FIELD OJF THE.INVENTION
i:
The field of the invention relates to novel amorphous form of ivabradine hydrochloride and process of its preparation thereof.
BACKGROUND OF THE INVENTION
Ivabradine of formula I, and its additional salts more specifically hydrochloride, have very valuable (pharmacological and therapeutic properties, and are 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- tctrahydro-2H-3-benzazepin-2-onc.
(Formula Removed)
Ivabradinte hydrochloride is first disclosed in US patent 5,296,482. The process comprises the condensation of (S)-N-[(4,5-dimethoxybenzocyclobut-l-yl)-methyl]-N-(nietliyl)amine of Formula l].
(Formula Removed)

Formula II
with 7,8-dimethoxy-3-[3-iodopropyl]-l,3-dihydro-2H-3-benzazepin-2-one Formula III.
(Formula Removed)
Formula III
in acetone) and in presence of a base such as potassium carbonate. The resulting benzazepine intermediate of formula IV.
(Formula Removed)
Formula TV
is further reduced with palladium hydroxide in glacial acetic acid under the atmosphere of hydrogen gas to get ivabradine which is converted into its hydrochloride salt by the action of aqueous hydrochloric acid.
The methyl amine derivative of formula 11 is prepared by the reduction of l-cyano-4,5-dimethoxybenzocyclobutene of Formula V,
(Formula Removed)
Formula V
with borane tetrahydrofuran complex which upon condensation with ethyl chloroformate and further reducion with lithium aluminium hydride in tetrahydrofuran resulted in racemic
I
compound of methyl amine derivative of formula II. The racemic compound is resolved to (+) isomer of methyl amine derivative of formula II with (d)-camphosulphonic acid.
Benzazcpine derivative of formula 111 is prepared by the reaction of sodium iodide with 7.8-dimethoxy-3-[3-chloropropyl]-l ,3-dihydro-2H-3-benzazepin-2-one of formula VI.
(Formula Removed)

Formula VI
in acetone and the resulting iodo intermediate is purified by dissolving it in water and extracted with dichloromethane.
It has observed that the said process suffers from many drawbacks such as use of reagents such as borane tetrahyclrofuran complex which are unstable at room temperature, purification of intemtediates and ivabradine by chromatographic techniques. The chromatographic technique for purification is cumbersome, tedious and difficult to utilize on an industrial scale.
The use of aqueous hydrochloride in preparation of ivabradine hydrochloride is not suggested because the removal of hydrochloric acid by distillation may leads to decomposition and results in [he generation of impurities and hence further purification is required.
The above mentioned drawbacks calls for an alternative and improved process tor the preparation of highly pure ivabradine hydrochloride that is cost effective, commercially viable, reproducible on industrial scale and meets the needs of regulatory agencies.
It is. therefore, desirable to provide an efficient process for the preparation of highly pure ivabradine hydrochloride where impurity formation is less and hence avoids chromatographic purification and is convenient to operate on a commercial scale.
US patent 7.176,197 reports a crystalline form of ivabradine hydrochloride. Several other crystalling forms such as beta, gamma, beta-d, gamma-d and delta -d are also reported by Les Laboratories. There is no data available in the prior art for the existence of amorphous ivabradine hydrochloride.
Crystalline solids normally require a significant amount of energy for dissolution due to their highly organized, lattice like structures. For example, the energy required for a drug molecule to escape from a crystal is more than from an amorphous or a non- crystalline form, It is known that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form (Econno T., Chem. Phazm Bull., 1990; 38 : 2003-2007).
For some therapeutic indications, one bioav liability pattern may be favoured over another. An amorphous form of cefuroxime axietil is an example of one amorphous drug exhibiting much higher bioavailability than the crystalline forms, which leads to the selection of the amorphous form as the final drug substance for cefuroxime axietil pharmaceutical dosage form development. Additionally, the aqueous solubility of crystalline atorvastatin calcium is lower than its amorphous form, which may result in the difference in their in vivo bioavailability. Therefore, it is desirable to have amorphous forms of drugs and highly reproducible processes for their preparation. An amorphous form of ivabradine hydrochloride has now been discovered.
