DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for making the pharmaceutically advantageous crystalline alpha-form of ivabradine hydrochloride.

BACKGROUND OF THE INVENTION
Ivabradine, chemically 3-[3-({ [(75')-3,4-dimethoxybicyclo[4.2.0]octa-l,3,5-trien-7- yl]methyl}(methyl)amino)propyl]-7,8-dimethoxy-2,3,4,5-tetrahydro-lH-3-benzazepin-2-one of Formula (I) is a pharmaceutically active substance, which is used for the symptomatic management of stable angina pectoris. It reduces the heart rate by a mechanism different from beta- blockers and calcium channel blockers, which are commonly prescribed antianginal drugs.

In the marketed products, which are film-coated tablets for oral administration and are sold, e.g., under trade name Procolan by Servier, ivabradine is present as a hydrochloride.

Ivabradine hydrochloride was first disclosed in US5296482. A crystalline ivabradine hydrochloride was obtained therein by treatment of ivabradine base with 0. IN HCl and recrystallization of the residual mass after evaporation of the mixture from acetonitrile in 55% yield.
Various crystalline forms of ivabradine hydrochloride, which are characterized by a certain distinct pattern of signals in XRPD spectrum, are known in the art.

Alpha- crystalline form has been disclosed in US7176197 and is obtainable by a crystallization of ivabradine hydrochloride from a toluene/1 -methyl-2-pyrrolidone mixture.

Beta- crystalline form was disclosed in US7361649 and is obtainable by crystallization of ivabradine hydrochloride from water or an isopropanol-water mixture. This form is a hydrate and, if heated, it may be converted to an anhydrate beta-d crystalline form as shown in US7361652.

Gamma- crystalline form was disclosed in US7361650 and is obtainable by a crystallization of ivabradine hydrochloride from 2-ethoxtethanol, a mixture of 2- ethoxyethanol and water or a mixture of ethanol and water. This form is a hydrate and, if heated, it may be converted to an anhydrate gamma-d crystalline form as shown in US7361651.

US7358240 discloses delta-form of crystalline ivabradine hydrochloride. The product was prepared by a crystallization of the product of US5296482A from acetonitrile and isolation of the crystalline product from the reaction mixture after 2 days standing by filtration and drying at ambient temperature and humidity conditions. According to the analysis, the crystalline form delta is a hydrate comprising about 2.8% of water.

US7384932 discloses delta-d form of crystalline ivabradine hydrochloride. The product was prepared by a crystallization of the product of US5296482A from acetonitrile and isolation of the crystalline product from the reaction mixture after 2 days standing by filtration and heating of the solid product at 85°C for 4 hours.

According to the analysis, the crystalline alpha-form is an anhydrate product.

The alpha-form of crystals of ivabradine hydrochloride has good handling properties for pharmaceutical applications and thus it was considered by the present inventor as an advantageous crystalline form.

Thus, it is an objective need of finding an improved crystallization process which would lead to reliable formation of the stable anhydrate alpha- form of ivabradine hydrochloride, advantageously with less potential of contamination with other forms. Advantageously, such process would not employ toluene and N - methyl pyrrolidone as crystallization solvent. Since boiling point of N - methyl pyrrolidone is very high (about 203 °C) it is not is not easy to remove the residual solvent, in order to meet the quality requirements of the solvent residues.
OBJECT OF THE INVENTION
It is an object of the present invention to provide the process of making the alpha-form of crystalline ivabradine hydrochloride essentially free from other crystalline forms thereof, which is simple, rapid and reliable.

It is an object of the present invention to provide the process for making crystalline alpha-form of ivabradine hydrochloride.

