DESC:Field of the Invention
The present invention relates to an improved process for the preparation of Beta Polymorphic form of Ivabradine Hydrochloride.

Background of the Invention
Ivabradine hydrochloride, 3-{3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl] methyl}(methyl)amino]-propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one hydrochloride is represented by the structural formula (I):

Ivabradine hydrochloride is currently marketed under the trade names Corlentor® and Procolaran®. It is used for treatment of chronic stable angina pectoris in coronary artery disease patients with normal sinus rhythm.

Ivabradine was first disclosed in EP 534859 and US 5296482. The process involves the treatment of Ivabradine base with 0. IN HCl followed by recrystallization in acetonitrile to give 55% of Ivabradine Hydrochloride.

Polymorph form Beta is the most stable form and is present in the marketed product. WO 2006/092493 A1 discloses polymorph Form beta of Ivabradine hydrochloride, its process of preparation and compositions comprising this polymorph. Ivabradine hydrochloride Beta form is obtained by crystallization of Ivabradine hydrochloride from water or isopropanol-water mixture.

Still there is a need in the art for an improved process for the preparation of Beta polymorphic form of Ivabradine Hydrochloride.

Objects of the Invention
The primary object of the invention is to provide an improved process for the preparation of Beta polymorphic form of Ivabradine Hydrochloride.

Summary of the Invention
In one aspect, the present invention provides an improved process for the preparation of Beta polymorphic form of Ivabradine Hydrochloride.

In yet another aspect, the present invention provides a process for the preparation of Beta polymorphic form of Ivabradine Hydrochloride comprising the steps of:
a) dissolving Ivabradine hydrochloride in methylene dichloride (MDC);
b) removing the solvent from the reaction mixture obtained in the step a) to half of the volume;
c) cooling the reaction mixture to 25-35ºC;
d) adding mixture of acetone and water to the reaction mixture;
e) aging the reaction for 16-20 hours and
f) isolating Ivabradine hydrochloride Beta polymorphic form.

In yet another aspect, the present invention provides a process for the preparation of Beta polymorphic form of Ivabradine Hydrochloride comprising the steps of:
a) suspending Ivabradine hydrochloride in THF;
b) adding 10% HCl to the reaction mixture obtained in the step a);
c) stirring the reaction mixture for 4 hours and
d) isolating Ivabradine hydrochloride Beta polymorphic form.

In yet another aspect, the present invention provides a process for the preparation of Beta polymorphic form of Ivabradine Hydrochloride comprising the steps of:
a) suspending Ivabradine hydrochloride in mixture of ethanol and water to form a clear solution.
b) adding ethylacetate to the reaction mixture obtained in the step a);
c) stirring the reaction mixture for 60 minutes and
d) isolating Ivabradine hydrochloride Beta polymorphic form.

In yet another aspect, the present invention provides a process for the preparation of Beta polymorphic form of Ivabradine Hydrochloride comprising the steps of:
a) dissolving Ivabradine hydrochloride in a mixture of MDC and water;
b) adding THF to the reaction mixture obtained in the step a) and
c) isolating Ivabradine hydrochloride Beta polymorphic form.

Detailed Description of the Invention
In one embodiment, the present invention provides a process for the preparation of Beta polymorphic form of Ivabradine Hydrochloride comprising the steps of:
a) dissolving Ivabradine hydrochloride in methylene dichloride (MDC);
b) removing the solvent from the reaction mixture obtained in the step a) to half of the volume by particle free distillation;
c) cooling the reaction mixture to 25-35ºC;
d) adding solvent mixture of acetone and water to the reaction mixture;
e) aging the reaction for 16-20 hours and
f) isolating Ivabradine hydrochloride Beta polymorphic form.

In another embodiment, the present invention provides a process for the preparation of Beta polymorphic form of Ivabradine Hydrochloride comprising the steps of:
a) suspending Ivabradine hydrochloride in THF;
b) adding 10% HCl to the reaction mixture obtained in the step a);
c) stirring the reaction mixture for 4 hours and
d) isolating Ivabradine hydrochloride Beta polymorphic form.

In yet another embodiment, the present invention provides a process for the preparation of Beta polymorphic form of Ivabradine Hydrochloride comprising the steps of:
a) suspending Ivabradine hydrochloride in a mixture of ethanol and water to form a clear solution.
b) adding ethylacetate to the reaction mixture obtained in the step a);
c) stirring the reaction mixture for 60 minutes and
d) isolating Ivabradine hydrochloride Beta polymorphic form.

