FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
"PROCESS FOR PREPARATION OF IVABRADINE"
Glenmark Pharmaceuticals Limited;
Glenmark Generics Limited
an Indian Company, registered under the Indian company's Act 1957 and having its
registered office at
Glenmark House,
HDO- Corporate Bldg, Wing-A,
B. D. Sawant Marg, Chakala, Andheri (East), Mumbai- 400 099
The following specification particularly describes the invention and the manner in which it is to be performed.

BACKGROUND OF THE INVENTION
Technical Field
The present invention relates to a process for the preparation of ivabradine and
pharmaceutically acceptable salts thereof. The present invention relates to a process for
the preparation of amorphous form of ivabradine hydrochloride.
Description of the Related Art
Ivabradine, also known as (5)-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) is
represented by the structure of formula I.
Ivabradine hydrochloride, a compound of formula II, is indicated for the symptomatic treatment of chronic stable angina pectoris in patients with normal sinus rhythm who have a contraindication or intolerance to beta-blockers. It is also indicated for the treatment of stable chronic heart failure (NHYA II-IV).
United States Patent No. 5296482 discloses ivabradine and its salts.
The present invention provides a process for the preparation of amorphous form of
ivabradine hydrochloride.
SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of amorphous form of
ivabradine hydrochloride, the process comprising:
(a) dissolving a crystalline ivabradine hydrochloride in a solvent or mixture of solvents or aqueous mixtures thereof to provide a solution; and
(b) removing the solvent from the solution obtained in (a).
In another embodiment, the present invention provides amorphous ivabradine hydrochloride wherein the compounds of formula A, III or IVa are present to an extent of less than 0.15% w/w relative to the amount of ivabradine hydrochloride as determined by high performance liquid chromatography.

In another embodiment, the present invention provides a process for the preparation of amorphous ivabradine hydrochloride, the process comprising:
(a) reacting ivabradine borate with a base to form ivabradine;
(b) treating ivabradine with hydrochloric acid to form a reaction mixture; and
(c) isolating the amorphous form of ivabradine hydrochloride from the reaction mixture. In another embodiment, the present invention provides ivabradine borate characterized by an X-ray powder diffraction pattern, which is substantially in accordance with Figure 1; a differential scanning calorimetry endotherm curve, which is substantially in accordance with Figure 2; a thermogravimetric analysis endotherm curve, which is substantially in accordance with Figure 3; a Fourier transform infrared spectrum, which is substantially in accordance with Figure 4; a C nuclear magnetic resonance spectrum, which is in accordance with Figure 5; and a combination thereof.
In another embodiment, the present invention provides a process for the preparation of ivabradine borate, the process comprising:
(a) combining ivabradine and boric acid in a solvent or mixture of solvents or aqueous mixtures thereof; and
(b) isolating the ivabradine borate obtained in (a).
In another embodiment, the present invention provides use of ivabradine borate in the
preparation of ivabradine hydrochloride.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a characteristic XRPD of ivabradine borate as obtained in Example 15.
Figure 2 is a DSC thermogram of ivabradine borate as obtained in Example 15.
Figure 3 is a TGA thermogram of ivabradine borate as obtained in Example 15.
Figure 4 is an IR spectrum of ivabradine borate as obtained in Example 15.
Figure 5 is a 13C NMR spectrum of ivabradine borate as obtained in Example 15.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of amorphous form of
ivabradine hydrochloride, the process comprising:
(a) dissolving a crystalline ivabradine hydrochloride in a solvent or mixture of solvents or aqueous mixtures thereof to provide a solution; and
(b) removing the solvent from the solution obtained in (a).

In the present application, the term "room temperature" means a temperature of about 25°C to about 30°C.
In (a) of the process for the preparation of amorphous form of ivabradine hydrochloride, a crystalline ivabradine hydrochloride is dissolved in a solvent or mixture of solvents or aqueous mixtures thereof to provide a solution.
The solvent used for dissolution of crystalline ivabradine hydrochloride includes but is not limited to alcohols such as methanol, ethanol, 1-propanol. 2-propanol. 1-butanol, 2-butanol. 1-pentanol, 1-octanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; ethers such as diethyl ether, diisopropyl ether, tert-butylmethyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, clilorobenzene and the like; haloalkanes such as methylene dichloride, ethylene dichloride, chloroform and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; water; or mixtures thereof. Preferably the solvent selected is water. Stirring may be continued for any desired time period to achieve a complete dissolution of the compound. The stirring time may range from about 30 minutes to about 3 hours, or longer. The solution may be optionally treated with charcoal and filtered to get a particle-free solution. In (b) of the process for the preparation of amorphous form of ivabradine hydrochloride, the solvent is removed from the solution obtained in (a).
Removal of solvent may be accomplished by substantially complete evaporation of the solvent or concentrating the solution, cooling the solution if required and filtering the obtained solid. The solution may also be completely evaporated by lyophilization, freeze-drying technique, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying. Preferably solvent was removed by lyophilization to give amorphous form of ivabradine hydrochloride. In one embodiment, the present invention provides a process for the preparation of amorphous form of ivabradine hydrochloride, the process comprising:
(a) dissolving a crystalline form of ivabradine hydrochloride selected from 5-crystalline form, 8d-crystalline form, or mixture thereof, in a solvent or mixture of solvents or aqueous mixtures thereof to provide a solution; and
(b) removing the solvent from the solution obtained in (a).

The solvent may be selected from the solvents as discussed supra and the removal of
solvent may be carried out as discussed supra.
In one preferred embodiment, the solvent is water and the solvent removal is by lyophilization,
Lyophilization is typically done by a process comprising cooling the solution to obtain a
cooJed mixture, and evaporating the solvent while maintaining the mixture cooJed at low
temperatures. Preferably, the solution is cooled to a temperature of about -84°C to about -
65°C, providing the cooled mixture, which is a frozen mass. The lyophilizing step may be
done under vacuum (not less than about l00millitorr).
Jn one embodiment, the present invention provides a process for the preparation of
amorphous form of ivabradine hydrochloride, the process comprising:
(a) dissolving a crystalline form of ivabradine hydrochloride selected from 8-crystalline form, 6d-crystalline form, or mixture thereof, in water to provide a solution; and
(b) removing the solvent from the solution obtained in (a) by iyophihzation.
In one embodiment, the present invention provides a process for the preparation of amorphous form of ivabradine hydrochloride, the process comprising: (a) dissolving a crystalline form of ivabradine hydrochloride, having XRPD peaks as below, in a solvent or mixture of solvents or aqueous mixtures thereof to provide a solution; and

Pos. I°2Th.l d-spacing
[A] Rel. Int. I%1 Pos. [°2Th.] d-spacing
! [A] Rel. Int. Pos.
f°2Th.j d-spacing
[A] Rel. Int.
f%!
4.08 21.60 80.33 19.63 4.52 14.75 29.57 3.02 19.33
8.38 10.54 27.82 20.18 4.39 8.14 29.98 2.97 9.29
8.52 10.37 17.55 20.63 4.30 13.53 30.76 2.90 10.69
9.03 9.79 6.79 21.00 4.23 26.99 31.25 2.86 5.31
11.00 8.03 57.23 21.51 4.13 32.97 32.73 2.73 9.61
11.59 7.62 9.15 21.71 4.09 22.72 33.37 2.68 10.22
14.35 6.16 37.03 22.25 3.99 62.85 34.17 2.62 17.07
14.52 6.09 45.19 22.56 3.93 17.04 34.94 2.56 9.79
14.69 6.02 44.18 22.94 3.87 13.82 36.60 2.45 7.42
15.26 5.80 56.13 23.31 3.81 13.58 37.50 2.39 5.81
16.17 5.47 . 11.12 23.87 3.72 31.46 38.40 2.34 12.65
16.48 5.37 73.06 24.62 3.61 32.73 39.39 2.28 2.60
16.86 5.25 100.00 25.44 3.50 35.66 1 40.44 2.23 5.77
17.13 5.17 65.30 25.93 3.43 66.53 41.01 2.20 7.67
17.49 5.06 14.59 26.25 3.39 35.42 J 41.94 2.15 6.41
17.81 4.97 33.00 26.55 3.35 54.83 42.71 2.11 4.33
18.05 4.91 55.91 26.84 3.32 21.63 43.73 2.07 2.50
18.17 4.88 47.69 27.58 3.23 27.87 44.65 2.02 3.53
18.99 4.67 19.79 28.38 3.14 5.11 45.83 1.97 2.46
19.23 4.61 20.21 28.94 3.08 13.41
(b) removing fing the sol vent from the soluti ion obtained d in (a).

