DESC:This application claims the benefit of priority of our Indian patent application numbers 3250/MUM/2013 filed on 17th October 2013 which are incorporated herein by reference.

FIELD OF THE INVENTION
The present invention relates to improved process for preparation of Ivabradine Adipate.

BACKGROUND OF THE INVENTION

Ivabradine hydrochloride of formula I, has very valuable pharmacological and therapeutic properties, and is useful in many cardiovascular diseases such as angina pectoris, myocardial infarct and associated rhythm disturbances and is chemically known as (S)-7,8-dimethoxy-3-{3-{N-[(4,5-dimethoxybenzocyclobut-l-yl)methyl]-N-(methyl)amino)propyl)-l,3,4,5-tetrahydro-2H-3-benzazepin-2-one hydrochloride.

Ivabradine with a pharmaceutically acceptable acid have very valuable pharmacological and therapeutic properties, especially bradycardic properties, making those compounds useful in the treatment or prevention of various clinical situations of myocardial ischemia such as angina pectoris, myocardial infarct and associated rhythm disturbances, and also in various pathologies involving rhythm disturbances, especially supraventricular rhythm disturbances, and in heart failure. Ivabradine hydrochloride is first disclosed in U.S. Patent No. 5,296,482.

Ivabradine and the addition salts of it with pharmaceutical acceptable acid have highly valuable pharmacological and therapeutic effects, especially bradycardic effects, thus these compounds can be used not only for the treatment or prevention of various clinical symptoms of myocardial ischemia such as angina, myocardial infarction and the associated rhythm disorders, but also for the treatment or prevention of various diseases involving rhythm disorders, especially supraventricular rhythm disorder. In particular the Ivabradine hydrochloride applied by Servier has been approved to be listed in 27 Europe countries by the European medical review administration (EMEA) in November 2005 for the treatment of chronic stable angina pectoris of normal sinus rhythm which has contraindication or intolerance to the beta receptor blocking agent.

U.S. Patent 5,296,482A, (EP534859A1) describes a synthetic route of Ivabradine in detail.

Ivabradine and its acid addition salts thereof with a pharmaceutically acceptable acid were first described in US patent 5,296,482. The patent discloses genetically several acid addition salts for the (benzocycloalkyl)alkylamines compounds. These are hydrochloric, hydrobromic, sulfuric, nitric acid, phosphoric acid; acetic acid, propionic, maleic, fumaric, tartaric acid, oxalic, benzoic, methansulfonic, isethionic, benzenesulfonic acids. However, out of the listed salts, patent specifically exemplified the preparation of only two salts of ivabradine namely, dibenzoyltartrate salts and hydrochloride salt (mono-hydrochloride and di-hydrochloride salts). The disclosure of the patent is silent about the preparation of other salts for ivabradine as disclosed in the patent.

US patent 7,176,197 discloses a process for the preparation of various acid addition salts of ivabradine with a pharmaceutically acceptable -acid, and hydrates thereof by the reaction of 3-(2- [l,3]dioxolan-2-yl-ethyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[d]azepin-2-one with acid addition salt of (3,4-dimethoxy-bicyclo[4.2.0]octa-l,3,5-trien-7-ylmethyl)-methyl-amine in the presence of hydrogen and a catalyst as shown in the following scheme,

•HX Similar to the above patent, this patent also specifically describes the synthesis of ivabradine hydrochloride using hydrochloride salt of secondary amine intermediate and silent about the synthesis of other acid addition salts of ivabradine. Patent particularly describes the synthesis of a-crystalline form of ivabradine hydrochloride.

US patents 7,176,197; 7,361,650; 7,361,651; 7,361,649; 7,361,652; 7,358,240; 7,384,932; and PCT publications WO 2008/065681 and WO2008/125006 describe different polymorphic forms of ivabradine hydrochloride and process of preparation thereof.

The compound stability is one of the most important criteria by most of the regulatory agencies. Therefore one need to demonstrate that even after the formulation the stability of the compound or its respective form is intact over a period of shelf life. The compound transformations can occur also in the different solid state, because of changes in humidity or temperature or oxidative degradation conditions.

The prior art discloses the importance of the production conditions of the medicinal products reported to undergo unwanted and undesirable transformations, if the process conditions are not opportunistically controlled. Consequently, a stable Ivabradine salt would be a significant contribution to the art.

PCT publication WO2008/146308 discloses the amorphous ivabradine hydrochloride and process for preparation thereof. Application also discloses ivabradine oxalate and method of its preparation.

