Acetone solvate of ivabradine hydrochloride

Patent metadata

Field	Value
Publication number	US-9440924-B2
Application number	US-201214236608-A
Country	US
Kind code	B2
Filing date	Jul 31, 2012
Priority date	Aug 2, 2011
Publication date	Sep 13, 2016
Grant date	Sep 13, 2016

Abstract

The present invention relates to a novel solvate of ivabradine hydrochloride, a process of its preparation and its use for the preparation of specific polymorphic forms of ivabradine hydrochloride.

First claim

The invention claimed is:

1. A crystalline acetone solvate of the compound of formula (I)

2. The acetone solvate of claim 1 , comprising acetone in the range of from 0.7 to 1.1 mol per mol of the compound of formula (I).

3. The acetone solvate of claim 1 , exhibiting monoclinic unit cells having space group P2 1 and having the parameters
a=5.72+/−0.05 Angstrom
b=11.82+/−0.05 Angstrom
c=22.03+/−0.05 Angstrom
alpha=90.0°
beta=93.2+/−0.1°
gamma=90°
as determined by X-ray structural analysis.

4. A process comprising
a) providing a crystalline compound of formula (I)

or a solvate, other than an acetone solvate, thereof, wherein the crystalline compound of formula (I) is provided as crystalline form alpha, or beta, or beta-d, or gamma, or gamma-d, or delta, or delta-d, or as a mixture of two or more of these crystalline forms;

b) combining the compound provided in a) with acetone at a temperature in the range of from 0 to 30° C. and crystallizing the acetone solvate for a time in the range of from 1 to 48 h and at a temperature in the range of from 0 to 30° C.;
c) recovering a crystalline acetone solvate of the compound of formula (I).

5. The process of claim 4 , wherein in b), combining and crystallizing is performed at a temperature in the range of from 20 to 30° C., or wherein in b), combining is performed at a temperature in the range of from 20 to 30° C. and crystallizing is performed according to a method comprising
(i) stirring the compound provided in a) combined with the acetone for a time in the range of from 0.5 to 6 h and at a temperature in the range of from 20 to 30° C.;
(ii) keeping the mixture obtained from (i) for a time in the range of from 0.5 to 42 h at a temperature in the range of from 0 to 10° C.

6. The process of claim 4 , wherein before or during b), the compound provided in a) is combined with no compound other than acetone.

7. The process of claim 4 , further comprising
d-i) drying the crystalline acetone solvate recovered in c), wherein a crystalline compound of formula (I) is obtained, at least partially, having crystalline form delta-d, said drying being performed at a temperature in range of from 20 to 100° C., in vacuo; or
d-ii) subjecting the crystalline acetone solvate recovered in c) to an atmosphere having a relative humidity up to 50%, wherein a crystalline compound of formula (I) is obtained, at least partially having crystalline form delta, said subjecting according to d-ii) being performed at a temperature in the range of from 20 to 30° C. and for a time in the range of from 72 to 168 h.

8. A process for the preparation of a crystalline compound of formula (I)

said compound at least partially having polymorphic form delta, said process comprising subjecting a crystalline acetone solvate of the compound of formula (I) to an atmosphere having a relative humidity up to 50%.

9. The process of claim 8 , wherein subjecting said crystalline acetone solvate to said atmosphere is performed at a temperature in the range of from 20 to 30° C. at ambient pressure.

10. The process of claim 8 , wherein subjecting said crystalline acetone solvate to said atmosphere is performed for a time in the range of from 72 to 168 h.

11. The process of claim 8 , wherein subjecting said crystalline acetone solvate to said atmosphere is performed at a temperature in the range of from 20 to 25° C. at ambient pressure for a time in the range of from 72 to 120 h, wherein the relative humidity of the atmosphere is in the range of from 41 to 45%.

12. A crystalline compound of formula (I)

at least partially having crystalline form delta-d and/or delta, said crystalline compound having an acetonitrile content of less than 200 ppm.

13. The crystalline compound of claim 12 , having an acetone content of less than or equal to 0.5 weight-%, and having a water content of up to 9 weight-%.

14. A crystalline compound, obtainable or obtained by the process according to claim 7 , said crystalline compound having an acetonitrile content of less than 200 ppm.

15. A pharmaceutical composition, comprising the crystalline compound according claim 12 , and at least one pharmaceutically acceptable excipient.

16. The pharmaceutical composition of claim 15 , having an equilibrium relative humidity in the range of from 30 to 50% determined according to the ERH method.

17. The pharmaceutical composition of claim 15 , wherein at least 90% of the compound of formula (I) comprised in the composition and having polymorphic form delta are stably present as polymorphic form delta.

18. The pharmaceutical composition of claim 15 , comprised in a container containing means for keeping the equilibrium relative humidity of the pharmaceutical composition in a range of from 30 to 50% determined according to the ERH method for at least 180 d.

19. A container comprising a pharmaceutical composition according to claim 15 , the container containing means for keeping the equilibrium relative humidity of the pharmaceutical composition in a range of from 30 to 50% determined according to the ERH method, for at least 180 d.

Assignees

• Wieser Josef
• Griesser Ulrich
• Enders Michael
• Kahlenberg Volker
• Sandoz Ag

Inventors

• Wieser Josef
• Griesser Ulrich
• Enders Michael
• Kahlenberg Volker

Classifications

• C07D223/16 Primary

  Benzazepines; Hydrogenated benzazepines · CPC title