In yet another embodiment, the present invention provides a process for the preparation of Beta polymorphic form of Ivabradine Hydrochloride comprising the steps of:
a) dissolving Ivabradine hydrochloride in a mixture of MDC and water;
b) adding THF to the reaction mixture obtained in the step a) and
c) isolating Ivabradine hydrochloride Beta polymorphic form.

According to the present invention Ivabradine Hydrochloride used as starting material for the preparation of Beta polymorphic form may be obtained by any of processes reported in literature or any known form of the Ivabradine Hydrochloride.

As used herein, the term “isolating” means isolating Beta polymorphic form of Ivabradine Hydrochloride, the by way of solvent crystallization method, partial removal of the solvent from the solution, sonication, solvent/anti-solvent method, slurry, cooling, seeding, filtration, filtration under vacuum, centrifugation, decantation, distillation, evaporation, evaporation under reduced pressure. The product obtained may be further or additionally dried to achieve the desired moisture values.

EXAMPLES FOR THE PREPARATION OF BETA POLYMORPHIC FORM OF IVABRADINE HYDROCHLORIDE.
Example 1:
Ivabradine hydrochloride (2 g) was dissolved in MDC (20 mL; 10 Volumes). Distilled the reaction mixture up to 5 volumes. Cooled the reaction mixture to 25-35°C and a solvent mixture of acetone (30 mL) and water (2.4 mL) were charged to the reaction mixture. Aged the reaction mixture by keeping it hold for 16-20 hours. Filtered the solid and dried under vacuum at 40±5°C for 12 hours to obtain 1.7 g of the title compound.

Example 2:
Ivabradine hydrochloride (5 g) was suspended in THF (150 mL). 10% HCl (8 mL) was charged to the reaction mixture. The obtained solid was stirred for 4 hours, filtered the solid and dried under vacuum at 60±5°C to obtain 4.1 g of the title compound.

Example 3:
Ivabradine hydrochloride (2 g) was suspended in ethanol (6 mL) and water (2 mL) was added to the suspension to obtain the clear solution. Ethyl Acetate (20 mL) was added to the reaction mixture. The obtained solid was stirred for 60 minutes, filtered and dried under vacuum at 40±5°C to obtain 1.7 g of the title compound.

Example 4:
Ivabradine hydrochloride (2 g) was dissolved in mixture of MDC (30 mL) and water (1 mL). THF (40 mL) was added to the reaction mass. The solid obtained was filtered and dried at 40±5°C to obtain 1.7 g of the title compound.
,CLAIMS:We claim:
1. An improved process for the preparation of Beta polymorphic form of Ivabradine Hydrochloride comprising the steps of:
a) dissolving Ivabradine hydrochloride in methylene dichloride;
b) removing the solvent from the reaction mixture obtained in the step a) to half of the volume by particle free distillation;
c) cooling the reaction mixture to 25-35ºC;
d) adding solvent mixture of acetone and water to the reaction mixture;
e) aging the reaction for 16-20 hours and
f) isolating Ivabradine hydrochloride Beta polymorphic form.

2. A process for the preparation of Beta polymorphic form of Beta polymorphic form of Ivabradine Hydrochloride comprising the steps of:
a) suspending Ivabradine hydrochloride in THF;
b) adding 10% HCl to the reaction mixture obtained in the step a);
c) stirring the reaction mixture for 4 hours and
d) isolating Ivabradine hydrochloride Beta polymorphic form.

3. A process for the preparation of Beta polymorphic form of Ivabradine Hydrochloride comprising the steps of:
a) suspending Ivabradine hydrochloride in a mixture of ethanol and water to form a clear solution,
b) adding ethylacetate to the reaction mixture obtained in the step a);
c) stirring the reaction mixture for 60 min and
d) isolating Ivabradine hydrochloride Beta polymorphic form.

4. A process for the preparation of Beta polymorphic form of Ivabradine Hydrochloride comprising the steps of:
a) dissolving Ivabradine hydrochloride in a mixture of MDC and water;
b) adding THF to the reaction mixture obtained in the step a) and
c) isolating Ivabradine hydrochloride Beta polymorphic form.