Crystalline form of vortioxetine hydrobromide

Patent metadata

Field	Value
Publication number	US-9499504-B2
Application number	US-201314429388-A
Country	US
Kind code	B2
Filing date	Sep 18, 2013
Priority date	Sep 19, 2012
Publication date	Nov 22, 2016
Grant date	Nov 22, 2016

Abstract

The present invention is directed to a crystalline compound comprising a hydrobromide acid (HBr) salt of a compound of formula (I) (1-{2-[(2,4-dimethylphenyl)sulfanyl]phenyl}piperazine, INN: vortioxetine), having an XRPD pattern with characteristic peaks (expressed in 2θ±0.2° 2θ (CuKα radiation)) at 5.5°, 14.8°, 16.7° and 20.0° and processes for obtaining the same.

First claim

The invention claimed is:

1. A crystalline compound comprising a hydrobromic acid (HBr) salt of a compound of formula I (1-{2-[(2,4-dimethylphenyl) sulfanyl]phenyl}piperazine)-{2-[(2,4-dimethylphenyl)-sulfanyl]phenyl}piperazine),

having an XRPD pattern with characteristic peaks (expressed in 2θ±0.2° 2θ (CuKα radiation)) at 5.5°, 14.8°, 16.7° and 20.0°.

2. The crystalline compound of claim 1 , characterized in that it has an XRPD pattern with characteristic peaks (expressed in 2θ±0.2° 2θ (CuKα radiation)) at 5.5°, 14.8°, 16.7°, 20.0°, 27.6°, 28.1°, 28.4°, 28.6°, 29.1°, 30.5° and 34.4°.

3. The crystalline compound of claim 1 , characterized in that the molar ratio of the compound of formula I and the hydrobromic acid is in the range of from 1:0.8 to 1:1.2.

4. The crystalline compound according to claim 1 , characterized in that it has an infrared spectrum comprising peaks at wavenumbers of 2484±2 cm −1 , 2472±2 cm −1 , 1586±2 cm −1 , 1438±2 cm −1 and 764±2 cm −1 .

5. The crystalline compound according to claim 1 , characterized in that it has a water content of less than 0.7 wt-%.

6. The crystalline compound according to claim 1 , characterized in that it has an amount of residual solvents of less than 0.2 wt-%.

7. A pharmaceutical composition comprising the crystalline compound of claim 1 and at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in an oral dosage form.

8. A method for the treatment of major depressive disorder and/or generalized anxiety disorder comprising administering an effective amount of the pharmaceutical composition according to claim 7 to a patient suffering from major depressive disorder and/or generalized anxiety disorder.

9. A crystalline monohydrate of vortioxetine hydrobromide exhibiting monoclinic cells having space group P2 t/c. and having the parameters
a=37.33+/−0.6 Å
b=6.46+/−0.1 Å
c=31.36+/−0.5 Å
α=90°
β=94.9°+/−0.5°
γ=90°
Z=16
as determined by X-ray structural analysis; and
wherein the monohydrate has an XRPD pattern comprising characteristic peaks (expressed in 2θ±0.2° 2θ (CuKα radiation)) at 5.6°, 8.7°, and 9.4°.

10. The crystalline monohydrate of vortioxetine hydrobromide according to claim 9 , wherein the molar ratio of vortioxetine hydrobromide and water is in the range from 1:0.8 to 1:1.2.

11. A method for the preparation of the crystalline monohydrate of vortioxetine hydrobromide according to claim 9 comprising the step of evaporating an aqueous alcoholic solution of vortioxetine hydrobromide at room temperature and recovering the crystals, wherein the alcohol in the aqueous alcoholic solution is selected from methanol, ethanol or mixtures thereof.

12. The method according to claim 11 , wherein the concentration of the alcohol in the aqueous alcoholic solution is in the range from 50 to 96 wt-%.

13. A method for the preparation of the crystalline compound according to claim 1 , comprising heating a crystalline hydrate of vortioxetine hydrobromide to a temperature ranging from 120° C. to 150° C. and recovering the crystals, where the crystalline hydrate of vortioxetine hydrobromide exhibits monoclinic cells having space group P2 t/c. and having the parameters
a=37.33+/−0.6 Å
b=6.46+/−0.1 Å
c=31.36+/−0.5 Å
α=90°
β=94.9°+/−0.5°
γ=90°
Z=16
as determined by X-ray structural analysis.

Assignees

• Sandoz Ag

Inventors

• Hotter Andreas
• Enders Michael
• Griesser Ulrich

Classifications

• C07D295/096 Primary

  with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61K31/495

  having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53}) · CPC title