SUMMARY OF THE INVENTION
In one general aspect there is provided a process for the preparation of highly pure ivabradine of formula 1 and its hydrochloride which comprises: condensing methylamine derivative of formula 11,
(Formula Removed)

Formula II
with 7,8-dimethoxy-3-|3-iodopropyl]-l ,3-dihydro-2H-3-benzazepin-2-one of formula 111.
(Formula Removed)

Formula III
in suitable polar solvent, in presence of a base to prepare benzazepine intermediate of formula IV.
(Formula Removed)
Formula IV
reducing the compound of formula IV with palladium carbon in glacial acetic acid under the atmosphere of hydrogen gas to get ivabradine.
treating ivabradine in situ with alcoholic hydrogen chloride in suitable solvent to prepare its hydrochloride salt.
In other aspect there is provided a process for the preparation of highly pure ivabradine hydrochloride which comprises,
treating ivabradine with alcoholic hydrogen chloride in suitable solvent to prepare its hydrochloride salt.
In yet another aspect of the present invention provides a novel form of ivabradine hydrochloride i.e. amorphous ivabradine hydrochloride.
In still yet another aspect of the present invention provides a process tor preparing
amorphous ivabradine hydrochloride comprising
treating ivabradine hydrochloride with base in a suitable solvent.
treating the resulting ivabradine with alcoholic hydrogen chloride in organic solvent.
In still yet another aspect of the present invention provides a process for preparing o
crystalline form of ivabradine hydrochloride comprising the steps of:
heating a solution ivabradine hydrochloride in suitable solvent,
distilling off some of the solvent,
filtering the reaction mixture to obtain ivabradine hydrochloride,
heating a mixture of ivabradine hydrochloride in suitable solvent.
distilling of some of the solvent,
isolating of form of ivabradine hydrochloride.
In still yet another aspect of the present invention provides a process for preparing u-
crystalline form of ivabradine hydrochloride comprising the steps of:
heating a mixture of ivabradine hydrochloride in suitable solvent,
distilling off some of the solvent,
isolating a form of ivabradine hydrochloride.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a powdered X-ray diffraction pattern for amorphous ivabradine hydrochloride. Figure 2 is a powdered X-ray diffraction pattern for crystalline ivabradine hydrochloride a form ;
DETAILED DESCRIPTION OF THJE INVENTION
The instant invention relates to an improved, efficient and industrially advantageous process for the preparation of highly pure ivabradine hydrochloride particularly in amorphous form.
One aspect of the present invention relates to an improved process for the preparation of highly pure ivabradine hydrochloride by condensing methylamine derivative of formula II with benzazepine derivative of formula III in some polar aprotic or protic solvents and in presence of a base. The base can be selected from alkali metal carbonates, bicarbonates and hydroxides and preferably potassium carbonate. The polar aprotic or protic solvent is selected from tetrahydrofuran, acetone, acetonitrile, dimethylformamide. dimethylsulfoxide. isopropanjol, C1-C4 linear aliphatic alcohols such as methanol, cthanol etc. and mixtures thereof, More preferably the solvent is dimethylformamide or dimethylsulfoxide and most preferably the solvent is dimethylformamide, It is advantageous to use dimethylformamide during condensation reaction because reaction rate is faster and it takes only 2-3 hours for completion of reaction as compared to prior art process where 18 hours arc required in
acetone. Reaction is conducted at 30-75°C and preferably at 50-60°C. The completion of reaction is- monitored by high performance liquid chromatography. After completion of the reaction, the reaction mass is cooled to ambient temperature and is diluted with water, '['lie product is extracted in organic solvent from aqueous layer and some impurities remain in the aqueous layer. The solvent can be selected from lialogenated hydrocarbon such as inethylene dichloridq. ethylene dichloridc, carbon tetrachloridc, chloroform and aliphatic ester such as ethyl acetate and preferably methylene chloride is used. Thereafter solvent is distilled off complete the product is purified by acid base wash treatment. Specifically the residue treated with hydrochloric acid in water and washed with solvent such as ethyl acetate, there after the aqueous layer is neutralized with base and the desired compound is extracted in organic solvent. The organic solvent can be selected from lialogenated hydrocarbons and aliphatic esters as mentioned above and preferably ethyl acetate is used. The product is obtained and no chromatographic purification is required.