PCT publication WO2009/124940 discloses ivabradine hydrobromide in amorphous, crystalline and dissolved state and process for preparation thereof.

PCT publication WO2011/157720 discloses ivabradine adipate in amorphous, crystalline and dissolved state and process for preparation thereof.

The different solubility profiles of the polymorphic forms lead to an undesirable non uniform uptake of the active substance in the patient. It was therefore also an object of the present invention to provide stable forms of ivabradine which can be processed to give an administration form which permits as uniform an uptake as possible in the patient. Both inter individual and intra individual deviations should be substantially avoided.

It has now surprisingly been found that the ivabradine adipate can be achieved by the combination of the active substance ivabradine in the form of its adipate salt (a) with a water-soluble (b) and a water-insoluble excipient (c) in a pharmaceutical composition with modified release. By embedding the active substance (a) in a mixture of the water- insoluble and the water-soluble excipient, surprisingly not only can the active substance advantageously be released in a modified manner but it is also stabilized in its polymorphic form as well as chemically. Corresponding compositions show little hygroscopicity and outstanding modified release. Corresponding mixtures can be further processed in an excellent manner to give pharmaceutical compositions, in particular tablets.

There is no prior art reference which describes the preparation of ivabradine adipate other than hydrochloride, hydrobromide, dibenzoyltartrate, and oxalate. Therefore, present invention provides improved process for the preparation of ivabradine adipate in crystalline forms which can be easily employed on industrial scale.

It was surprisingly found during the research that that the Ivabradine adipate process was more suitable than the prior art process.

OBJECT OF THE INVENTION:

It is therefore an object of the present invention to provide a process for preparation of Ivabradine adipate.

Another object of the present invention is to provide a process for preparation of new crystalline Form of Ivabradine adipate.

SUMMARY OF THE INVENTION:

According to one aspect of the present invention, process of preparing Ivabradine adipate comprises, reacting Ivabradine solution with adipic acid.

In another aspect, of the present invention ivabradine adipate is prepared by:
(i) dissolving ivabradine in a suitable solvent, preferably in solvent;
(ii) adding a solution of adipic acid, preferably an alcoholic solution or more preferably an ketones solution, most preferably acetone solution of adipic acid;
(iii) evaporating the solvent to dryness, preferably under vacuum.

In another aspect, of the present invention a process of preparing Ivabradine adipate comprising steps of:
(i) reacting Ivabradine hydrochloride with base in solvent;
(ii) extracting ivabradine base;
(iii) dissolving Ivabradine base in solvent;
(iv) adding adipic acid solution in solvent to Ivabradine solution;
(v) isolating Ivabradine adipate.

According to another aspect of the present invention, there is provided a process for preparation of a crystalline Form of Ivabradine adipate comprising steps of:
(i) providing a solution or suspension of Ivabradine adepate in solvent;
(ii) crystallizing the product from the said solution;
(iii) isolating crystalline Ivabradine adipate.

Other features and advantages will be apparent from the specification which describes an embodiment of this invention.

BRIEF DESCRIPTION OF THE DRAWINGS:

Fig. 1 shows the X-ray powder diffraction pattern of crystalline Form of Ivabradine adipate.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention provides a process of preparing Ivabradine adipate comprises, reacting Ivabradine solution with adipic acid.

Here the term “crystallizing” means crystallizing compounds using methods known in the art. For example either reducing the volume of the solvent with respect to solute or decreasing the temperature of the solution or using both so as to crystallize the compound.

The term “treating” as used hereinabove refers to suspending, dissolving or mixing and contacting or reacting of Ivabradine adipate with solvent or reagents followed by isolating Ivabradine adipate by removal of reagents and solvents.

The term “triturating” as used hereinabove refers to suspending Ivabradine adipate in solvent and stirring for period of time sufficient for surface contact of solid with solvent and then filtering the compound from the mixture.

Here the term “mixing” means contacting the compound with solution which may be by means of shaking or stirring or keeping so as to the both compound and solution come in contact with each other.

In one of the preferred embodiment, of the present invention a process of preparing Ivabradine adipate comprises, reacting Ivabradine solution with adipic acid.