SUMMARY OF THE INVENTION
In one aspect of the present invention encompasses the process for the preparation of crystalline alpha-form of ivabradine hydrochloride.
In another aspect of the present invention encompasses the process for the preparation of crystalline alpha-form of ivabradine hydrochloride comprising the steps of;
a) providing the solution of ivabradine hydrochloride in suitable solvent,
b) adding a suitable anti-solvent to the solution of step (a),

c) optionally, heating the reaction mass of step(b) and
d) isolating alpha-form of ivabradine hydrochloride.
In another aspect of the present invention encompasses the process for the preparation of crystalline alpha-form of ivabradine hydrochloride comprising the steps of;
a) providing the solution of ivabradine hydrochloride in suitable solvent,
b) adding a suitable anti-solvent to the solution of step (a) and

c) isolating alpha-form of ivabradine hydrochloride.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure-1: shows the X-ray powder diffraction pattern of alpha-form of ivabradine hydrochloride.
DETAILED DESCRIPTION OF THE INVENTION
As discussed above, many polymorphic forms of crystalline ivabradine hydrochloride are known in the art. The anhydrous alpha-form of ivabradine hydrochloride is relatively stable at ambient conditions of storage and has good handling properties in pharmaceutical applications. The present invention is a result of a thorough study of properties of this crystalline form and methods for making it.
For clarity, the "alpha-form" of ivabradine hydrochloride is the polymorph, which has been characterized in US7176197 as shown below:
Ray no. Angle 2 theta
(degress) Height
(counts) Area(column x degress) FWHM(degrees) Interplanar distance(A0)
1 4.1 1341 177 0.1338 21.486
2 7.7 1266 146 0.1171 11.440
3 8.1 1325 197 0.1506 10.923
4 10.4 1630 161 0.1004 8.488
5 11.8 753 87 0.1171 7.473
6 12.1 292 29 0.1004 7.301
7 13.2 917 106 0.1171 6.709
8 13.8 875 130 0.1506 6.423
9 15.3 281 37 0.1338 5.790
10 16.2 816 108 0.1338 5.478
11 16.5 2784 459 0.1673 5.381
12 17.4 1308 129 0.1004 5.106
13 18.1 455 52 0.1171 4.885
14 19.4 223 37 0.1673 4.569
15 20.2 3282 487 0.1506 4.389
16 20.6 305 45 0.1506 4.310
17 21.3 550 91 0.1673 4.165
18 21.9 1266 230 0.184 4.050
19 22.4 416 41 0.1004 3.972
20 23.0 262 35 0.1338 3.861
21 23.3 184 27 0.1506 3.814
22 24.4 309 51 0.1673 3.651
23 25.0 362 72 0.2007 3.566
24 25.7 1076 142 0.1338 3.459
25 26.5 2925 579 0.2007 3.363
26 26.8 821 135 0.1673 3.325
27 27.8 488 97 0.2007 3.212
28 28.4 620 123 0.2007 3.142
29 29.2 428 56 0.1338 3.057
It appears that the alpha-form of ivabradine hydrochloride has been only obtained when toluene and N-Methylpyrrolidone has been used as the solvent for crystallization process. Toluene and N-Methylpyrrolidone, however, is a classified (class 2) solvent in pharmaceutical industry that needs to be properly removed from any product that is intended to be formulated in pharmaceutical compositions.
It was now found out with surprise that the desired alpha- form of ivabradine hydrochloride may be formed by a crystallization of ivabradine hydrochloride from another solvent system, wherein such crystallization exhibits the advantage in that the form alpha is formed without contamination with other crystalline forms. The solvent system of the present invention is also pharmaceutically more acceptable than toluene and N-Methylpyrrolidone.

In one embodiment of the present invention encompasses the process for the preparation of crystalline alpha-form of ivabradine hydrochloride comprising the steps of;
a) providing the solution of ivabradine hydrochloride in suitable solvent,
b) adding a suitable anti-solvent to the solution of step (a),

c) optionally, heating the reaction mass of step(b) and
d) isolating alpha-form of ivabradine hydrochloride.

