Polymorphic forms of ivabradine hydrochloride

Patent metadata

Field	Value
Publication number	US-9650344-B2
Application number	US-201615168880-A
Country	US
Kind code	B2
Filing date	May 31, 2016
Priority date	Nov 14, 2011
Publication date	May 16, 2017
Grant date	May 16, 2017

Abstract

Stable crystalline Form II and stable crystalline Form III of ivabradine hydrochloride and processes for their preparation are disclosed.

First claim

We claim:

1. A crystalline Form II of ivabradine hydrochloride characterized by having characteristic X-ray powder diffraction peaks at about 8.69°, 15.50°, 17.08°, 19.80° and 24.16°±0.2° (2θ).

2. The crystalline Form II of ivabradine hydrochloride according to claim 1 , characterized by having characteristic X-ray powder diffraction peaks at about 8.05°, 8.69°, 15.50°, 17.08°, 19.00°, 19.80°, 21.72°, 22.42°, 24.16°, and 24.46°±0.2° (2θ).

3. The crystalline Form II of ivabradine hydrochloride according to claim 1 , which is further characterized by a differential scanning calorimetry (DSC) having one or more endothermic peaks in the range of 152° C. to 159° C. and in the range of 197° C. to 199° C.

4. A pharmaceutical composition comprising the crystalline Form II of ivabradine hydrochloride according to claim 1 together with one or more pharmaceutically acceptable carriers, excipients or diluents.

5. A storage stable crystalline Form II of ivabradine hydrochloride characterized by having characteristic X-ray powder diffraction peaks at about 8.69°, 15.50°, 17.08°, 19.80° and 24.16°±0.2° (2θ).

6. A process for preparing crystalline Form II of ivabradine hydrochloride according to claim 1 , the process comprising:
(a) providing a solution of ivabradine hydrochloride in one or more solvents comprising methanol, ethanol, isopropanol, butanol, dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, methyl ethyl ketone, acetone, methyl isobutyl ketone, ethyl acetate, butyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, water and mixtures thereof, by heating at about 35° C. to about 80° C.;
(b) obtaining the crystalline Form II of ivabradine hydrochloride by the removal of the solvents.

7. The process according to claim 6 , wherein the process further comprises drying the crystalline Form II of ivabradine hydrochloride at about 40° C. to about 70° C.

8. The process according to claim 6 , wherein the solvent comprises methyl ethyl ketone, tetrahydrofuran and mixture thereof.

9. A process for preparing crystalline Form II of ivabradine hydrochloride according to claim 1 , the process comprising:
(a) contacting ivabradine base with one or more first solvents at a temperature of about 0° C. to 5° C. to obtain ivabradine solution, wherein the first solvent comprises one or more of methanol, ethanol, isopropanol, butanol, dimethylformamide, dimethyl acetamide, dimethylsulfoxide, N-methylpyrrolidone, methyl ethyl ketone, acetone, methyl isobutyl ketone, ethyl acetate, butyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, water, or mixtures thereof;
(b) adding a solution of hydrochloric acid to obtain ivabradine hydrochloride;
(c) preparing a solution of ivabradine hydrochloride in one or more second solvents, wherein the second solvent comprises one or more of dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, 2-methyltetrahydro- furan, 1,4-dioxane, water, or mixtures thereof;
(d) optionally adding water to the solution, heating the solution and cooling to obtain ivabradine hydrochloride wet-cake;
(e) treating the wet-cake with one or more of first solvents to obtain crystalline Form II of ivabradine hydrochloride;
(f) drying the crystalline Form II of ivabradine hydrochloride at about 40° C. to about 70° C.

10. The process according to claim 9 , wherein the first solvent comprises methyl ethyl ketone, tetrahydrofuran and mixture thereof.

Assignees

• Cadila Healthcare Ltd

Inventors

• Dwivedi Shriprakash Dhar
• Prasad Ashok
• Sharma Mukul Hariprasad
• Sharma Piyush Rajendra
• Parihar Jayprakash Ajitsingh

Classifications

• B65D81/266

  for absorbing gases, e.g. oxygen absorbers or desiccants (B65D51/244, B65D51/30 take precedence) · CPC title

• Y10T428/2982

  Particulate matter [e.g., sphere, flake, etc.] · CPC title

• B65D31/04

  with multiple walls (B65D81/3881 takes precedence; for shock absorbing purposes B65D81/03) · CPC title

• A61P9/06

  Antiarrhythmics · CPC title

• C30B7/02

  by evaporation of the solvent · CPC title