in one preferred embodiment, the present invention provides a process for the preparation of amorphous form of ivabradine hydrochloride, the process comprising:
(a) dissolving a crystalline form of ivabradine hydrochloride, having XRPD peaks as above, in water to provide a solution; and
(b) removing the solvent from the solution obtained in (a) by lyophilization.
In one embodiment, the present invention provides a process for the preparation of amorphous form of ivabradine hydrochloride, wherein the amorphous form of ivabradine hydrochloride obtained has compounds of formula A, III or IVa present to an extent of less than 0.15% w/w relative to the amount of ivabradine hydrochloride as determined by high performance liquid chromatography,

the process comprising:
(a) dissolving a polymorph mixture of 8-crystalline form and Sd-crystalline form of ivabradine hydrochloride in water to provide a solution; and
(b) removing the solvent from the solution obtained in (a) by lyophilization.
The present invention provides amorphous ivabradine hydrochloride wherein the compounds of formula A, III or IVa are present to an extent of less than 0.15% w/w relative to the amount of ivabradine hydrochloride, as determined by high performance liquid chromatography (HPLC).
The present invention provides amorphous ivabradine hydrochloride wherein the compounds of formula A, III or IVa are present to an extent of less than 0.15% w/w relative to the amount of ivabradine hydrochloride, preferably less than 0.05% w/w, more preferably absent, as determined by high performance liquid chromatography (HPLC). The present invention provides amorphous ivabradine hydrochloride wherein the compounds of formula A, III or IVa are present to an extent of less than 0.15% w/w relative to the amount of ivabradine hydrochloride, obtained by above process, as

analyzed by chemical purity using high performance liquid chromatography (HPLC) with
the conditions described below:
Reagents, Solvents and Standards: Water (Milli Q or equivalent), Perchloric acid (GR
Grade), Acetonitrile (HPLC Grade), Methanol (HPLC Grade)
Chromatographic Conditions: Apparatus: A High Performance Liquid Chromatograph
equipped with quaternary gradient pumps, variable wavelength UV detector attached
with data recorder and integrator software; Column: Inertsil ODS 3V, 250 x 4.6mm, 5µ;
Column temperature: 35°C; Sample Cooler temperature: 10°C
Mobile Phase A: Buffer; Buffer: 0.1% Perchloric acid in water.
Mobile Phase B: Methanol

Time (min.) % Mobile Phase A % Mobile Phase B
0.01 75 25
40 65 35
55 30 70
65 30 70
68 75 25
75 75 25
Diluent: Water: Acetonitrile (80:20, v/v); Flow Rate: l.0mL/minute; Detection: UV
230nm; Injection Volume: 20µL
The retention time of ivabradine hydrochloride is about 37.0 minutes under these
conditions. Relative retention time for compound of formula IV is about 0.19, for
compound of formula III is about 1.14, for compound of formula A is about 1.17 with
respect to ivabradine hydrochloride.
The present invention provides a process for the preparation of crystalline ivabradine
hydrochloride, the process comprising:
(a) condensing a compound of formula IV or salt thereof with a compound of formula V,
wherein X is selected from the group consisting of CI, Br, 1,

III
(b) reacting a compound of formula III with a reducing agent to obtain ivabradine;

(c) treating ivabradine with alcoholic hydrochloric acid to obtain ivabradine
hydrochloride; and
(d) optionally recrystallizing the ivabradine hydrochloride from alcohol or nitrile or
mixtures thereof.
In (a) of the process for the preparation of crystalline ivabradine hydrochloride, a compound of formula IV or salt thereof is condensed with a compound of formula V, wherein X is selected from the group consisting of CI, Br, I, to give a compound of formula III. In one embodiment, the compound of formula IV or alt thereof is condensed with the compound of formula V, wherein X is I, to give the compound of formula III. The reaction may be carried out in the presence of a suitable base. The suitable base includes, but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide. potassium hydroxide; alkaline earth metal hydroxides; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkaline earth metal carbonates; alkali metal bicarbonates such as sodium bicarbonate; alkali metal hydrides such as sodium hydride, potassium hydride; alkali metal alcoholates such as lithium methoxide, sodium methoxide. potassium methoxide, rubidium methoxide, caesium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, sodium pentoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide; alkaline earth metal alcoholates such as calcium ethoxide, magnesium iso-propoxide; alkyl lithium such as n-butyl lithium; alkali metal acetates, tertiary amines such as triethylamine, N,N,-diisopropylethylamine; ammonia, pyridine, piperidine, 4-dimethylaminopyridine, l,4-diazabicyclo[2.2.2]octane. l,8-diazabicyclo[5.4.0]undec-7-ene, potassium bis(trimethylsilyl)amide. Preferably the base selected is potassium carbonate. The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes, but is not limited to ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene and the like; dimethyl formamide; dimethyl acetamide; water or mixtures thereof. Preferably the solvent selected is dimethyl formamide. The reaction may be carried out at a temperature in the range of about 100C to about 80°C. The reaction is carried out for a period of about 3 hours to about 20 hours.

Preferably the reaction is carried out at a temperature of about 20°C to about 30°C for a period of about 5 hours to about 16 hours.
In one embodiment, the compound of formula IV or salt thereof is condensed with 7,8-dimethoxy-3-[3-iodopropyl]-l,3-dihydro-2H-3-benzazepin-2-one, a compound of formula Va,

Va to give the compound of formula III.
In one embodiment, the compound of formula IV or salt thereof is condensed with the
compound of formula Va, in the presence of potassium carbonate in dimethyl formamide.
In one embodiment, the compound of formula III is not isolated from the reaction mixture.
The compound of formula Va is obtained by converting 7,8-dimethoxy-3-[3-
chloropropy!]-l,3-dihydro-2H-3-benzazepin-2-one, a compound of formula Vb,

using metal iodide to give the compound of formula Va.
The metal iodide includes, but is not limited to alkali metal iodide such as sodium iodide,
potassium iodide and the like.
The reaction may be carried out in the presence of a suitable solvent. The suitable solvent
includes, but is not limited to ketones such as acetone, ethyl methyl ketone and methyl isobutyl
ketone and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl
methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate,
n-propyl acetate, tert-butyl acetate and the like; haloalkanes such as dichloromethane,
chloroform and the like; acetonitrile; dimethyl formamide; dimethyl acetamide; water or
mixtures thereof. Preferably the solvent selected is acetone, methyl ethyl ketone.
The reaction may be carried out at a temperature in the range of about 20°C to about
100°C. The reaction is carried out for a period of about 5 hours to about 40 hours.
Preferably the reaction is carried out at a temperature of about 50°C to about 80°C for a
period of about 5 hours to about 15 hours.
In one embodiment, the compound of formula V, wherein X is CI, is converted to a
compound of formula V, wherein X is I, in methyl ethyl ketone,

