Valbenazine salts and polymorphs thereof

Patent metadata

Field	Value
Publication number	US-10844058-B2
Application number	US-202016899641-A
Country	US
Kind code	B2
Filing date	Jun 12, 2020
Priority date	Oct 30, 2015
Publication date	Nov 24, 2020
Grant date	Nov 24, 2020

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,l-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.

First claim

What is claimed is:

1. A crystalline form 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,l-a]isoquinolin-2-yl ester tosylate salt having a differential scanning calorimetric (DSC) peak temperature within 2% of 243° C.

2. The crystalline form of claim 1 , wherein the DSC peak temperature is within 1% of 243° C.

3. The crystalline form of claim 1 , wherein the DSC peak temperature is within 0.5% of 243° C.

4. The crystalline form of claim 1 , wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a two-theta angle of 6.3°±0.2°.

5. The crystalline form of claim 1 , wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a two-theta angle of 17.9°±0.2°.

6. The crystalline form of claim 1 , wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a two-theta angle of 19.7°±0.2°.

7. The crystalline form of claim 1 , wherein the crystalline form is stable upon exposure to about 25° C. and about 60% relative humidity.

8. The crystalline form of claim 1 , wherein the crystalline form has a D90 particle size of about 70 μM in length.

9. The crystalline form of claim 1 , wherein the crystalline form has a D10 particle size of about 10 μM in length.

10. The crystalline form of claim 1 , wherein the crystalline form 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,l-a]isoquinolin-2-yl ester tosylate salt.

11. The crystalline form of claim 1 , wherein the crystalline form has a purity of no less than 98% 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,l-a]isoquinolin-2-yl ester tosylate salt.

12. The crystalline form of claim 1 , wherein the crystalline form 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,l-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°±0.2°, 17.9°±0.2°, and 19.7°±0.2°.

13. The crystalline form of 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:

14. A pharmaceutical composition comprising the crystalline form of claim 1 and a pharmaceutically acceptable carrier.

15. The pharmaceutical composition of claim 14 , wherein the composition is formulated for oral administration.

16. The pharmaceutical composition of claim 14 , wherein the pharmaceutical composition is a unit dosage form.

17. The pharmaceutical composition of claim 14 , wherein the pharmaceutical composition is in the form of a capsule.

18. A pharmaceutical composition comprising the crystalline form of claim 12 and a pharmaceutically acceptable carrier.

19. The pharmaceutical composition of claim 18 , wherein the composition is formulated for oral administration.

20. The pharmaceutical composition of claim 18 , wherein the pharmaceutical composition is a unit dosage form.

21. The pharmaceutical composition of claim 18 , wherein the pharmaceutical composition is in the form of a capsule.

22. A pharmaceutical composition comprising the crystalline form of claim 13 and a pharmaceutically acceptable carrier.

23. The pharmaceutical composition of claim 22 , wherein the composition is formulated for oral administration.

24. The pharmaceutical composition of claim 22 , wherein the pharmaceutical composition is a unit dosage form.

25. The pharmaceutical composition of claim 22 , wherein the pharmaceutical composition is in the form of a capsule.

26. A method of treating a hyperkinetic movement disorder comprising administering the crystalline form of claim 1 , wherein the treating is ameliorating one or more symptoms of the hyperkinetic movement disorder.

27. The method of claim 26 , wherein the hyperkinetic movement disorder is tardive dyskinesia.

Assignees

• Neurocrine Biosciences Inc

Inventors

• Mcgee Kevin
• Zook Scott E
• Carr Andrew
• Bonnaud Thierry
• Li Bin-Feng

Classifications

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61K31/4745

  condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48) · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D455/06 Primary

  containing benzo [a] quinolizine ring systems · CPC title