WO2012025940A1

WO2012025940A1 - Polymorphic form of ivabradine hydrochloride and process for preparation thereof

Info

Publication number: WO2012025940A1
Application number: PCT/IN2011/000572
Authority: WO
Inventors: Shriprakash Dhar Dwivedi; Ashok Prasad; Mahesh Shankarbhai Patel; Piyush Rajendra Sharma
Original assignee: Cadila Healthcare Limited
Priority date: 2010-08-25
Filing date: 2011-08-24
Publication date: 2012-03-01

Abstract

The present invention discloses Crystalline Form Zeta "ζ" of ivabradine hydrochloride and process for its preparation..

Description

POLYMORPHIC FORM OF IVABRADINE HYDROCHLORIDE AND PROCESS FOR PREPARATION THEREOF

FIELD OF THE INVENTION

The invention relates to a polymorphic form of ivabradine hydrochloride. More particularly, it relates to a stable crystalline form of ivabradine hydrochloride designated as Zeta "ζ" Form and processes for its preparation. The invention also relates to pharmaceutical compositions that include the stable crystalline Form Zeta "ζ" of ivabradine hydrochloride.

BACKGROUND OF THE INVENTION

Ivabradine hydrochloride, 3-{3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-l,3,5- trien-7-yl] methyl} (methyl)amino]-propyl } -7,8-dimethoxy- 1 ,3,4,5-tetrahydro-2H-3- benzazepin-2-one hydrochloride of Formula (I) has very valuable pharmacological and therapeutic properties, especially bradycardic properties, making it useful in the treatment or prevention of various clinical situations of myocardial ischemia such as angina pectoris, myocardial infarct and associated rhythm disturbances, and also of various pathologies involving rhythm disturbances, especially supraventricular rhythm disturbances, and in the treatment of heart failure.

(I)

The preparation and therapeutic use of ivabradine and salts thereof with a pharmaceutically acceptable acid, and especially its hydrochloride, have been described in the European Patent EP 0534859. The patent describes the synthesis of ivabradine hydrochloride by reacting the compound of Formula (V-a) with the compound of Formula (IV-a):

(V-a) (IV-a) to give a compound of Formula (H-a), the catalytic hydrogenation of which results in ivabradine, which is then converted into its hydrochloride:

(Il-a)

This disclosed process yielding ivabradine hydrochloride in only a very low yield-less than 17% over the 3 steps as a whole.

Another process for preparing ivabradine is disclosed in U.S. Patent No. 5,296,482. According to the process, (+)-isomer of ivabradine is treated with aqueous HC1 and then recrystallization in acetonitrile leads to the formation of ivabradine hydrochloride salt having m.p. 135-140°C.

International (PCT) Publication WO 2008/146308 A2 discloses process for the preparation of ivabradine hydrochloride by treating ivabradine with alcoholic hydrogen chloride. The specification also discloses the amorphous form of ivabradine hydrochloride and process for its preparation using suitable acid addition salts of ivabradine.

International (PCT) Publication WO 2008/125006 Al discloses a process for the preparation of ivabradine hydrochloride by catalytic hydrogenation of the 7- membered ring of the compound of Formula (IV-a), wherein (R = CI, Br, I, phenylsulfonyloxy, 4-methylbenzene sulfonyloxy, methylsulfonlyoxy) and reacting with the compound of Formula (V-a) in the presence of a base, which results in ivabradine.

(V-a) (IV-a)

International (PCT) Publication WO 2008/065681 A2 discloses a process for the preparation of ivabradine or the pharmaceutically acceptable salts thereof which is incorporated herein as a reference in its entirety. Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x- ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid-state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. The polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. For a general review of polymorphs and the pharmaceutical applications of polymorphs, See G. M. Wall, Pharm Manuf. 3, 33 (1986); J. K. Haleblian and W. McCrone, J. Pharm. Sci., 58, 91 1 (1969); and J. K. Haleblian, J. Pharm. Sci., 64, 1269 (1975), all of which are incorporated herein by reference.