The compound of formula V is obtained by condensing 7,8-dimethoxy-l,3-dihydro-2#-3-benzazepin-2-one, a compound of formula VI,

VI with a compound of formula VII,

wherein X is selected from the group consisting of CI, Br, I,
to give the compound of formula V.
The compound of formula Vb is obtained by condensing 7.8-dimethoxy-l,3-dihydro-2//-
3-benzazepin-2-one, a compound of formula VI,

with l-bromo-3-chioropropane, a compound of formula Vila,
to give the compound of formula Vb.
The reaction may be carried out in the presence of a suitable base. The base may be selected
from the bases as disclosed supra.
The reaction may be carried out in the presence of a suitable solvent. The suitable solvent
includes, but is not limited to ketones such as acetone, ethyl methyl ketone and methyl
isobutyl ketone and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl
ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl
acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; dimethyl
formamide; dimethyl sulfoxide; dimethyl acetamide; water or mixtures thereof.
Preferably the solvent selected is dimethyl sulfoxide.
The reaction may be carried out at a temperature in the range of about 20°C to about
60°C. The reaction is carried out for a period of about 2 hours to about 8 hours.
Preferably the reaction is carried out at a temperature of about 20°C to about 35°C for a
period of about 2 hours to about 5 hours.
In (b) of the process for the preparation of crystalline ivabradine hydrochloride, a
compound of formula III is reacted with a reducing agent to obtain ivabradine.

The reducing agent is selected from the group consisting of sodium dithionite, zinc/hydrochloric acid, tin/hydrochioric acid, iron/hydrochJoric acid, stannous chloride, stannous chloride/hydrochloric acid, activated aluminium, salts of hydrogen sulfide, hydrazine hydrate/Raney nickel, hydrazine hydrate/palladium on carbon, hydrazine hydrate/platinum on carbon, zinc/calcium chloride dihydrate, zinc/ammonium chloride, alkali metal borohydride/alkali metal halide, lithium aluminium hydride, sodium cyanoborohydride, sodium triacetoxyborohydride, or reduction using hydrogen transfer reagent such as ammonium formate, sodium formate, trialkyl ammonium formates, formic acid, phosphoric acid, hydrazine, monosodium dihydrogen orthophosphate, cyclohexene, cyclohexadiene, hydrazinium monoformate in the presence of magnesium powder, or reduction by catalytic hydrogenation using hydrogenation catalyst including, but not limited to palladium on carbon, palladium hydroxide, platinum on carbon, platinum oxide, rhodium on carbon, rhodium on alumina, Raney nickel, zinc dust. Preferably the compound of formula III is reduced to ivabradine by catalytic hydrogenation using palladium on carbon catalyst. The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; haloalkanes such as dichloromethane, chloroform and the like; dimethyl formamide: dimethyl acetamide; water or mixtures thereof. Preferably the solvent selected is methanol, ethyl acetate. The reaction may be carried out at a temperature in the range of about 20°C to about 110°C. The reaction is carried out for a period of about 5 hours to about 30 hours. Preferably the reaction is carried out at a temperature of about 50°C to about 80°C for a period of about 8 hours to about 20 hours.
In (c) of the process for the preparation of crystalline ivabradine hydrochloride, ivabradine is treated with alcoholic hydrochloric acid to obtain ivabradine hydrochloride. The alcohol containing hydrochloric acid, is selected from ethanol, methanol, n-propyl alcohol, isopropy! alcohol, butanol and the like; or mixtures thereof. Preferably the alcohol selected is isopropyl alcohol.
The reaction may be carried out by using suitable organic solvent which includes, but is not limited to, esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate

and the like; haloalkanes such as dichloromethane, chloroform and the like; ethers such as diethyl ether, dimethyl ether, ethyl methyl ether, diisopropyl ether, methyl tertiary-butyl ether and the like; alcohols such as ethanol, methanol, propanol, butanol and the like: ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like; acetonitrile; water or mixtures thereof. Preferably the solvent selected is acetonitrile. The reaction may be carried out at a temperature in the range of about 0°C to about 85°C for a period of about 2 hours to about 10 hours. Preferably the reaction is carried out at a temperature of about 0°C to about 50°C for a period of about 2 hours to about 6 hours. In (d) of the process for the preparation of crystalline ivabradine hydrochloride, the ivabradine hydrochloride is recrystallized from alcohol or nitrile or mixtures thereof. The ivabradine hydrochloride may be recrystallized by addition of alcohol which includes, but is not limited to ethanol, methanol, propanol, butanol and the like; nitrile which includes, but is not limited to acetonitrile; or mixtures thereof. Preferably, the ivabradine hydrochloride is recrystallized from methanoi-acetonitrile mixture. In one embodiment, the crystalline ivabradine hydrochloride obtained is a polymorph mixture of 5-crystalline form and 5d-crystalline form of ivabradine hydrochloride. In one embodiment, the present invention provides the compound of formula III in a purity of at least 95%, preferably at least 99%, as determined by high performance liquid chromatography (HPLC).
The present invention provides a process for the preparation of the compound of formula III in a purity of at least 95%, as determined by high performance liquid chromatography, by a process comprising:
(a) reacting the compound of formula III, with acid to form salt of compound of formula III;
(b) reacting the salt of compound of formula III with a base to form compound of formula III; and
(c) isolating the compound of formula III.
In (a) of the process for the preparation of the compound of formula III in a purity of at least 95%, the compound of formula III is reacted with acid to form salt of compound of formula III.
The suitable acid includes, but is not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, boric acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, and the like. Preferably the acid is boric acid.

The reaction may be carried out by using suitable organic solvent which includes, but is not limited to, esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like; haloalkanes such as dichloromethane, chloroform and the like; ethers such as diethyl ether, dimethyl ether, ethyl methyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, dioxane and the like; alcohols such as ethanol, methanol, propanol, butanol and the like; ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like; acetonitrile; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; water or mixtures thereof. Preferably the solvent selected is acetonitrile. The reaction may be carried out at a temperature in the range of about 0°C to about the reflux temperature of the solvent for a period of about 2 hours to about 20 hours. Preferably the reaction is carried out at a temperature of about 40°C to about 90°C for a period of about 2 hours to about 10 hours.
In (b) of the process for the preparation of the compound of formula III in a purity of at least 95%, the salt of compound of formula III is reacted with a base to form compound of formula III.
The suitable base includes, but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxides; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkaline earth metal carbonates; alkali metal bicarbonates such as sodium bicarbonate; a source of ammonia such as ammonia water (aqueous ammonia), ammonium carbonate, ammonia gas, liquid ammonia. Preferably the base selected is aqueous ammonia. In (c) of the process for the preparation of the compound of formula III in a purity of at least 95%, the compound of formula III is isolated from the reaction mixture by any method known in the art.
The method, may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like or extraction in an organic solvent followed removal of solvent. Removal of solvent may be accomplished by substantially complete evaporation of the solvent or concentrating the solution, cooling the solution if required and filtering the obtained solid. The solution may also be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum.