It has also found that during condensation process an unknown impurity has also formed. which is not easily removed by using the prior art isolation process and hence decreases the purity of (he condensed product. But during the process of present invention it has found that the said unknown impurity can be easily removed by extracting the desired product from the reaction mixture with halogenated solvents such as methylene dichloride. ethylene dichloride, carbon terachloride. chloroform. This further avoids the use of tedious chromatographic purification.
There after. the condensed product i.e. (S)-7.8-dimethoxy-3-{-N-|(4,5-dimethoxybenzocyclobut.-l-yl)methlyl]-N-(methyl)amino)propyl)-1.3-dihydin-2H-3-benzazepin 2-one of formula IV is converted to amorphous ivabradine hydrochloride. The compound of formula IV is catalytically hydrogenated using palladium on carbon catalyst in acetic acid under hydrogen pressure of 1-7 kg. The hydrogcnation reaction is conducted at ambient temperature and it takes 4-10 hours for completion of reaction, which is monitored by high performance liquid chromatography (IIPLC). The catalyst is filtered out and the product is extracted in organic solvent from filtrate. The organic solvent consists of
methylene dichloride. ethylene dichloride, carbon tetrachloride. chlorofonn. the filtrate is further treated with dilute hydrochloric acid and extracted with same organic solvent. There after the combined extracts were distilled and the resulting residue is treated with dilute hydrochloride acid. The aqueous layer is washed with organic solvent such as ethyl acetate to remove impurities and neutralized with base. Thereafter the desired compound is extracted in organic solvent. The organic solvent can be selected from above mentioned solvents such as halogenated hydrocarbon and aliphatic esters and preferably ethyl acetate is used. Optionally the ivabradine is isolated, otherwise organic layer itself is treated with alcoholic hydrogen chloride to prepare highly pure ivabradine hydrochloride. It is advantageous to dry the organic layer using drying agent such as sodium sulphate or the like before adding alcoholic hydrogen chloride.
In another aspect ivabradine of formula 1 is converted into pharmaceutically acceptable acid addition salts using alcoholic acid mixture. Particularly the hydrochloride salt preparation is carried out using alcoholic hydrogen chloride. In general, a solution of alcohol- hydrogen chloride is prepared by purging dry hydrogen chloride in alcohol by follow ing the methods reported in prior art. The percentage of hydrogen chloride in alcohol is preferably selected between (0-25%. The alcohol used in the solution of alcohol-hydrogen chloride is selected from C1-C4 branched or linear aliphatic alcohols and more preferably the solvent is n-butanol or isopropanol and most preferably the solvent is isopropanol. The precipitated ivabradine hydrochloride is isolated in high yield and purity of greater than 99.0% area by HPLC. XRD pattern shows that material is amorphous in nature. Amorphous Ivabradine hydrochloride is novel and-forms one aspect of the present invention.
X-ray diffraction of ivabradine hydrochloride are measured on a PANalytical XPert Pro diffractometer with Cu radiation and expressed in terms of two-theta. d-spacings and relative intensities. One of the ordinary skills in the art understands that experimental differences may arise due to differences in instrumentation, sample preparation or other factors.
Melting point was conducted using a Polmon MP Apparatus MP 96 with a sample weight of about 10 mg.
The intermediates 11 and 111 can be prepared by the methods reported in the prior art with minor modifications. Specifically the methyl amine derivative of Formula II is prepared
(Formula Removed)

Formula II
by the reduction of (R,S)-1- (cyano)-4,5-(dimethoxy)-benzocyclobutane of formula V using reducing agent such as borane complexes like borane dimethyl sulphide complex in tetraliydrofuran which is converted to acid addition salt by treatment with acid in suitable solvent. Particularly hydrochloride salt is prepared by treating the amino derivative with alcoholic hydrogenchloride, ethereal hydrogenchloride such as ethanol hydrogen chloride, isopropyl acetate hydrogen chloride, isopropylether hydrogen chloride etc.
(Formula Removed)
Hydrochlorie acid salt of the obtained amino intermediate is further condensed with ethyl chlorofoninate in presence of a suitable base to prepare the corresponding amide. The resulting amide is reduced with lithium aluminium hydride in tetrahydrofuran to prepare racemic methyl amine intermediate of formula 11. Racemic intermediate is further resolved with suitable resolving agent such as (d)-camphosulphonic acid to produce desired (') isomer methyl amine formula 11. The racemic compound can optionally be used in oily form or can be isolated.