Several crystalline forms of ivabradine hydrochloride and their processes for preparation have been disclosed, for example in U.S. Patent Nos. 7,176, 197 B2, 7,384,932 B2, 7,361,652 B2, 7,361,651 B2, 7,361,650 B2, 7,361,649 B2, and 7,358,240 B2.

The known crystalline forms of ivabradine hydrochloride are pseudopolymorphs, which are very susceptible in presence of water. They are either hydrates like hemihydrate, monohydrate or tetrahydrate or anhydrous compounds. Therefore, the present invention provides new crystalline form of ivabradine hydrochloride, which is stable and useful for pharmaceutical compositions that include the crystalline ivabradine hydrochloride.

SUMMARY OF THE INVENTION

The inventors have discovered a novel crystalline polymorphic form of ivabradine hydrochloride and have developed a process for the preparation of the crystalline form. The new crystalline form of ivabradine hydrochloride is designated as

Zeta "ζ" Form.

In one general aspect there is provided a novel crystalline Form Zeta "ζ" of ivabradine hydrochloride. The Form Zeta "ζ" of ivabradine hydrochloride may have the X-ray diffraction pattern of Figure 1, differential scanning calorimetry thermogram of Figure 2, and infrared spectrum of Figure 3.

In one general aspect there is provided a process for the preparation of crystalline Form Zeta "ζ" of ivabradine hydrochloride. The process includes obtaining a solution of ivabradine hydrochloride in one or more organic solvents; and isolating the crystalline Form Zeta "ζ" of ivabradine hydrochloride by the removal of solvents.

Removing the solvents may include, for example, one or more of filtration, filtration under vacuum, decantation, centrifugation, distillation, and distillation under vacuum.

Embodiments of the process may include one or more of the following features. For example, the solution of ivabradine hydrochloride may be obtained by heating ivabradine hydrochloride in one or more organic solvents. The solution may be seeded with one or more crystals of Form Zeta "ζ" of ivabradine hydrochloride prior to the initiation of product crystallization or the slurry may be cooled prior to filtration.

The process may include further drying of the product obtained. The process may include further forming of the product so obtained into a finished dosage form.

In another general aspect there is provided a process for the preparation of crystalline Form (Zeta "ζ") of ivabradine hydrochloride. The process includes contacting ivabradine base with hydrogen chloride in one or more solvents to get ivabradine hydrochloride; obtaining a solution of ivabradine hydrochloride in one or more organic solvents; and isolating the crystalline Form Zeta "ζ" of ivabradine hydrochloride by the removal of solvents.

In another general aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of the crystalline Form Zeta "ζ" of ivabradine hydrochloride; and one or more pharmaceutically acceptable carriers, excipients or diluents.

An aspect of the present application provides compositions comprising crystalline Zeta "ζ" form of ivabradine hydrochloride substantially free of one or more its corresponding impurities as measured by HPLC.

In another general aspect there is provided a stable crystalline Form Zeta "ζ" of ivabradine hydrochloride which is substantially free from known crystalline forms β, δ, or γ or amorphous form. In another general aspect there is provided a stable crystalline Form Zeta "ζ" of ivabradine hydrochloride having a water content from about 2.0% to about 8.0% w/w.

In another general aspect there is provided a crystalline Form Zeta "ζ" of ivabradine hydrochloride having particle size distributions wherein the 10th volume percentile particle size (D10) is less than about 50 um, the 50th volume percentile particle size (D50) is less than about 200 μπι, or the 90th volume percentile particle size (D90) is less than about 400 um, or any combination thereof.

The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is an X-ray powder diffraction pattern of crystalline ivabradine hydrochloride (Zeta "ζ") form.

Figure 2 is a Differential Scanning Calorimetry analysis of crystalline ivabradine hydrochloride (Zeta "ζ") form.

Figure 3 is an Infrared spectrum of crystalline ivabradine hydrochloride (Zeta "ζ") form.