In one embodiment, the present invention provides a process for the preparation of the compound of formula III in a purity of at least 99%. as determined by high performance liquid chromatography, by a process comprising:
(a) reacting the compound of formula III, with boric acid to form a borate salt of compound of formula III,-
(b) reacting the borate salt of compound of formula III with a base to form compound of formula III; and
(c) isolating the compound of formula III.
In one embodiment, the present invention provides borate salt of compound of formula III.
In one embodiment, the present invention provides ivabradine borate.
In one embodiment, the present invention provides ivabradine borate characterized by an
X-ray powder diffraction pattern, which is substantially in accordance with Figure 1; a
differential scanning calorimetry endotherm curve, which is substantially in accordance
with Figure 2; a thermogravimetric analysis endotherm curve, which is substantially in
accordance with Figure 3; a Fourier transform infrared spectrum, which is substantially in
accordance with Figure 4; a C nuclear magnetic resonance spectrum, which is in
accordance with Figure 5; and a combination thereof.
The present invention provides ivabradine borate that exhibits an X-ray powder
diffraction pattern having characteristic peaks expressed in degrees 20 ± 0.2°θ at about
5.63,10.12,14.21,19.12,19.67,22.16.
The present invention provides a process for the preparation of ivabradine borate, the
process comprising:
(a) combining ivabradine and boric acid in a solvent or mixture of solvents or aqueous mixtures thereof: and
(b) isolating the ivabradine borate obtained in (a).
In (a) of the process for the preparation of ivabradine borate, ivabradine and boric acid are combined in a solvent or mixture of solvents or aqueous mixtures thereof. The reaction may be carried out by using suitable organic solvent which includes, but is not limited to, esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like; haloalkanes such as dichloromethane, chloroform and the like; ethers such as diethyl ether, dimethyl ether, ethyl methyl ether, diisopropyl ether, methyl tertiary-butyl ether,

tetrahydrofuran, dioxane and the like; alcohols such as'ethanol, methanol, propanol, butanol and the like; ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like; acetonitrile; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; water or mixtures thereof. Preferably the solvent selected is acetonitrile. The reaction may be carried out at a temperature in the range of about 0°C to about the reflux temperature of the solvent for a period of about 2 hours to about 20 hours. Preferably the reaction is carried out at a temperature of about 400C to about 90°C for a period of about 2 hours to about 10 hours.
In (b) of the process for the preparation of ivabradine borate, the ivabradine borate obtained is isolated by any method known in the art. The method, may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like.
The ivabradine borate salt may be purified by addition of solvent which includes, but is not limited to, esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like; alcohols such as ethanol, methanol, propanol, butanol and the like; ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like; ethers such as diethyl ether, dimethyl ether, ethyl methyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, dioxane and the like; acetonitrile; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; water or mixtures thereof. Preferably, the solvent is acetonitrile-methanoi mixture.
Suitable temperatures for dissolution of ivabradine borate salt in a solvent may range from about 40°C to about the reflux temperature of the solvent. Stirring may be continued for any desired time period to achieve complete dissolution of the compound. The stirring time may range from about 2 hours to about 20 hours.
The product is isolated by conventional methods known in the art. preferably, filtration. The ivabradine borate salt may be further dried. Drying may be suitably carried out in an equipment known in the art, such as a tray drier, vacuum oven, air oven, fluidized bed drier, spin flash drier, flash drier and the like. The drying may be carried out at temperatures from about room temperature to about 100°C with or without vacuum. The drying may be carried out for any desired time until the required product quality is achieved. The drying time may vary from about 1 hour to about 20 hours, or longer.

The present invention provides ivabradine borate, obtained by the above process, as characterized and analyzed by following techniques:
A. X-ray powder diffraction profile was obtained using an X-ray Diffractometer (Philips
X'Pert Pro, PANalytical). The measurements were carried out with a Pre FIX module
programmable divergence slit and anti-scatter Slit (Offset 0,00°) ; target, Cu; filter, Ni;
detector, X'Celerator; Scanning Mode; Active length (2Theta) = 2.122°; generator 45KV
; tube current 40mAmp. The samples were scanned in the full 20 range of 2-50° with a
"time-per-step" optimized to 50 sec.
B. DSC (Mettler Toledo 822e): Temperature range is "30°C to 350°C" and heating rate is
10°C/minute.
C. Thermo Gravimetric Analyzer: TGA Q500 V6.5. Thermogram was recorded at 30-
350°C at the rate of l0°C/min.
D. IR was recorded using IR instrument- Perkin Elmer Spectrum One FTIR.
E. I3C NMR was recorded using instrument- Varian-NMR-mercury300 using DMSO solvent
F.Content of Boric acid by Titrimetry
The present invention provides a process for the preparation of amorphous ivabradine hydrochloride, the process comprising;
(a) reacting ivabradine borate with a base to form ivabradine;
(b) treating ivabradine with hydrochloric acid to form a reaction mixture; and
(c) isolating the amorphous form of ivabradine hydrochloride from the reaction mixture. In (a) of the process for the preparation of amorphous ivabradine hydrochloride, ivabradine borate is reacted with a base to form ivabradine.
The suitable base includes, but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxides; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkaline earth metal carbonates; alkali metal bicarbonates such as sodium bicarbonate; a source of ammonia such as ammonia water (aqueous ammonia), ammonium carbonate, ammonia gas, liquid ammonia. Preferably the base selected is aqueous ammonia.
In (b) of the process for the preparation of amorphous ivabradine hydrochloride, ivabradine is treated with hydrochloric acid to form a reaction mixture.

The hydrochloric acid may be in an aqueous, anhydrous or gaseous form. For example,
aqueous hydrochloric acid or solvent containing hydrogen chloride or gas containing
hydrogen chloride may be used. Preferably, aqueous hydrochloric acid is used. Suitable
temperature for addition of hydrochloric acid may range from about 0°C to about 85°C.
Preferably, addition of hydrochloric acid is carried at about 15°C to about 35°C.
The solution may be optionally treated with charcoal and filtered to get a particle-free
solution.
In (c) of the process for the preparation of amorphous ivabradine hydrochloride, the
amorphous form of ivabradine hydrochloride is isolated from the reaction mixture.
Isolation of amorphous ivabradine hydrochloride may be accomplished by substantially
complete evaporation of the solvent or concentrating the solution, cooling the solution if
required and filtering the obtained solid. The solution may also be completely evaporated in. for
example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above
about 720mm Hg, or evaporated by solvent distillation, lyophilization, freeze-drying technique,
spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying. Preferably
solvent was removed lyophilization to give amorphous form of ivabradine hydrochloride.
The present invention provides use of ivabradine borate in the preparation of ivabradine
hydrochloride.
In one embodiment, the present invention provides use of ivabradine borate in the preparation
of ivabradine hydrochloride, wherein ivabradine hydrochloride is in amorphous form.
The present invention provides a process for the preparation of ivabradine, a compound
of formula I, and pharmaceutically acceptable salts thereof, the process comprising:
(a) reducing (S)-7,8-dimethoxy-3-{3-{N'-[(4,5-dimethoxybenzocycIobut-l-yI)methyl]-N-
(methyl)amino}propyl}-13-dihydro-2H-3-benzazepin-2-one, a compound of formula III,

'0' ^ ^ III
using hydrogen transfer reagent to give ivabradine, the compound of formula I;
(b) and optionally, converting the compound of formula I to its pharmaceutically
acceptable salt.
In (a) of the above process, the compound of formula III is reduced using hydrogen
transfer reagent to give ivabradine, the compound of formula I.

