Crystalline form of Valbenazine dibesylate
The present invention provides a novel crystalline form of Valbenazine dibesylate, Valbenazine dibesylate Form APO-I, compositions and processes for the preparation thereof, and the use of this crystalline form in the treatment of hyperkinetic disorders, including tardive dyskinesia.
1. A crystalline form of Valbenazine dibesylate characterized by a PXRD diffractogram comprising peaks, expressed in degrees 2θ (±0.2°), at 6.3°, 9.8° and 15.6°.
2. The crystalline form of claim 1 , characterized by a PXRD diffractogram further comprising at least three peaks, expressed in degrees 2θ (±0.2°), selected from the group consisting of: 5.3°, 7.7°, 8.5°, 12.5°, 14.0°, 16.8°, 17.1°, 17.8°, 18.6° and 19.7°.
3. The crystalline form of claim 1 , characterized by a PXRD diffractogram further comprising peaks, expressed in degrees 2θ (±0.2°), at 5.3°, 7.7°, 8.5°, 12.5°, 14.0°, 16.8°, 17.1°, 17.8°, 18.6° and 19.7°.
4. The crystalline form of claim 1 , characterized by a DSC thermogram comprising an endothermic peak with a peak onset of approximately 235° C. and a peak maximum of approximately 238° C.
5. The crystalline form of claim 1 , characterized by a DSC thermogram that is substantially the same in appearance as the DSC thermogram provided in FIG. 2 .
6. The crystalline form of claim 1 , providing a PXRD diffractogram comprising peaks in substantially the same positions (±0.2° 2 θ) as those shown in FIG. 1 .
7. A pharmaceutical composition comprising the crystalline form of Valbenazine dibesylate according to claim 2 , and one or more pharmaceutically acceptable excipients.
8. The pharmaceutical composition of claim 7 , wherein the pharmaceutical composition is a capsule.
9. The pharmaceutical composition of claim 7 , wherein the pharmaceutical composition comprises an amount of the crystalline form that is equivalent to 40 mg or 80 mg Valbenazine free base.
10. A process for the preparation of the crystalline form of Valbenazine dibesylate according to claim 1 , the process comprising:
(i) reacting, in the presence of a first solvent (S1), a compound of Formula (2):
with at least two equivalents of benzenesulfonic acid to afford Valbenazine dibesylate;
(ii) forming a suspension by crystallization of the Valbenazine dibesylate; and
(iii) filtering the suspension to isolate the crystalline Valbenazine dibesylate,
wherein P is an acid-labile protecting group, wherein P is tert-butoxycarbonyl.
11. The process of claim 10 , wherein the first solvent (S1) is selected from the group consisting of nitriles and halogenated hydrocarbons.
12. The process of claim 11 , wherein the first solvent (S1) is acetonitrile or dichloromethane.
13. The process of claim 10 , wherein the suspension of crystalline Valbenazine dibesylate in step (ii) is formed by the addition of a second solvent (S2).
14. The process of claim 13 , wherein the second solvent (S2) is butanone.
15. The process of claim 13 , wherein the first solvent (S1) is partially or wholly removed prior to addition of the second solvent (S2).
16. The crystalline form of claim 2 , characterized by a DSC thermogram comprising an endothermic peak with a peak onset of approximately 235° C. and a peak maximum of approximately 238° C.
17. The crystalline form of claim 2 , characterized by a DSC thermogram that is substantially the same in appearance as the DSC thermogram provided in FIG. 2 .
18. The crystalline form of claim 5 , providing a PXRD diffractogram comprising peaks in substantially the same positions (±0.2° 2 θ) as those shown in FIG. 1 .