DETAILED DESCRIPTION OF THE INVENTION

The inventors have found a new polymorphic form of ivabradine hydrochloride and, in particular, the crystalline form designated as Form Zeta "ζ" of ivabradine hydrochloride. The new form is characterized by its X-ray powder diffraction pattern, differential scanning calorimetry thermogram, and infrared spectrum as shown in Figures 1, 2, and 3, respectively. The inventors also have developed a process for the preparation of the crystalline Form Zeta "ζ" of ivabradine hydrochloride, by obtaining a solution of ivabradine hydrochloride in one or more suitable solvents and isolating the crystalline Form Zeta "ζ" of ivabradine hydrochloride by the removal of the solvents.

In general, the solution of ivabradine hydrochloride may be obtained by dissolving any known form of ivabradine hydrochloride in a suitable solvent. The solution may be obtained by heating the ivabradine hydrochloride in a solvent. The resultant solution may be clarified to remove foreign particulate matter or treated with charcoal to remove coloring and other related impurities. The solution so obtained may be concentrated to reduce the amount of solvent. The solution may be concentrated by removing the solvent completely to get a residue. Alternatively, such a solution may be obtained directly from a reaction in which ivabradine hydrochloride is formed. The solvent may be removed by a technique which includes, for example, filtration, filtration under vacuum, decantation, centrifugation, distillation and distillation under vacuum.

The inventors have found that the crystalline Form Zeta "ζ" of ivabradine hydrochloride is stable and is substantially free from known crystalline forms β, δ, γ, or amorphous form. The stable crystalline Form Zeta "ζ" of ivabradine hydrochloride has no detectable quantity of crystalline β, δ, γ, or amorphous forms after storage for 3 months at 40°C and a relative humidity of 75% or at 25°C and a relative humidity of 60%.

All ranges recited herein include the endpoints, including those that recite a range "between" two values. Terms such as "about", "general", "substantially" and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

The term "controlled humidity" refers to a relative humidity of less than about 60%, particularly it should be in between 20% to 5Q% and most particularly in between 20% to 40%.

It has been surprisingly found by the inventors of the present invention that humidity plays a vital role for the isolation and stabilization of Zeta "ζ" crystalline form. The contrary to the earlier reported forms which are pseudopolymorphs having water content from about 2.2% (δ) to 12.8% (β) form, the Zeta "ζ" crystalline form gets stabilized in the water range of 4%-6%. The isolation is therefore under controlled humidity conditions. Further, the prolonged drying to the hydrated forms converts to an amorphous form of ivabradine hydrochloride wherein the water level decreases to less than 1%.

Thus, the advantage of the present invention is to provide at least a storage stable Zeta "ζ" crystalline form of ivabradine hydrochloride which doesn't change to amorphous form and doesn't

tends to decrease the water content.

When a molecule or other material is identified herein as "substantially free", it generally means, unless specified otherwise, that the material is about 99% pure or more. In general, this refers to purity with regard to unwanted residual solvents, reaction byproducts, impurities and unreacted starting materials. In the case of substantially free crystalline ivabradine hydrochloride, "free" also means about 99% of one crystalline form free from known crystalline forms, as appropriate or in the case of crystalline solids.

As used herein, stable crystalline Form Zeta "ζ" includes either: ivabradine hydrochloride that after exposure to a relative humidity of 75% at 40°C or 60% at 25°C, for a period of at least three months does not contains peaks at about 6.8° and 12.2° 2Θ and having less than about 5% of known crystalline forms like β or δ or γ crystalline forms, particularly less than about 1% crystalline forms like β or δ or γ crystalline forms, most particularly not in detectable amount forms like β or δ or γ crystalline forms.

As used herein, stable crystalline Form Zeta "ζ" includes either: ivabradine hydrochloride that after exposure to a relative humidity of 75% at 40°C or 60% at 25°C, for a period of at least three months is having less than about 5% of amorphous form, particularly less than about 1% amorphous form, most particularly not in detectable amount amorphous form.

As used here in the term "isolation" may include filtration, filtration under vacuum, centrifugation, and decantation. The product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be dried in a hot air oven, tray drier, dried under vacuum and/or in a Fluid Bed Drier.

"Suitable solvent" means a single or a combination of two or more solvents. As used herein, the term "contacting" includes mixing, adding, slurrying, stirring, or a combination thereof.