A suitable hydrogen transfer reagent is selected from the group consisting of ammonium formate, sodium formate, trialkyl ammonium formates, formic acid, phosphoric acid, hydrazine, monosodium dihydrogen orthophosphate, cyclohexene, cyclohexadiene, hydrazinium monoformate in the presence of magnesium powder. Preferably, the hydrogen transfer reagent selected is ammonium formate.
The reaction may be carried out in the presence of a hydrogenation catalyst. A suitable hydrogenation catalyst includes, but is not limited to palladium on carbon, palladium hydroxide, platinum on carbon, platinum oxide, rhodium on carbon, rhodium on alumina, Raney nickel, zinc dust. Preferably, the hydrogenation catalyst selected is palladium on carbon. The reaction may be earned out in the presence of a suitable solvent. The suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; haloalkanes such as dichloromethane. chloroform and the like; dimethyl formamide; dimethyl acetamide; water or mixtures thereof. Preferably the solvent selected is methanol. In one embodiment, the present invention provides a process for the preparation of ivabradine, the process comprising reducing the compound of formula III using ammonium formate and palladium on carbon in methanol to give ivabradine, the compound of formula I. In (b) of the above process, ivabradine, the compound of formula I is converted to its pharmaceutically acceptable salt.
The ivabradine acid addition salts may be prepared by reacting ivabradine with a pharmaceutically acceptable acid, where the acid may be an aqueous, anhydrous or gaseous form, for example, an aqueous acid or solvent containing an acid or a gas containing-an acid. For example, such acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like; and organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, and the like. Preferably the acid is hydrochloric acid. Preferably, a solvent containing an acid can be used. The suitable solvent containing an acid, includes esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like; haloalkanes such as dichloromethane, chloroform and the like; ethers such as diethyl ether, dimethyl ether, ethyl methyl ether, diisopropyl ether, methyl tertiary-butyl ether and the like; alcohols such as ethanol,

methanol, n-propyl alcohol, isopropyl alcohol, butanol and the like;'ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like; acetonitrile; water or mixtures thereof. Preferably the solvent selected is isopropyl alcohol. The reaction may be carried out by using suitable organic solvent which includes, but is not limited to. esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like; haloalkanes such as dichloromethane, chloroform and the like; ethers such as diethyl ether, dimethyl ether, ethyl methyl ether, diisopropyl ether, methyl tertiary-butyl ether and the like; alcohols such as ethanol, methanol, propanol, butanol and the like; ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like; acetonitrile; water or mixtures thereof. Preferably the solvent selected is acetonitrile. The ivabradine acid-addition salt formation may be carried out at a temperature in the range of about 0°C to about 85°C for a period of about 2 hours to about 10 hours. Preferably the reaction is carried out at a temperature of about 0°C to about 56°C for a period of about 2 hours to about 6 hours.
The ivabradine acid-addition salts may be purified by addition of solvent which includes, but is not limited to, esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like; alcohols such as ethanol, methanol, propanol, butanol and the like; ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like; ethers such as diethyl ether, dimethyl ether, ethyl methyl ether, diisopropyl ether, methyl tertiary-buty! ether and the like; acetonitrile; water or mixtures thereof. Preferably, the solvent is acetonitrile. Suitable temperatures for dissolution of ivabradine acid-addition salts in a solvent may range from about 40°C to about the reflux temperature of the solvent. Stirring may be continued for any desired time period to achieve complete dissolution of the compound. The stirring time may range from about 2 hours to about 6 hours. The product is isolated by conventional methods known in the art, preferably, filtration. The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

EXAMPLES EXAMPLE 1 Preparation of 7,8-dimethoxy-3-[3-chloropropyI]-l,3-dihydro-2//-3-bcnzazepin-2-one: A mixture of 7,8-dimethoxy-1,3-dihydro-2H/-3-benzazepin-2-one (50g) and dimethyl sulfoxide (350mL) was stirred for about l0min and potassium tert-butoxide (30.7g) was added to it. The reaction mixture was stirred for about 30min at about room temperature. A solution of l-bromo-3-chloropropane (43.1lg) in dimethyl sulfoxide (110mL) was added to the stirred reaction mixture. The reaction mixture was cooled to about 15°C to about 20°C and stirred for about 30min at about the same temperature. The reaction mixture was quenched into ice water and was stirred for about 3h. The solid obtained was filtered, washed with water and dried under vacuum. Yield: 60g. (89%); HPLC purity: > 95% EXAMPLE 2 Preparation of 7,8-dimethoxy-3-[3-iodopropyl]-l,3-dihydro-2H-3-benzazepin-2-one: A mixture of 7,8-dimethoxy-3-[3-chloropropyl]-l,3-dihydro-2H-3-benzazepin-2-one (40g) prepared as in Example 1, and acetone (320mL) was stirred for about l0min and sodium iodide (20g) was added to it. The reaction mixture was stirred at about reflux temperature for about 24h. The reaction mixture was cooled to about room temperature, filtered and washed with acetone. The filtrate obtained was concentrated under reduced pressure to give a solid residue. The residue obtained was dissolved in dichloromethane (400mL). The solution obtained was washed with aqueous sodium dithionate solution and demineralized water and was concentrated under reduce pressure. The solid obtained was recrystallized with acetone and then with acetonitrile and dried under vacuum. Yield: 44.5g (85%); HPLC purity: > 95%
EXAMPLE 3 Preparation of (5)-7,8-dimethoxy-3-{3-{N-[(4,5-dimethoxybenzocyclobut-l-yl)methyl]-A/-(methy0amino}propyl}-l^-diliydro-2H-3-benzazepin-2-one: A mixture of (5)-N-[(4,5-dimethoxybenzocyclobut-l-yl)methyI]-N-(methyl)amine (19.4g) and dimethyl formamide (270mL) was stirred for about 5min and potassium carbonate (66.13g) was added to it. The reaction mixture was stirred for about 30min at about room temperature. 7,8-dimethoxy-3-[3-iodopropyl]-l,3-dihydro-2H-3-benzazepin-2-one (36g) prepared as in Example 2, was added to the stirred reaction mixture. The reaction mixture was stirred for about 12h at about 40°C to about 45°C. The reaction mixture was cooled, quenched into chilled water and stirred at about 20°C to about 25°C for about 30min. The reaction mixture was acidified to pH of about 3 to about 4 using hydrochloric acid and ethyl acetate was added

to it. The reaction mixture was stirred and the two layers were separated. The aqueous layer was basified to pH of about 8 to about 9 using aqueous ammonia and toluene was added to it. The reaction mixture was stirred and the two layers were separated. The organic layer was washed with water and concentrated under reduce pressure at about 45°C to about 50°C. Yield: 16.3g (70%); HPLC purity: > 95%
EXAMPLE 4 Preparation of ivabradine: A mixture of (5)-7,8-dimethoxy-3-{3-{N-[(4,5-dimethoxybenzocyclobut-1 -yl)methyl]-N(methyi)amino} propyl}-1,3-dihydro-2H-3-benzazepin-2-one (30g) prepared as in Example 3, and methanol (350mL) was stirred for about 5min at about room temperature and ammonium formate (26.21g) was added to it. The reaction mixture was stirred for about 5min and 10% palladium charcoal (3g) was added to it. The reaction mixture was stirred for about l0min at about room temperature and then at about 60°C to about 65°C for about 12h. The reaction mixture was cooled, filtered and concentrated and demineralized water was added to it. Ethyl acetate was added to the reaction mixture. The reaction mixture was stirred and the two layers were separated. The organic layer was washed with water and concentrated to give a solid product. Yield: 22.5g (75%); HPLC purity: > 95% EXAMPLE 5 Preparation of ivabradine hydrochloride: A mixture of ivabradine (27g) prepared as in Example 4, and acetonitrile (150mL) was stirred for about l0min. lsopropyl alcohol hydrogen chloride (20-25% IPA-HC1) (15mL) was added to the reaction mixture at about 15°C to about 20°C till the pH reaches to about 2 to about 3. The reaction mixture was stirred for about 4h. The solid obtained was filtered, washed with acetonitrile and dried under vacuum. Yield: 25g (90%); HPLC purity: > 99% EXAMPLE 6: A mixture of ivabradine hydrochloride (25g) and acetonitrile (500mL) was heated to about reflux temperature and was maintained at about the same temperature for about 30min. The mixture was gradually cooled to about room temperature and was stirred for about 4h at about the same temperature. The solid obtained was filtered, washed with acetonitrile and dried under vacuum. Yield: 19g (76%); HPLC purity: > 99.5% EXAMPLE 7 Preparation of 7,8-dimerhoxy-3-[3-ch]oropropy]]-l,3-dihydro-2H-3-benzazepin-2-one: A mixture of 7!8-dimethoxy-l,3-dihydro-2H-3-benzazepin-2-one (l00g) and dimethyl sulfoxide (700mL) was stilted for about 15min at about room temperature and potassium hydroxide powder (33.23g) was added to it. The reaction mixture was stirred for about lh at about room temperature. A solution of l-bromo-3-