In another embodiment of the present invention, suitable solvent in the step (a) is selected from the group comprising of alcohol solvents that include methanol, ethanol, n-propanol, 2-propanol, preferably methanol.
In another embodiment of the present invention, suitable anti-solvent in the step (b) is selected from the group comprising of ester solvents that include ethyl acetate, n-propyl acetate and isopropyl acetate, preferably ethyl acetate.
In yet, another embodiment of the present invention encompasses the process for the preparation of crystalline alpha-form of ivabradine hydrochloride comprising the steps of;
a) providing the solution of ivabradine hydrochloride in methanol,
b) adding a ethyl acetate to the solution of step (a),

c) optionally, heating the reaction mass of step(b) and
d) isolating alpha-form of ivabradine hydrochloride.
In yet, another embodiment of the present invention encompasses the process for the preparation of crystalline alpha-form of ivabradine hydrochloride comprising the steps of;
a) providing the solution of ivabradine hydrochloride in suitable solvent,
b) adding a suitable anti-solvent to the solution of step (a) and

c) isolating alpha-form of ivabradine hydrochloride.

In yet, another embodiment of the present invention, suitable solvent in the step (a) is selected from the group comprising of alcohol solvents that include methanol, ethanol, n-propanol, 2-propanol, preferably methanol.
In yet, another embodiment of the present invention, suitable anti-solvent in the step (b) is selected from the group comprising of ester solvents that include ethyl acetate, n-propyl acetate and isopropyl acetate, preferably ethyl acetate.
In yet, another embodiment of the present invention encompasses the process for the preparation of crystalline alpha-form of ivabradine hydrochloride comprising the steps of;
a) providing the solution of ivabradine hydrochloride in methanol,
b) adding ethyl acetate to the solution of step (a) and

c) isolating alpha-form of ivabradine hydrochloride.

In yet, another embodiment of the present invention encompasses the process for making crystalline alpha-form of ivabradine hydrochloride comprising the steps of;
a) providing the solution of ivabradine hydrochloride in suitable solvent or mixture of solvents thereof,
b) heating the reaction mass,
c) cooling the reaction mass to obtain alpha-form of ivabradine hydrochloride.
In yet, another embodiment of the present invention encompasses the process for the preparation of crystalline alpha-form of ivabradine hydrochloride comprising the steps of;
a) providing the solution of ivabradine hydrochloride in methanol and toluene,
b) heating the reaction mass,
c) cooling the reaction mass to obtain alpha-form of ivabradine hydrochloride.

In yet, another embodiment of the present invention encompasses the process for the preparation of crystalline alpha-form of ivabradine hydrochloride comprising the steps of;
a) providing the solution of ivabradine hydrochloride in water and toluene,
b) heating the reaction mass,
c) cooling the reaction mass to obtain alpha-form of ivabradine hydrochloride.

In yet, another embodiment of the present invention encompasses the process for the preparation of crystalline alpha-form of ivabradine hydrochloride comprising the steps of;
a) providing the solution of ivabradine hydrochloride in water and cyclohexane,
b) heating the reaction mass,
c) cooling the reaction mass to obtain alpha-form of ivabradine hydrochloride.

The term "solvent" includes any solvent or solvent mixture, for example, water, esters, alcohols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, hydrocarbons or mixtures thereof.

The suitable solvent of the present invention may be selected from the group consisting of water, alcohols, ketones, ethers, polar aprotic solvents, hydrocarbons, or mixtures thereof.

Suitable alcohol solvents include methanol, ethanol, n-propanol, 2-propanol, ethylene glycol, PEG and butanol. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include tetrahydrofuran and the like. A suitable polar aprotic solvent includes N,N-dimethylformamide, ?,?-dimethylacetamide, dimethylsulphoxide, acetonitrile, and N-methylpyrrolidone. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane. Examples of hydrocarbons are hexanes, n-heptane, n-pentane, cyclohexane, methylcyclohexane and the like. Examples of aromatic hydrocarbons like toluene, xylene, ethylbenzene and the like. Examples of ethers like diethyl ether, diisopropyl ether, methyltert-butyl ether, dibutyl ether, tetrahydrofuran, 1 ,4-dioxane, 2-methoxyethanol and the like.

Heating is carried out at a effective temperature, preferably at a temperature of from about 50 to about 115° C., more preferably from about 50° C. to about 60° C.

Cooling is carried out at a effective temperature of about -10°C to about 30°C, more preferably from about 20°C to about 30°C.

In the foregoing section, embodiments are described by way of an example to illustrate the process of the invention. However, this is not intended in any way to limit the scope of the present invention. Several variants of the example would be evident to persons ordinarily skilled in the art which are within the scope of the present invention.