In one aspect, the invention provides a novel crystalline Form Zeta "ζ" of ivabradine hydrochloride characterized by X-ray powder diffraction pattern having characteristics peaks at about 11.0°, 14.5°, 16.5°, 16.8°, 22.2°, 23.5°, 25.9°, 27.6°, 28.9°, 30.7° and 34.06° (2Θ).

The crystalline Form Zeta "ζ" of ivabradine hydrochloride is further characterized X-ray powder diffraction pattern having substantially as depicted in Figure- 1.

TABLE-1 Characteristic X-ray Powder Diffraction Pattern Peaks (expressed in 2Θ ±0.2° 2Θ) and Relative Intensities of Diffraction Lines for Form (Zeta "ζ") of Ivabradine Hydrochloride

Degree 2Θ ±0.2° 2Θ I/Io

4.17 29.9

8.43 17.5

1 1.04 44.0

14.45 42.0

14.71 46.1

15.26 37.7

16.54 92.9

16.86 100.0

17.60 22.7

17.91 44.7

19.12 38.1

19.66 5.8

20.68 19.6

21.00 17.6

21.86 35.0

22.27 69.2

22.94 8.7

23.58 12.1

24.64 37.4

25.48 51.8

25.91 90.7

26.57 48.2

27.62 34.8

28.95 19.0

29.59 19.7

29.86 13.8

30.75 20.2

31.22 2.5 32.66 10.3

33.33 12.6

34.06 29.6

34.84 10.3

36.52 10.1

38.38 29.4

The crystalline Form Zeta "ζ" of ivabradine hydrochloride is further characterized by differential scanning calorimetry substantially as depicted in Figure-2, and it provides endothermic peak in the range of 148°C-158°C and another endothermic peak in the range of 190°C-198°C.

The crystalline Form Zeta "ζ" of ivabradine hydrochloride is characterized by having peaks at 2947, 2833, 2358, 2337, 1631, 1517, 1483, 1467, 1305, 1247, 1222, 1209, 1105, 1058, 1002, 864, and 831 cm^"1 in infrared spectrum and substantially as depicted in Figure-3.

In another aspect, the present invention provides a process for preparation of crystalline Form Zeta "ζ" of ivabradine hydrochloride comprising (a) obtaining a solution of ivabradine hydrochloride in one or more suitable solvents; and (b) isolating the crystalline Form Zeta "ζ" of ivabradine hydrochloride by the removal of the solvents.

In general, the suitable solvent as in step (a) comprises one or more of dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, acetonitrile, water, or mixtures thereof. The removing of solvent as in step (b) comprises one or more of filtration, filtration under vacuum, decantation, centrifugation, distillation and distillation under vacuum.

According to further embodiments, the process further comprising additional drying of the ivabradine hydrochloride obtained. The drying is carried out under controlled humidity conditions. In general, the drying comprises at a temperature of above about 40°C in hot air oven for about 1 hour to about 12 hours, and drying under control humidity at a temperature of less than about 40°C. The process may include further forming of the product so obtained into a finished dosage form.

In another aspect, the present invention provides a process for the preparation of crystalline Form Zeta "ζ" of ivabradine hydrochloride, the process comprising:

(a) contacting ivabradine base with hydrogen chloride in one or more suitable solvents to get ivabradine hydrochloride;

(b) obtaining a solution of ivabradine hydrochloride in one or more suitable solvents; and

(c) isolating the crystalline Form Zeta "ζ" of ivabradine hydrochloride by the removal of the solvents.

In general, the process includes contacting ivabradine base with hydrogen chloride in one or more suitable solvents. The suitable solvent comprises one or more of dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, acetonitrile, water, or mixtures thereof.

According to another aspect, the present invention provides storage stable crystalline Form Zeta "ζ" of ivabradine hydrochloride.

In general, the storage stable crystalline Form Zeta "ζ" of ivabradine hydrochloride is substantially free from known crystalline forms β, δ, or γ. Further, the storage stable crystalline Form Zeta "ζ" of ivabradine hydrochloride is substantially free from amorphous form.

