Claims for Patent: 10,851,104

Summary for Patent: 10,851,104

Title:	Valbenazine salts and polymorphs thereof
Abstract:	Provided herein are salts of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]-isoquinolin-2-yl ester in amorphous and crystalline forms, and processes of preparation, and pharmaceutical compositions thereof. Also provided are methods of their use for treating, preventing, or ameliorating one or more symptoms of neurological disorders and diseases including hyperkinetic movement disorders or diseases.
Inventor(s):	McGee; Kevin (San Diego, CA), Zook; Scott E. (San Diego, CA), Carr; Andrew (Cambridge, GB), Bonnaud; Thierry (Cambridge, GB), Li; Bin-Feng (Suzhou Industrial Park, CN)
Assignee:	Neurocrine Biosciences, Inc. (San Diego, CA)
Application Number:	16/899,654
Patent Claims:	1. A process for preparing crystalline Form I of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester tosylate salt comprising the steps of: contacting (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester tosylate salt with a solvent; and isolating crystalline Form I of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester tosylate salt. 2. The process according to claim 1, wherein the solvent is selected from: acetonitrile, dichloromethane, N,N-dimethylformamide (DMF), 1,4-dioxane, methanol, 2-methoxyethanol, methyl isobutyl ketone (MIBK), acetone, 1-butanol, methyl t-butyl ether (MTBE), dimethyl sulfoxide (DMSO), ethanol, ethyl acetate, isobutyl acetate, isopropyl acetate, 1-propanol, isopropanol (IPA), methyl ethyl ketone (MEK), tetrahydrofuran (THF), water; and a mixture thereof. 3. The process according to claim 2, wherein the solvent is methyl isobutyl ketone (MIBK). 4. The process according to claim 2, wherein the solvent is isopropanol (IPA). 5. The process according to claim 2, wherein the solvent is acetonitrile. 6. The process according to claim 1, wherein prior to the contacting with the solvent (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester tosylate salt is a form selected from: an oil, a semisolid, a solid, and mixtures thereof. 7. The process according to claim 6, wherein the solid of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester tosylate salt is selected from: an amorphous form, Form I, Form II, Form III, Form IV, Form V, Form VI, and mixtures thereof. 8. The process according to claim 1, wherein the isolating comprises filtering crystalline Form I of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester tosylate salt from the solvent. 9. The process according to claim 1, wherein crystalline Form I of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester tosylate salt has a purity of no less than 97% by weight of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester tosylate salt. 10. The process according to claim 1, wherein crystalline Form I of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester tosylate salt has a differential scanning calorimetric (DSC) onset temperature within 2% of 240.degree. C. 11. The process according to claim 10, wherein the DSC onset temperature is within 0.5% of 240.degree. C. 12. The process according to claim 1, wherein crystalline Form I of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9, 10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester tosylate salt has a differential scanning calorimetric (DSC) peak temperature within 2% of 243.degree. C. 13. The process according to claim 12, wherein the DSC peak temperature is within 0.5% of 243.degree. C. 14. The process according to claim 1, wherein crystalline Form I of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9, 10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester tosylate salt has an X-ray powder diffraction (XRPD) pattern comprising a peak at a two-theta angle of 6.3.degree..+-.0.2.degree.. 15. The process according to claim 1, wherein crystalline Form I of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9, 10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester tosylate salt has an X-ray powder diffraction (XRPD) pattern comprising a peak at a two-theta angle of 17.9.degree..+-.0.2.degree.. 16. The process according to claim 1, wherein crystalline Form I of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9, 10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester tosylate salt has an X-ray powder diffraction (XRPD) pattern comprising a peak at a two-theta angle of 19.7.degree..+-.0.2.degree.. 17. The process according to claim 1, wherein crystalline Form I of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9, 10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester tosylate salt is stable upon exposure to about 25.degree. C. and about 60% relative humidity. 18. The process according to claim 1, wherein crystalline Form I of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester tosylate salt has a purity of no less than 97% by weight of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester tosylate salt; and has a differential scanning calorimetric (DSC) onset temperature within 2% of 240.degree. C. and a differential scanning calorimetric (DSC) peak temperature within 2% of 243.degree. C. 19. The process according to claim 1, wherein the solvent is acetonitrile; and crystalline Form I of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester tosylate salt has a purity of no less than 97% by weight of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester tosylate salt; and has a differential scanning calorimetric (DSC) onset temperature within 2% of 240.degree. C. and a differential scanning calorimetric (DSC) peak temperature within 2% of 243.degree. C. 20. The process according to claim 1, wherein crystalline Form I of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester tosylate salt has a purity of no less than 97% by weight of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester tosylate salt; and has an X-ray powder diffraction (XRPD) pattern comprising peaks at two-theta angles of 6.3.degree..+-.0.2.degree., 17.9.degree..+-.0.2.degree., and 19.7.degree..+-.0.2.degree.. 21. The process according to claim 1, wherein the solvent is acetonitrile; and crystalline Form I of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester tosylate salt has a purity of no less than 97% by weight of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester tosylate salt; and has an X-ray powder diffraction (XRPD) pattern comprising peaks at two-theta angles of 6.3.degree..+-.0.2.degree., 17.9.degree..+-.0.2.degree., and 19.7.degree..+-.0.2.degree.. 22. The process according to claim 1, wherein the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester tosylate salt is: ##STR00006## 23. Crystalline Form I of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester tosylate salt prepared according to claim 1. 24. Crystalline Form I of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester tosylate salt prepared according to claim 18. 25. Crystalline Form I of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester tosylate salt prepared according to claim 19. 26. Crystalline Form I of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester tosylate salt prepared according to claim 21. 27. Crystalline Form I of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester tosylate salt prepared according to claim 22. 28. A method of treating a hyperkinetic movement disorder comprising administering the crystalline form of claim 23, wherein the treating is ameliorating one or more symptoms of the hyperkinetic movement disorder. 29. The method of claim 28, wherein the hyperkinetic movement disorder is tardive dyskinesia.