The said process is very useful during its application at large-scale production because borane dimethyl Sulphide complex is stable at room temperature hence its storage and handing is not difficult during large scale production.
Specifically the benzazepme compound of formula 111 is prepared by
(Formula Removed)
Formula III
the reaction of 7,8-dimethoxy-3-f3-c.hloropropyl]-l,3-dihydro-2H-3-benzazepin-2-one of formula Vl with sodium iodide in acetone followed by its purification by slurry washing of the residue with acetone.
The intendediates of formula V and VI are prepared by the methods reported in the literatures (I. Kametani et al. Tetrahedron 1973; vol. 29: pages 73-76 and Reiffer M. et al., .1. Med. Chem.. 19190: vol 33 (5): 1496-1504).
The intermediate of formula V can also be prepared by the reaction of 6 bromovaretraldehyde with cyanoacetic acid in presence of ammonium acetate and in solvents optionally selected from pyridine. toluene, benzene etc. or mixtures thereof. The isolated intermediate is further reduced with sodium borohydride in the presence of aqueous base. Generally; bases are selected from sodium bicarbonate, sodium carbonate, potassium hydroxide!, sodium hydroxide or mixtures thereof to get p-(2-bromo-4,5-dimethoxypheinyl)-u-cyanopropionic acid. The resulting acid upon decarboxylation in N-N-dirnethyl acctamide and reaction with sodium amide or potassium amide in liquid ammonia is converted to 1-cyano-4.5-dimethoxybenzocyclobutene of formula V.
Further more, the intermediate of formula VI can also be prepared by the halogenation of 3,4-dimethoxy phenyl acetic acid with some halogenating agents such as thionyl chloride in chlorinated solvents such as methylene dichloride. The obtained chloro compound is further condensed with aminoacetaldehyde dimethyl acetal in presence of a suitable base to prepare corresponding amide derivative. The ring closure of resulting amide into benzazepin moiety is carried out in presence of an acid, for example, hydrochloric acid, glacial acetic acid or mixtures (hereof Obtained benzazepin moiety is further alkylated with l-bromo-3-chloro-
propane in presence of a suitable base such as potassium tertiary butoxide in an organic solvent tq obtain 7,8-dimethoxy-3-[3-chloropropyl]-1,3-dihydro-2H-3-benzazepin-2.-one of formula Vl, The organic solvents can be selected from acetone, dimethylsulfoxide. dimethylformamide. etc. or mixtures thereof.
In yet another aspect of the present invention amorphous ivabradine hydrochloride can also be prepaid from crystalline ivabradine hydrochloride. Specifically the crystalline ivabradine hydrochloride is treated with suitable base and in a suitable solvent followed by regeneration of ivabradine hydrochloride from the solution of isopropyl alcohol/HCI to get amorphous ivabradine hydrochloride.The bases can be selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate. The solvents can be selected from ethyl acetate, isopropyl acetate, methyl isobutyl ketone and acetone.
In still yet another aspect of the present invention the a-crystalline form of the ivabradine hydrochloride can also be prepared by recrystallization of ivabradine hydrochloride in suitable organic solvent such as acetonitrile followed by addition of lower aliphatic ketone. ester, straight branched or cyclic ethers or mixtures thereof heat the mixture, removed solvents and recovered the a-crystalline form of ivabradine hydrochloride.
In still yet another aspect of the present invention the a-crystalline form of the ivabradine hydrochloride can also be prepared from amorphous Ivabradine in suitable organic solvent such as lower aliphatic ketone, ester, straight branched or cyclic ethers or nitrites or mixtures thereof, The lower aliphatic ketonic solvents can be selected from methyl isobutyi ketone. acetone or the like. The esters can be selected from ethyl acetate and isopropyl acctatc. The ether can be selected from isopropyl ether, tetrahydrofuran and the like. The nitrile can be acetonitrile and the like. Ivabradine hydrochloride is taken in suitable solvent and heated at 60-90°C I for sufficient time to transform to a-crystalline form of the ivabradine hydrochloride.
Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. 1 he invention is further defined by reference to the following examples describing in detail the preparation of the product and methods of use of the invention, it will be apparent to those skilled in the art that main modifications, both to materials and methods. may be practiced without departing from the scope of the invention.