According to another aspect, the present invention provides stable crystalline Form Zeta "ζ" of ivabradine hydrochloride, wherein the Zeta "ζ" form of ivabradine hydrochloride is having a water content from about 2.0% to about 8.0% w/w.

In another aspect, the present invention provides a process for packaging crystalline Form Zeta "ζ"

the process comprising:

(a) placing crystalline Form Zeta "ζ" of ivabradine hydrochloride under nitrogen atmosphere in a non-permeable bag and tying with a thread;

(b) placing the bag of step (a) inside a black color polyethylene bag, optionally containing oxygen busters and sealing it;

(c) placing the bag of step (b) inside a triple laminated bag, optionally containing oxygen busters and sealing it; and (d) placing the sealed triple laminated bag inside a high density polyethylene (HDPE) container and sealing it.

In an aspect, the present invention accordingly provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline Form Zeta "ζ" of ivabradine hydrochloride and one or more pharmaceutically acceptable carriers, excipients or diluents.

In further aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a storage stable crystalline Form Zeta "ζ" of ivabradine hydrochloride having no detectable quantity of crystalline β, δ, γ, or amorphous forms, and one or more pharmaceutically acceptable carriers, excipients, or diluents.

An aspect of the present application provides a pharmaceutical compositions comprising therapeutically effective amount of a crystalline Form Zeta "ζ" form of ivabradine hydrochloride substantially free of one or more its corresponding impurities as measured by HPLC.

The impurities for ivabradine hydrochloride can be one or more of the following.

S-methyl amine: (S)- 1 -(4,5-dimethoxy- 1 ,2-dihydrocyclobutanbenzen- 1 -yl)-N- methylmethamine.

Tetrahydrobenzazepine: 7,8-Dimethoxy- 1 ,3,4,5-tetrahydro-2H-3-benzazepine-

2-one.

BCP condense: ( 1 S)-4,5-Dimethoxy- 1 -(methylaminomethyl)benzocyclobutane hydrochloride.

Dimer impurity: 1 -(4,5-Dimethoxy-l ,2-dihydrocyclobutanebenzen- 1 -yl)-N-((4,5- dimethoxy- 1 ,2-dihydrocyclobutanbenzen- 1 -y l)methy 1-N-methylmetham ine .

According to one aspect there is provided a pharmaceutical composition comprising a therapeutically effective amount of crystalline Form Zeta "ζ" of ivabradine hydrochloride substantially free from residual acetonitrile.

An aspect of the invention provides crystalline Zeta "ζ" of ivabradine hydrochloride form having particle size distributions wherein the 10th volume percentile particle size (D10) is less than about 50 um, the 50th volume percentile particle size (D50) is less than about 200 um, or the 90th volume percentile particle size (D90) is less than about 400 um, or any combination thereof. According to another aspect there is provided a process for the preparation of crystalline Form Zeta "ζ" of ivabradine hydrochloride comprising:

(a) suspending ivabradine base in one or more suitable solvents;

(b) adding hydrochloric acid solution in one or more suitable solvents to the suspension of step (a);

(c) adjusting the pH to precipitate ivabradine hydrochloride;

(d) isolating ivabradine hydrochloride as wet-cake followed by recrystallization in one or more suitable solvents;

(e) optionally purifying wet-cake of step (d) with one or more suitable solvents; and (f) drying to isolate ivabradine hydrochloride under controlled humidity to obtain crystalline Form Zeta "ζ".

In general, the suitable solvent the suitable solvent comprises one or more of dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, acetonitrile, water, or mixtures thereof. The addition of hydrochloric acid solution in one or more suitable solvent can be hydrochloric acid in acetonitrile thereby to adjust less than 2.

Further aspect of the process includes recrystallization of ivabradine hydrochloride in step (c). The suitable solvent comprises one or more of tetrahydrofuran (THF), dimethylsulfoxide (DMSO), dimethylformamide, diethylether, dimethylether, water or a mixture thereof. The wet-cake obtain in step (d) can be purified with suitable solvent comprises one or more of dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, acetonitrile or mixture thereof.