Examples
Example 1: Preparation of alpha-form of Ivabradine Hydrochloride
Ivabradine Hydrochloride (100 g) in Methanol (150 ml) was charged in to the round bottomed flask equipped with a mechanical stirrer at 25°C-35°C. Ethyl acetate(250 ml) was charged in to the reaction mass at 25-35°C. The reaction mixture was heated at 50-60°C and stirred for 30 minutes. Methanol and ethyl acetate were distilled and the reaction mass was cooled at 25-30 °C to obtain the alpha-form of Ivabradine Hydrochloride. (80-90 gm, 90%, purity: >99 %).
Example 2: Preparation of alpha-form of Ivabradine Hydrochloride
Ivabradine Hydrochloride (100 g) in Methanol (200 ml) was charged in to the round bottomed flask equipped with a mechanical stirrer at 25°C-35°C. Toluene(1500 ml) was charged in to the reaction mass at 25-35°C. The reaction mixture was heated at 90-115°C. Methanol was removed azeotropically at 90-115°C.The reaction mass was cooled at 25-30 °C to obtain the alpha-form of Ivabradine Hydrochloride. (80-90 gm, 90%, purity: >98 %).
Example 3: Preparation of alpha-form of Ivabradine Hydrochloride
Ivabradine Hydrochloride (100 g) in water (100 ml) was charged in to the round bottomed flask equipped with a mechanical stirrer at 25°C-35°C. Toluene(1500 ml) was charged in to the reaction mass at 25-35°C. The reaction mixture was heated at 110-115°C. water was removed azeotropically at 110-115°C. The reaction mass was cooled at 25-30 °C to obtain the alpha-form of Ivabradine Hydrochloride. (85-90 gm, 85%, purity: >95%).
Example 4: Preparation of alpha-form of Ivabradine Hydrochloride
Ivabradine Hydrochloride (100 g) in water (100 ml) was charged in to the round bottomed flask equipped with a mechanical stirrer at 25°C-35°C. cyclohexane(1500 ml) was charged in to the reaction mass at 25-35°C. The reaction mixture was heated at 85-90°C. water was removed azeotropically at85-90°C. The reaction mass was cooled at 25-30 °C to obtain the alpha-form of Ivabradine Hydrochloride. (80-85 gm, 80%, purity: >95%).
,CLAIMS:Claims
We claim,
1. The process for the preparation of crystalline alpha-form of ivabradine hydrochloride comprising the steps of;
a) providing the solution of ivabradine hydrochloride in suitable solvent,
b) adding a suitable anti-solvent to the solution of step (a),
c) optionally, heating the reaction mass of step(b) and
d) isolating alpha-form of ivabradine hydrochloride.

2. The process for the preparation of crystalline alpha- form of ivabradine hydrochloride comprising the steps of;
a) providing the solution of ivabradine hydrochloride in suitable solvent,
b) adding a suitable anti-solvent to the solution of step (a) and
c) isolating alpha-form of ivabradine hydrochloride.

3. The process according to claim 1 and 2, wherein the suitable solvent is selected from the group comprising of methanol, ethanol, n-propanol and 2-propanol, preferably methanol.

4. The process according to claim 1 and 2, wherein the suitable anti-solvents is selected from the group comprising of ethyl acetate, n-propyl acetate and isopropyl acetate, preferably ethyl acetate.

5. The process for the preparation of crystalline alpha-form of ivabradine hydrochloride comprising the steps of;
a) providing the solution of ivabradine hydrochloride in methanol,
b) adding ethyl acetate to the solution of step (a),
c) optionally, heating the reaction mass of step(b) and
d) isolating alpha-form of ivabradine hydrochloride.

6. The process for the preparation of crystalline alpha-form of ivabradine hydrochloride comprising the steps of;
a) providing the solution of ivabradine hydrochloride in methanol,
b) adding ethyl acetate to the solution of step (a) and
c) isolating alpha-form of ivabradine hydrochloride.

Dated this 15th day of September, 2017
Dr. Subramaniam Ganesan