chloropropane (86.09 g) in dimethyl sulfoxide (I20mL) was added to the stirred reaction
mixture at about 10°C to about 15°C. The reaction mixture was stirred for about 3h at
about 20°C to about 25°C. The reaction mixture was quenched into ice water and was
stirred for about 5h. The solid obtained was filtered, washed with water and dried in tray
dryer oven at about 50°C to about 55°C for about 12h. Yield: 89%; HPLC purity: > 95%
EXAMPLE 8 Preparation of 7,8-dimethoxy-3-[3-iodopropyl]-l,3-dihydro-2H-3-
benzazepin-2-one: A mixture of 7,8-dimethoxy-3-[3-chloropropyl]-l,3-dihydro-2H-3-
benzazepin-2-one (l00g) prepared as in Example 7, and methyl ethyl ketone (800mL) was
stirred for about l0min and sodium iodide (101.45g) was slowly added to it at about room
temperature. The reaction mixture was stirred at about reflux temperature for about 8h. The
reaction mixture was concentrated at about below 50°C under reduced pressure and acetone
(250mL) and water (250mL) was added to it. The reaction mixture was stirred, concentrated
at about below 50°C under reduced pressure and acetone (250ml,) and demineralized, water
(250mL) was added to it. The reaction mixture was heated to about 55°C to about 60°C and
stirred for about lh at about the same temperature. The reaction mixture was cooled to about
room temperature. The solid obtained was filtered, washed with water and dried at about
55°C to about 60°C for about 12h. Yield: 85%; HPLC purity: > 96%
EXAMPLE 9 Preparation of (S)-7,8-dimethoxy-3-{3-{Ar-[(4,5-
dimethox)'bcnzocyclobi[t-I-yJ)methy)]-N-(methyl)amino}propyJ}-l,3-dihydro-2^-3-benzazepin-2-one: A mixture of {S)-N-[(4,5-dimethoxybenzocyclobut-l-yl)methyl]-Af-(methyl)amine hydrochloride (l00g) and dimethyl formamide (400mL) was stirred for about 5min and potassium carbonate (178.46g) was added to it. The reaction mixture was stirred for about lh at about room temperature. The reaction mixture was cooled to about 5°C to about 10°C. 7,8-dimethoxy-3-[3-iodopropyl]-l,3-dihydro-2H-3-benzazepin-2-one (36g) prepared as in Example 8, was added to the stirred reaction mixture. The reaction mixture was stirred for about 4h at about 20°C to about 25°C. The reaction mixture was quenched into chilled demineralized water at about 5°C to about 10°C. The reaction mixture was acidified to pH of about 1 to about 2 using concentrated hydrochloric acid and ethyl acetate was added to it. The reaction mixture was stirred and the two layers were separated. The aqueous layer was basified to pH of about 8 to about 9.5 using 20-25% aqueous ammonia solution and ethyl acetate was added to it. The reaction mixture was stirred and the

two layers were separated. The organic layer was washed with demineralized water and concentrated under reduce pressure at about below 55°C. Yield: 75%; HPLC purity: > 96% EXAMPLE 10 Preparation of ivabradine hydrochloride: A mixture of (5)-7,8-dimethoxy-3-{3-{N[(4,5-dimethoxybenzocyclobut-l-yl)methyl]-iV-(methyl)aniino}propyl}-l,3-dihydro-2H-3-benzazepin-2-one (100g) prepared as in Example 9, and ethyl acetate (500mL) was stirred for about 5min and activated charcoal was added to it. The reaction mixture was stirred and filtered over hyflo bed. The hyflo bed was washed with ethyl acetate. To the reaction mixture, 10% palladium charcoal was added and the reaction mixture was hydrogenated in an autoclave under hydrogen pressure of about 8kg/cm3 to about 10kg/cm3 at about 70°C to about 75°C for about 6h. After completion of reaction, the reaction mixture is cooled to about 20°C to about 25°C and filtered over hyflo bed. The hyflo bed was washed with ethyl acetate. The reaction mixture was concentrated at about below 50°C under reduced pressure and acetonitrile and isopropyl alcohol hydrogen chloride (IPA-HC1) (30mL) was added to it at about 5°C to about 10°C. The reaction mixture was stirred for about 3h. The reaction mixture was concentrated at about below 50°C under reduced pressure and acetonitrile was added to it. The reaction mixture was heated to about 80°C to about 85°C and stirred at about the same temperature for about lh. The reaction mixture was cooled and the solid obtained was filtered, washed with acetonitrile and dried at about 50°C to about 55°C for about 12h. Yield: 80%; HPLC purity: > 99%
EXAMPLE 11 Preparation of ivabradine hydrochloride (Polymorph mixture of 8-crystalline form and 8d-crystalline form): A mixture of ivabradine hydrochloride (l00g) prepared as in Example 10, in methanol (500mL) was stirred for about l0 min to get a clear solution and filtered. The filtrate was concentrated at about below 50°C. Acetonitrile (2000mL) was added to it and the mixture was heated to about 80°C to about 85°C to get a clear solution and was maintained at about the same temperature for about lh. The reaction mixture was gradually cooled to about room temperature without stirring and maintained at about the same temperature for about 2h. The solid obtained was filtered, washed with acetonitrile, dried at about 45°C to about 50°C under vacuum for about 48h, jet milled and further dried for about 48h at about 45°C to about 50°C under vacuum. Yield: 85%; HPLC purity: >99.5% OV1 (Organic Volatile Impurity): residual solvent acetonitrile not more than l00ppm.

EXAMPLE 12 Preparation of ivabradine hydrochloride (Polymorph mixture of 8-crystalline form and 5d-crystalline form): A mixture of (5)-7,8-dimethoxy-3-{3-{N:-[(4,5-dimethoxybenzocyclobut-l-yl)methyl]-N-(methyl)amino}propyl}-l,3-dihydro-2H-3-benzazepin-2-one (l00g) prepared as in Example 9, and ethyl acetate (500mL) was stirred for about 5min and activated charcoal was added to it. The reaction mixture was stirred for about 30min and filtered over hyflo bed. The hyflo bed was washed with ethyl acetate. To the reaction mixture, 10% palladium charcoal was added and the reaction mixture was hydrogenated in an autoclave under hydrogen pressure of about 8kg/cm to about l0kg/cm at about 55°C to about 60°C for about l0h. After completion of reaction, the reaction mixture is cooled to about 20°C to about 25°C and filtered over hyflo bed. The hyflo bed was washed with ethyl acetate. The reaction mixture was concentrated at about below 50°C under reduced pressure and acetonitrile and isopropyl alcohol hydrogen chloride (IPA-HC1) was added to it at about 5°C to about 10°C. The reaction mixture was stirred at about 10°C to about 15°C for about 3h. The reaction mixture was concentrated at about below 50°C under reduced pressure and acetonitrile (500mL) was added to it. The reaction mixture was heated to about 80°C to about 85°C and stirred at about the same temperature for about lh. The reaction mixture was gradually cooled to about 20°C to about 25°C and maintained at about the same temperature for about 2h. The solid obtained was filtered and washed with acetonitrile. A mixture of the above wet solid in methanol (350mL) was stirred to get a clear solution and filtered. The filtrate was concentrated at about below 50°C under reduced pressure. Acetonitrile (1400mL) was added to the residue obtained and the mixture was heated to about 80°C to about 85°C to get a clear solution and was maintained at about the same temperature for about lh. The reaction mixture was gradually cooled to about room temperature without stirring and maintained at about the same temperature for about 2h. The solid obtained was filtered, washed with acetonitrile, dried at about 45°C to about 50°C under vacuum for about 48h, jet milled and further dried for about 48h at about 45°C to about 50°C under vacuum. Yield: 70%; HPLC purity: >99.5%
EXAMPLE 13 Preparation of amorphous form of ivabradine hydrochloride from polymorph mixture of δ-crystalline form and δd-crystalline form): To the polymorph mixture of δ-crystalline form and 5d-crystalline form of ivabradine hydrochloride (50g) prepared as in Example 12, was added demineralized water (500mL) and the mixture was stirred for