Ivabradine solutions or suspensions can be prepared by mixing the solution of ivabradine and a solution of adipic acid. Adipic acid and ivabradine solution is in a solvent selected from the group consisting of water, nitriles, ketones, esters, ethers, alcohols, sulfoxides, amides, halogenated hydrocarbons or/and any mixture thereof. Preferably, the solvent is water, methanol, ethanol, acetonitrile, DMSO, acetone, ethyl methyl ketone, ethyl acetate, i-propyl acetate, methylen chloride or/and any mixture thereof, preferably ketones or alcoholic solution, most preferably ketones solution such as acetone.

According another embodiment of the present invention ivabradine adipate is prepared by:
(i) dissolving ivabradine in a suitable solvent, preferably in solvent;
(ii) adding a solution of adipic acid, preferably an alcoholic solution or more preferably an ketones solution, most preferably acetone solution of adipic acid;
(iii) evaporating the solvent to dryness, preferably under vacuum.

Step (i) is preferably performed at a temperature within the range of 20 to 250C.

The process preferably comprises the following additional steps:
(iv) optionally redissolving or dispersing the product of step (iii) in a second solvent, preferably in ethyl acetate; (v) maintaining the mixture of step (iv) at a temperature of 20 to 25 0C for 8 to 16 hours, preferably 12 hours;
(v) isolating the product, preferably by filtration,
(vi) optionally washing the product of step (vi) with a solvent, preferably with the same solvent used in step (iv); and
(vii) drying the product of step (vii).

Drying is preferably performed under vacuum. It is also preferred to dry the product at a temperature within a range of from 35 to 65°C, more preferably 45 to 55°C and most preferably at about 50°C. During drying the product can be sieved to deagglomerate and/or remove lumps.

According to another embodiment, of the present invention a process of preparing Ivabradine adipate comprising steps of:
(i) reacting Ivabradine hydrochloride with base in solvent;
(ii) extracting ivabradine base;
(iii) dissolving Ivabradine base in solvent;
(iv) adding adipic acid solution in solvent to Ivabradine solution;
(v) isolating Ivabradine adipate.

According to present invention preparation of Ivabradine adipate comprises reacting Ivabradine hydrochloride with base to obtain free base wither in Suitable bases comprise both organic and inorganic bases. The bases include, but are not limited to, TEA (triethylamine), NMM (N-methyl morpholine), pyridine, NaH, NaOBu-t, KOBu-t, ethyldiisopropylamine, NaOH, KOH and/or LiOH.

According to present invention suitable solvents is selected from the group consisting of water, nitriles, ketones, esters, ethers, alcohols, sulfoxides, amides, halogenated hydrocarbons or/and any mixture thereof. Preferably, the solvent is water, methanol, ethanol, acetonitrile, DMSO, acetone, ethyl methyl ketone, ethyl acetate, i-propyl acetate, methylen chloride or/and any mixture thereof.

According to another embodiment, present invention provides a process for preparation of crystalline Form I of Ivabradine adipate comprising steps of:
(i) treating Ivabradine adipate in solvent
(ii) isolating Ivabradine adipate form the solution or suspension;
(iii) triturating the Ivabradine adipate solid with solvent

The adipc acid salt of ivabradine crystalline Form I according to present invention preparation of Ivabradine adipate comprises dissolving or suspending Ivabradine adipate in solvent at about reflux temperature. The solvent is taken 2 to 50 times the quantity of Ivabradine adipate. The solution is filtered through know filtration methods. The filtrate was kept at room temperature for crystallization. The precipitate were filtered and dried to give crystalline Form I of Ivabradine adipate. Crystalline ivabradine adipate can be prepared by cooling solution of ivabradine adipate to precipitate crystalline ivabradine adipate. Crystalline or amorphous ivabradine adipate can also be prepared by evaporating the solvent from ivabradine adipate solution or by addition of antisolvent to ivabradine adipate solution. Suitable solvents for preparation of ivabradine adipate can be selected from the group consisting of water, nitriles, ketones, esters, ethers, alcohols, sulfoxides, amides, halogenated hydrocarbons or/and any mixture thereof. Preferably, the solvent is water, methanol, ethanol, acetonitrile, DMSO, acetone, ethyl methyl ketone, ethyl acetate, i-propyl acetate, methylen chloride or/and any mixture thereof, preferably ketones or alcoholic solution, most preferably ketones solution such as acetone

Ivabradine base used in the present invention can be prepared according to methods disclosed in EP534859 and can also be further recrystallized and/or purified to a purity level more than 99%, 99.5% or 99.9 %. If the ivabradine adipate prepared by the present invention is not satisfactorily pure, it can be recrystallized to a purity level more than 99%, 99.5% or 99.9 %, determined by HPLC or UPLC.