In another aspect the process for preparation of wet-cake of ivabradine hydrochloride includes a mixture of ivabradine hydrochloride and suitable solvent comprises one or more of tetrahydrofuran (THF), dimethylsulfoxide (DMSO), dimethylformamide, diethylether, dimethylether, water or a mixture thereof.

In another aspect there is provided mixture of ivabradine hydrochloride, tetrahydrofuran (THF) and water is heated until dissolution is complete and is then cooled until crystallization is complete, and the product is collected by filtration. The product thus obtain is dried under controlled humidity wherein the wet-cake was dried at 35-45°C in hot air oven (20-40% humidity inside the oven) till moisture less than 6% (KF). Further, the product was dried at 40-50°C under fan drying (humidity less than 30% inside the oven) till moisture less than 2% (KF). Finally, the product was dried at 35-45°C in hot air oven (20-40% humidity inside the oven) to have moisture content between 4-6%, to obtain crystalline Form Zeta "ζ" of ivabradine hydrochloride.

The novel crystalline Form Zeta "ζ" of ivabradine hydrochloride can be characterized by any of the analytical technique like PXRD, DSC, IR as follows:

(a) Characterization by PXRD

The X-ray powder diffraction spectrum was measured under the following experimental conditions:

Instrument : X-Ray Diffractometer, D/Max-2200/PC Make: Rigaku,

Japan.

X- Ray Cu/40kv/40mA

Diverging 1°

Scattering Slit 1°

Receiving Slit 0.15 mm

Monochromator RS 0.8 mm

Counter Scintillation Counter

Scan Mode Continuous

Scan Speed 3.000°/Min

Sampling Width 0.020

Scan Axes Two Theta/Theta

Scan Range 2.000° to 40.000°

Theta Offset : 0.000'

(b) Characterization by Differential Scanning Calorimetry (DSC) Analytical method: Differential scanning calorimetric analysis was performed using a Perkin Elmer Diamond DSC control unit and a DSC 300°C differential scanning calorimeter. 2-5 mg samples were placed in crimped aluminum pans and heated from 50°C to 300°C in a liquid nitrogen atmosphere at a heating rate of 10°C/minute. Zinc- Indium was used as the standard substance.

(c) The IR spectrum was measured by the known KBr method.

The ivabradine hydrochloride used as the starting material can be in different crystalline forms for example and not limited to anhydrous (a), hemihydrate (δ), monohydrate (γ), tetrahydrate (β) or mixture thereof. The Ivabradine hydrochloride can also be wet-cake from the previous step. The suspension can be subjected to recrystallization conditions as mentioned herein after to isolate (Zeta "ζ") of ivabradine hydrochloride.

The present invention is further illustrated by the following example which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modification and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example 1: Preparation of Ivabradine Hydrochloride (I):

100 g of Ivabradine base and 300 mL acetonitrile were cooled to 0°C to 5°C and acetonitrile hydrochloric acid solution was added drop wise by adjusting the pH to about 1-2. The resulting mass was stirred till complete precipitation and maintained for 60 minutes. The product was filtered under nitrogen and washed with chilled acetonitrile. The wet-cake and acetonitrile were heated at 60-65°C and stirred for 30 min. The reaction mixture was gradually cooled to 25°C and stirred for 1 hour. The product was filtered under vacuum and nitrogen atmosphere. The wet-cake was washed with chilled acetonitrile. The product was dried under vacuum at 50-55°C to obtain 75% 80 g crude Ivabradine Hydrochloride. The product was packed in double polyethene bag under nitrogen.

Example 2: Preparation of Ivabradine Hydrochloride (I):

100 g of ivabradine hydrochloride crude and 450 mL of THF were heated at 60- 65°C. 50 mL of water was added drop wise to get a clear solution at 60-65°C. The reaction mixture was stirred for 30 minutes at the same temperature and cooled slowly to 20-25°C. The reaction mixture was stirred for 1.5 hour and filtered. The wet-cake was washed with THF and suck dried under nitrogen for 30 min. The wet-cake and 450 mL THF were heated again to get a clear solution at 60-65°C and stirred for 30 min. The reaction mixture was cooled at 25°C and stirred for 1.5 hour. The product thus obtained was filtered to obtain 110 g wet-cake, which was used as such for the preparation of Zeta "ζ" form.