EXAMPLES
Exam ple 1
Preparation of lyabradine hydrochloride
Stepl:. Preparation of (S)-7,8-diiqethoxv-3-(3-{N-f(4,5-dimethoxybenzocyclohut-l-yl)
methyl|-N-(mtfthyl)ainino)propvl)- 1.3-dihydro-2H-3-beuzazepin-2-one
To a mixture of (S)-N-[(4,5-dimethoxybenzocyclobut-l-yl)-methyl]-N-{methyl)amine (42g) and N-N-idimethylformamide (220ml) was charged 7,8-dimethoxy-3-[3-iodopropyl]-L3~ dihydro-2H-3-benzazepin-2-one (75g) and potassium carbonate (42g) at room temperature. The reaction mixture was heated and stirred the reaction mass at 50-550C for 2hrs and the completion of reaction was monitored by HPIC/TLC. After completion of reaction, reaction mass was; cooled to 25-30°C and diluted with dimineralized water (1000ml). The reaction mixture vias extracted with methylene clichloride (400ml x 200ml) and the layers were separated.; Methylene chloride was distilled off completely. To the residue, dimineralized water (200ml) and hydrochloric acid (50ml) were added and the aqueous solution is washed with ethyl acetate (200ml x 3). The layers were separated and to the aqueous layer 50 % (w/v) sodium hydroxide solution (120ml) was added at 25-30°C. The aqueous layer was extracted with ethyl acetate (400ml + 200 ml) and the combined ethyl acetate layer was washed vvjith 5%( w/v) sodium hydroxide solution (300ml). Ethyl acetate layer was dried over anhydrous sodium sulphate and then ethyl acetate was distilled out completely under vacuum to get the title compound.

Steu 2: . Preparation of (S)7,8-dimethpxv-3-{3-(N-[(4,5-dimethoxybenzocyelobut-l-vl)methyl-N-(incthvl)aniino)propvl)-A,3,4,5-tctrahvdro-2tl-3-benzazepin-2-one hydrochtyride (IVABRADINE HYDROCHLORIDE)
Benzazepine compound (85g) obtained in step 1 was taken in acetic acid (700ml). and was hydrogenated under a hydrogen pressure (1-2 kg) at room temperature in the presence of Pd/C (10%. 70g). Further hydrogenation was continued with 6-7 kg hydrogen pressure at 20"C for 4-8 hrs. After completion of hydrogenation (monitored by HPLC). the catalyst was filtered off and catalyst was washed with water (800ml). The filtrate was then extracted with methylenei chloride (700ml) and to the aqueous layer hydrochloric acid solution (50ml) was added. The aqueous layer was again extracted with methylene dichloride (300ml x 3). The combinediorganie layer was distilled off and to the residue dimineralized water (400ml) and hydrochloric acid solution (90 ml) were charged followed by ethyl acetate (400ml). The reaction mixture was stirred at 30-35"C for half an hour and the layers were separated. The aqueous layer was again washed with ethyl acetate (500ml). There after aqueous layer was treated with 50 % (w/v) sodium hydroxide solution (150ml). The aqueous layer was extracted with ethyl acetate (400ml 250ml) and combined ethyl acetate layer was washed with 5% (w/v) sodium hydroxide solution (400ml). Ethyl acetate layer was dried over anhydrous sodium sulphate and then solvent was distilled out completely. The residue was taken in ethyl acetate (400ml) and to this isopropyl alcohol-hydrogen chloride (50ml) was added slowly and was stirred for 4-5 hours. The product obtained was filtered, washed with ethyl acetate (85ml) and dried at 55-60uC to obtain the title compound in amorphous form having purity 98.5% area by HPLC.
Example 2
Preparatjon of amorphous ivabradine hydrochloride
a- Crystalline form of Ivabradin hydrochloride (6 gm) was taken in water (30 ml) and basified by sodium hydroxide solution (50 %). Ivabradin thus formed was extracted with ethyl acethte (50 nil).Which was dried anhydrous sodium sulphate. Solvent was distilled off. Residue Was taken in ethyl acetate (30ml) and isopropyl alcohol hydrogen chloride (5ml) was added slowly and was stirred for 2 hrs. Product thus obtained was filtered, washed with
ethyl acetate (6 ml) and dried at 55-60°c to obtained amorphous ivabradine hydrochloride having purity 99.03 % area by HPIC.