The term "average particle size" as used herein refers to the volume mean particle diameter, determined by laser light scattering using a Malvern Mastersizer instrument 2000.

The average particle size of ivabradine adipate prepared according to the present invention can be in the range of 0.1-600 µm, preferably 0.3 - 300 µm, most preferably 0.5 - 150 µm. Particle size is determined by laser diffraction method on Malvern Mastersizer 2000 instrument equiped with Hydro S dispersion unit, which is appropriate for measuring particle size distributions in the range of 20nm to 2000µm.

The following examples illustrate the invention further. It should be understood, however, that the invention is not confined to the specific limitations set forth in the individual examples but rather to the scope of the appended claims.

Example-1
Preparation of Ivabradine adipate

Ivabradine hydrochloride (50 g) was charged to a solution of NaOH (5.83 g) in water (190 ml). After stirring for 10 to 15 minutes Ivabradine base was extracted by dichloromethane (150 ml). Dichloromethane was removed completely under reduced pressure and the residue is dissolved in acetone (200 ml). To this, a solution of aipic acid (14 g) in acetone (300 ml) was added. This mixture was stirred for 1 hr and the precipitated solid was filtered and dried.
Output: 53 g
Purity: 99.9%

Example-2

Preparation of crystalline form of Ivabradine adipate
Ivabradine adipate (5.0g) was dissolved in acetone (20.0ml). The mixture was stirred at reflux temperature. The precipitated solid was filtered and washed with acetone. XRD of the compound is as shown in Fig. 1

Example-3

Preparation of Ivabradine adipate

1. Ivabradine Base (258.2 g) was charged to a solution Acetone(180ml). Activated carbon (2.06 g) was Charged to the solution and stirred for 30 minutes at 30-40°C. The reaction mixture was heated at 40-50 °C. Adipic acid (28.06 g) in acetone (1000 ml) was Charged at 40-55 °C to the reaction mixture. The reaction mass was cooled to 20-30°C for 1-2 hours.The obtained solid was washed with acetone(20 ml),filtered and dried to obtain Ivabradine Adipate.
Output: 80 g
Purity: 99.9%
,CLAIMS:We claim,

1. The process of preparation of Ivabradine adipate comprising reacting of Ivabradine solution with adipic acid.

2. The process of preparing Ivabradine adipate comprising the steps of;
a. providing ivabradine solution in a suitable solvent;
b. adding a solution of adipic acid;
c. evaporating the solvent to dryness to obatain Ivabradine adipate.

3. The process of preparing Ivabradine adipate comprising steps of;
a. reacting Ivabradine hydrochloride with base in solvent;
b. extracting ivabradine base;
c. dissolving Ivabradine base in solvent;
d. adding adipic acid solution in solvent to Ivabradine solution;
e. isolating Ivabradine adipate.

4. The process according to claim 3, wherein the base is selected from TEA (triethylamine), NMM (N-methyl morpholine), pyridine, NaH, NaOBu-t, KOBu-t, ethyldiisopropylamine, NaOH, KOH and/or LiOH.

5. The process for preparation of crystalline Form I of Ivabradine adipate comprising steps of;
a. treating Ivabradine adipate in solvent;
b. isolating Ivabradine adipate form the solution or suspension;
c. triturating the Ivabradine adipate solid with solvent.

6. The process according to claim 2, 3 and 5,wherein the solvent is selected from the group consisting of water, nitriles, ketones, esters, ethers, alcohols, sulfoxides, amides, halogenated hydrocarbons or/and any mixture thereof.

7. A crystalline Form I of Ivabradine Adipate characterized by an X-ray powder diffraction pattern comprising the characteristic peaks at 8.6±0.2° 2-Theta °, 14.7±0.2° 2-Theta, 16.1±0.2° 2-Theta, 17.3±0.2° 2-Theta and 20.85 ±0.2° 2-Theta.

8. A crystalline Form I of Ivabradine Adipate according to claim 7, is further characterized by additional X-ray powder diffraction peaks at 9.6±0.2° 2-Theta, 12.1±0.2° 2-Theta, 12.9±0.2° 2-Theta, 14.2±0.2° 2-Theta, 16.5±0.2° 2-Theta, 17.8±0.2° 2-Theta, 18.9±0.2° 2-Theta, 19.8±0.2° 2-Theta, 22.2±0.2° 2-Theta, 23.3±0.2° 2-Theta, 24.5±0.2° 2-Theta and 26.0 ±0.2° 2-Theta.