethyl ether, ethyl methyl ether, methyl-t-butyl ether, tetrahydrofuran, and 1,4-dioxane.
16. The process according to claim 14 wherein the alcoholic solvent is selected from the group consisting of methanol, ethanol, propanol, and butanol.
17. The process according to claim 14 , wherein the solvent is a mixture of methyl-t-butyl ether and ethanol.