about 30min. The reaction mixture was treated with Norit™ charcoal (5g) and was stirred for about 30min. The reaction mixture was filtered over hyflo bed followed by micron filtration and washed with demineralized water (l00mL). The reaction mixture was lyophilized by cooling to about -84°C to about -65°C under vacuum (not less than l00millitorr) for about 48h using lyophiJizer instrument (Freeze dryer Vitris 425117). Yield: 90%; HPLC purity: >99.5% OVI (Organic Volatile Impurity): residual solvent acetonitvile not more than 100ppm.

Sr. No. Impurity Structure % Impurity
1
Not detected
2 Br Not detected
-> j H,C.0J vOH 0.02
4 H3°V Not detected
5 H HCI 0.01
6 H3C0J - ^NH [jf "V0NCH3 Not detected
7 H3C'°-H3C^ CH^ |—- -^Y°XH3 0.03
8 CHj r .HCI "V0'CH3 Not detected
9

"^NH
HCI Not detected
10


k^0^H3 Not detected
U o Not detected

12 0
o o
CH, HjC Not detected
13 Not detected
14 Not detected
EXAMPLE 14 Preparation of ivabradine hydrochloride: A mixture of (S)-N-[(4,5-
dimethoxybenzocyclobut-l-yl)methyl]-N(methyl)amine hydrochloride (50.36g) and dimethyl formamide (200mL) was stiiTed for about 5min and potassium carbonate (178.46g) was added to it. The reaction mixture was stirred for about lh at about room temperature. The reaction mixture was cooled to about 5°C to about 10°C. 7,8-dimethoxy-3-[3-iodopropyl]-l,3-dihydro-2//-3-benzazepin-2-one (100g) prepared as in Example 8, was added to the stirred reaction mixture. The reaction mixture was stirred for about 6h at about 20°C to about 25°C. The reaction mixture was quenched into chilled demineralized water at about 5°C to about 10°C. The reaction mixture was acidified to pH of about 1 to about 2 using concentrated hydrochloric acid and ethyl acetate was added to it. The reaction mixture was stirred and the two layers were separated. The aqueous layer was basified to pH of about 8 to about 9.5 using 20-25% aqueous ammonia solution and ethyl acetate was added to it. The reaction mixture was stin'ed and the two layers were separated. The organic layer was treated with activated charcoal, stirred at about room temperature for about 30min, filtered over hyflo bed and washed with ethyl acetate. To the above ethyl acetate layer, was added 10% palladium charcoal (15g) and the reaction mixture was hydrogenated in an autoclave under hydrogen pressure of about 8kg/cmJ to about lOkg/cm at about 65°C to about 70°C for about 6h. After completion of reaction, the reaction mixture is cooled to about 20°C to about 25°C and filtered over hyflo bed. The hyflo bed was washed with ethyl acetate. The reaction mixture was concentrated at about below 50°C under reduced pressure and acetonitrile (400mL) and isopropyl alcohol hydrogen chloride (IPA-HC1) (30mL) was added to it at about 5°C to about 10°C. The reaction mixture was stirred at about 10°C to about 15°C for about 3h. The reaction mixture was concentrated at about below 50°C

under reduced pressure and acetonitrile (400mL) was added to it. The reaction mixture was heated to about 80°C to about 85°C and stirred at about the same temperature for about 1h. The reaction mixture was cooled and the solid obtained was filtered, washed with acetonitrile and dried at about 50°C to about 55°C. Yield: 85%; HPLC purity: > 98% EXAMPLE 15 Preparation of ivabradine borate salt: A mixture of (S)-7.8-dimethoxy-3-{3-{N-[(4,5-dimethoxybenzocyclobut-l-yl)methyl]-N-(methyl)amino}propyl}-1.3-dihydro-2H-3-benzazepin-2-one (100g) prepared as in Example 9, and ethyl acetate (800mL) was stirred for about 5min and activated charcoal was added to it. The reaction mixture was stirred for about 30min and filtered over hyflo bed. The hyflo bed was washed with ethyl acetate (200mL). To the reaction mixture, 10% palladium charcoal (17g) was added and the reaction mixture was hydrogenated in an autoclave under hydrogen pressure of about 8kg/cm3 to about 10kg/cm3 at about 55°C to about 60°C for about 12h. After completion of reaction, the reaction mixture is cooled to about 20°C to about 25°C and filtered over hyflo bed. The hyflo bed was washed with ethyl acetate. The reaction mixture was concentrated at about below 50°C under reduced pressure. Demineralized water was added to the residue obtained. The reaction mixture was acidified to pH of about 1 to about 2 using concentrated hydrochloric acid and ethyl acetate was added to it. The reaction mixture was stirred and the two layers were separated. The aqueous layer was basified to pH of about 8.5 using aqueous ammonia solution and ethyl acetate was added to it. The reaction mixture was stirred and the two layers were separated. The organic layer was washed with demineralized water and concentrated under reduce pressure at about 50°C to about 55°C to give an oily residue. To the oily residue (90g) was added acetonitrile (900mL) and boric acid (59.37g) and the reaction mixture was stirred at about 20°C to about 25°C for about 30min. The reaction mixture was heated to reflux at about 80°C to about 85°C for about 30min. The reaction mixture was gradually cooled to about 20°C to about 25°C and was maintained at about the same temperature for about 8h. The solid obtained was filtered and washed with acetonitrile. To the above wet cake was added acetonitrile (1000mL). The reaction mixture was heated to about 80°C to about 85°C and methanol (65mL) was added to it at about the same temperature. The reaction mixture was maintained at about 80°C to about 85°C for about 30min. The reaction mixture was gradually cooled to about 20°C to about 25°C and was maintained at about the same temperature for about 8h. The solid obtained was filtered,

washed with acetonitrile and dried in vaccum tray dryer oven at about 45°C to about 50°C for
about 12h. Yield: 55%; HPLC purity; > 99.5%; Boric acid content: 34.86%