Example 3
Preparation ot crystalline ivabradine hydrochloride a-forni
Ivabradine- hydrochloride (47g) was taken in acctonitrile (940ml) and heated to 80±2"C for 30minutes till clear solution.. Thereafter half of the acetonitrile was distilled off and the reaction mass was cooled, filtered and washed with acetonitrile to get wet cake of the product.
Obtained wet cake was further dissolved in ethyl acetate (611ml) at room temperature then heated the mixture to 75-80°C and maintain it for 60 minutes. The reaction mixture was concentrated by distillation of about one third of ethyl acetate. The reaction mass was cooled, filtered, washed with ethyl acetate and dried under vacuum to obtain the a-crystalline form of ivabradime hydrochloride.
Example 4
Preparation of a- Crystalline form of ivabradine hydrochloride from amorphous form
Amorphous ivabradine hydrochloride (4 gin) was taken in ethyl acetate (60 ml) and healed to reflux for;30 minutes, There after one third of ethyl acetate was distilled off and the reaction mass was; cooled to 25-30°C. The product obtained was filtered and dried to obtain ά-crystallintf form having purity 99.89 % area by HPLC.
Exampl-5
Preparatjon of a- Crystalline form of ivabradine hydrochloride
Ivabradint hydrochloride (2 gm) was taken in acetone (200 ml) and heated to reflux till cleat-solution, suspended material was filtered off. Thereafter 60 % of acetone was distilled off and reaction mass was cooled to room temperature. The product was filtered, washed with acetone (10 ml) and dried to obtain a- crystalline form having purity 99.73 %area by HPLC.

WE CLAIM
A process for the preparation of highly pure ivabradine of formula 1 and its salts
(Figure Removed)
which comprises:
a) condensing methylamine of formula FT.

(Figure Removed)
with 7.8-dimetlioxy-3-f3-iodopropyl]-1.3-dihydro-2H-3-benzazepin-2-one of formula III.
(Figure Removed)
in suitable polar solvent in presence of a base to prepare bcnzazcpinc intermediate of formula 1
(Figure Removed)
b) reducing the benzazepine intermediate of formula IV with palladium carbon
in glacial acetic acid under the atmosphere of hydrogen to get ivabradine.
c) converting ivabradine in situ to its hydrochloride salt using alcoholic
hydrogen chloride in suitable solvent.

2. The process according to claim 1. wherein the polar solvent used in step a. is
selected from tetrahydrofuran, acetone, acetonitrile. dimethylfonnaniicle.
dimethylsulfoxide. isopropanol. CpQ linear aliphatic alcohols such as methanol.
ethanol.
3. The process according to claim 1, wherein alcohol used in alcoholic hydrogen
chloride in step c. is selected from C|-d branched or linear aliphatic alcohols
such as n-butanol or isopropanol and most preferably the solvent is isopropanol
4. The process according to claim 1. wherein the solvent used in step c. is selected
from halogenatcd hydrocarbon and aliphatic esters such as methylene dichloridc.
ethylene dichloride. carbon tetrachloride, chloroform, ethylacetate.
methylacetate.
5. Amorphous ivabradine hydrochloride.
6. A process for the preparation of amorphous ivabradine hydrochloride comprises:
a) treating ivabradine hydrochloride with base in a suitable solvent.
h) treating the resulting ivabradine with alcoholic hydrogen chloride in organic solvent.
7. The process according to claim 6, wherein the solvent used in step a. is selected
from halogenated hydrocarbon and aliphatic esters such as inethylene dichloride.
ethylene dichloride, carbon tetrachloride, chloroform. ethylacetate.
methvlacetate.
8. A process for the conversion of amorphous ivabradine hydrochloridc to
crystalline ivabradine hydrochloride a form comprises:
a) heating amorphous ivabradine hydrochloride in suitable solvent.
b) distilling off some of the solvent.
c) isolating u form of ivabradine hydrochloride.
9. A process for the preparation of ivabradine hydrochloride a form comprises:
a) heating amorphous ivabradine hydrochloride in suitable solvent.
b) d isti 11 ing off some of the solvent.
c) isolating u form of ivabradine hydrochloride.
10. The process according to claim 8 and 9, wherein the suitable solvent is selected
from methyl isobutyl ketone, acetone, ethyl acetate and isopropyl acetate.
tetrahydrofuran, isopropyl ether and acetonitrile.