Pos. [°2Th.] d-spacing
[Al Rei. Int.
\%\ Pos. |°2Th.| d-spacing
lAl Rcl. Int.
I%1 Pos. [°2Th.] d-spacing [Al Rel. Int.
[%1
4.27 20.64 4.72 15.58 5.68 33.58 24.47 3.63 66.92
5.63 15.61 58.24 15.99 5.54 49.94 24.96 3.56 12.97
6.52 13.55 4.44 16.28 5.44 12.62 25.65 3.47 24.40
7.07 12.49 9.93 17.02 5.20 33.29 26.12 3.41 24.94
9.07 9.74 6.93 17.30 5.12 68.83 27.48 3.24 20.46
9.83 8.99 14.65 17.66 5.02 13.47 27.66 3.22 13.34
10.12 8.70 51.68 18.21 4.87 21.68 28.22 3.16 8.73
11.37 7.77 43.35 18.89 4.69 54.39 28.71 3.10 17.96
11.71 7.55 22.01 19.12 4.62 100.00 29.61 3.01 7.46
12.97 6.82 53.40 19,67 4.49 73.46 30.29 2.95 11.04
13.79 6.42 18.98 20.60 4.31 74.74 32,04 2.79 9.31
14.21 6.22 64.69 22.16 4.01 65.85 33.02 2.71 7.77
14.66 6.04 16.15 22.78 3.90 16.44 34.54 2.59 5.78
15.05 5.88 41.09 23.54 3.77 30.66 35.34 2.53 2.23
EXAMPLE 16 Preparation of amorphous form of ivabradine hydrochloride from ivabradine borate salt: To the ivabradine borate salt (50g) prepared as in Example 15, was added demineralized water (250mL). The reaction mixture was basified to pH of about 8.5 to about 9 using 25% aqueous ammonia solution (25mL) and ethyl acetate was added to it. The reaction mixture was stirred and the two layers were separated. The organic layer was acidified using 2N hydrochloric acid solution (550mL). The reaction mixture was stirred for about 20min and the two layers were separated. The aqueous layer was treated with Norit™ charcoal and the reaction mixture was stirred for about 30min. The reaction mixture was filtered over hyflo bed followed by filtration through micron filter and washed with demineralized water (100mL). The reaction mixture was lyophilized by cooling to about -84°C to about -65°C under vacuum (not less than 100millitorr) for about 48h using lyophilizer instrument (Freeze dryer Vitris 425117). Yield: 90%; HPLC purity: >99.5% OVI (Organic Volatile Impurity): residual solvent acetonitrile not more than 100ppm. EXAMPLE 17 Preparation of borate salt of compound of formula III: A mixture of (S)-7,8-dimethoxy-3- {3- {N-[(4,5-dimethoxybenzocyclobut-1 -yl)methyl]-/Y-(methyl)amino}propyl}-1.3-dihydro-2H-3-benzazepin-2-one (25g) prepared as in Example 9, and boric acid (59.37g) in acetonitrile (160mL) was stirred at about 20°C to about 25°C for about 30min. The reaction mixture was heated to reflux at about 80°C to about 85°C for about 30min. The reaction mixture was gradually cooled to about 20°C to

about 25°C and was maintained at about the same temperature for about 8h. The solid obtained was filtered, washed with acetonitrile and dried in vaccum tray dryer oven at about 50°C to about 55°C. Yield: 95%; HPLC purity: > 99.5%
EXAMPLE 18 Preparation of compound of formula III: To the borate salt of compound of formula III (25 g) prepared as in Example 17, was added demineralized water (250mL). The reaction mixture was basified to pH of about 8.5 to about 9 using 25% aqueous ammonia solution (25mL) and ethyl acetate was added to it. The reaction mixture was stirred and the two layers were separated. The organic layer was washed with demineralized water and concentrated under reduce pressure at about below 50°C. Yield: 90%; HPLC purity: > 99.5% EXAMPLE 19: A mixture of ivabradine borate salt (50g) in acetonitrile (500mL) was heated to about 80°C to about 85°C and methanol (50mL) was added to it. The reaction mixture was maintained at about the same temperature for about 30min. The reaction mixture was gradually cooled to about 20°C to about 25°C and was maintained at about the same temperature for about 8h. The solid obtained was filtered, washed with acetonitrile and dried in vaccum tray dryer oven at about 45°C to about 50°C for about 24h. Yield: 85%; HPLC purity: > 99.5% EXAMPLE 20 Preparation of amorphous form of ivabradine hydrochloride from 5-crystalline form of ivabradine hydrochloride: To the 5-crystalline form of ivabradine hydrochloride (l0g), was added demineralized water 100mL) and the mixture was stirred for about 30min. The reaction mixture was treated with Norit™ charcoal and was stirred for about 30min. The reaction mixture was filtered over hyflo bed followed by micron filtration and washed with demineralized water, The reaction mixture was lyophilized by cooling to about -84°C to about -65°C under vacuum (not less than 100millitorr) for about 48h using lyophilizer instruments. Yield: 90%; HPLC purity: >99% EXAMPLE 21 Preparation of amorphous form of ivabradine hydrochloride from δd-crystalline form of ivabradine hydrochloride: To the δd-crystalline form of ivabradine hydrochloride (5g), was added demineralized water (50mL) and the mixture was stirred for about 30min. The reaction mixture was treated with Norit™ charcoal and was stirred for about 30min. The reaction mixture was filtered over hyflo bed followed by micron filtration and washed with demineralized water. The reaction mixture was lyophilized by cooling to about -84°C to about -65°C under vacuum (not less than 100millitorr) for about 48h using lyophilizer instruments. Yield: 90%; HPLC purity: >99.5%

WE CLAIM
1. A process for the preparation of amorphous form of ivabradine hydrochloride, the
process comprising:
(a) dissolving a crystalline ivabradine hydrochloride in a solvent or mixture of solvents or aqueous mixtures thereof to provide a solution; and
(b) removing the solvent from the solution obtained in (a).

2. The process of claim 1, wherein the removal of solvent in (b) is carried out by spray drying, fluid bed drying, lyophilization, flash drying, spin flash drying, or thin-film drying.
3. The process of claim 1, wherein the amorphous form of ivabradine hydrochloride obtained has compounds of formula A, III or IVa present to an extent of less than 0.15% w/w relative to the amount of ivabradine hydrochloride as determined by high performance liquid chromatography,

4. Amorphous ivabradine hydrochloride wherein the compounds of formula A, III or IVa are present to an extent of less than 0.15% w/w relative to the amount of ivabradine hydrochloride as determined by high performance liquid chromatography.
5. The process of claim 1. wherein the crystalline ivabradine hydrochloride is prepared by a process comprising:
(a) condensing a compound of formula IV or salt thereof with a compound of formula V, wherein X is selected from the group consisting of CI, Br, I,

(b) reacting a compound of formula III with a reducing agent to obtain ivabradine;
(c) treating ivabradine with alcoholic hydrochloric acid to obtain ivabradine
hydrochloride; and
(d) optionally recrystallizing the ivabradine hydrochloride from alcohol or nitrile or
mixtures thereof.
6. A process for the preparation of amorphous ivabradine hydrochloride, the process
comprising:
(a) reacting ivabradine borate with a base to form ivabradine;
(b) treating ivabradine with hydrochloric acid to form a reaction mixture; and
(c) isolating the amorphous form of ivabradine hydrochloride from the reaction mixture.

7. The process of claim 6, wherein the amorphous form of ivabradine hydrochloride is isolated by removing the solvent from the reaction mixture by solvent distillation, spray drying, fluid bed drying, lyophilization, flash drying, spin flash drying, or thin-film drying.
8. Ivabradine borate characterized by an X-ray powder diffraction pattern, which is substantially in accordance with Figure 1; a differential scanning calorimetry endotherm curve, which is substantially in accordance with Figure 2; a thermogravimetric analysis endotherm curve, which is substantially in accordance with Figure 3; a Fourier transform infrared spectrum, which is substantially in accordance with Figure 4; a l3C nuclear magnetic resonance spectrum, which is in accordance with Figure 5; and a combination thereof.
9. A process for the preparation of ivabradine borate, the process comprising:

(a) combining ivabradine and boric acid in a solvent or mixture of solvents or aqueous mixtures thereof; and
(b) isolating the ivabradine borate obtained in (a).
10. Use of ivabradine borate in the preparation of ivabradine hydrochloride.