Example 3; Preparation of crystalline Zeta "C" form of Ivabradine Hydrochloride 100 g of ivabradine hydrochloride wet-cake and 1400 mL of acetonitrile were heated at 75-80°C for 15 minutes to get a clear solution. The reaction mixture was stirred for further 15 minutes and concentrated to remove acetonitrile under atmospheric pressure to collect 600 mL acetonitrile. The reaction mixture was cooled gradually to 10°C and stirred for 1 hour. The product was filtered and wet-cake was washed with chilled acetonitrile. The wet-cake was dried at 35-45°C in hot air oven (controlled humidity) till moisture less than 6% (KF). Further, the compound was dried at 40-50°C under fan drying (controlled humidity) till moisture less than 2% (KF). Finally, the compound was dried at 35-45°C in hot air oven (controlled humidity) to have moisture content between 4-6%, to obtain 85 g of crystalline Zeta "ζ" form of ivabradine hydrochloride. The residual acetonitrile is less than 600 ppm, particularly not in detectable amount.

Example 4; Packing of crystalline Zeta "C" form of Ivabradine Hydrochloride (I);

The crystalline polymorph (Zeta "ζ") of ivabradine hydrochloride obtained in example-3 was stored under nitrogen atmosphere and packed in a non-permeable bag tied with a thread, keeping primary packing inside a black color polyethylene bag containing oxygen busters and sealing it, placing above the non-permeable bag inside a triple laminated bag containing oxygen busters and sealing it, and placing the sealed triple laminated bag inside a closed high density polyethylene (HDPE) container.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Claims

We claim:

1. Crystalline Form Zeta "ζ" of ivabradine hydrochloride.

2. The crystalline Form Zeta "ζ" of ivabradine hydrochloride as claimed in claim 1 having characteristic X-ray powder diffraction peaks at about 1 1.0°, 14.5°, 16.5°, 16.8°, 22.2°, 23.5°, 25.9°, 27.6°, 28.9°, 30.7° and 34.06° (2Θ).

3. The crystalline Form Zeta "ζ" of ivabradine hydrochloride as claimed in claim 1 characterized by X-ray powder diffraction pattern substantially as depicted in Figure- 1.

4. The crystalline Form Zeta "ζ" of ivabradine hydrochloride as claimed in claim 1 characterized by X-ray powder diffraction pattern substantially as shown in Table-

1.

5. The crystalline Form Zeta "ζ" of ivabradine hydrochloride as claimed in claim 1 having endothermic peak in the range of 148°C -158°C and another endothermic peak in the range of 190°C-198°C.

6. The crystalline Form Zeta "ζ" of ivabradine hydrochloride as claimed in claim 1 characterized by differential scanning calorimetry substantially as depicted in Figure-2.

7. The crystalline Form Zeta "ζ" of ivabradine hydrochloride as claimed in claim 1 characterized by having peaks at 2947, 2833, 2358, 2337, 1631, 1517, 1483, 1467, 1305, 1247, 1222, 1209, 1105, 1058, 1002, 864, and 831 cm^"1 in infrared spectrum.

8. A process for the preparation of crystalline Form Zeta "ζ" of ivabradine hydrochloride, the process comprising:

(a) obtaining a solution of ivabradine hydrochloride in one or more suitable solvents; and

(b) isolating the crystalline Form Zeta "ζ" of ivabradine hydrochloride by the removal of the solvents.

9. The process as claimed in claim 8, wherein the suitable solvent comprises one or more of dimethylformamide, dimethylacetamide, dimethylsulfoxide, N- methylpyrrolidone, acetonitrile, water, or mixtures thereof.

10. The process as claimed in claim 8, wherein removing the solvent comprises one or more of filtration, filtration under vacuum, decantation, centrifugation, distillation and distillation under vacuum.

11. The process as claimed in claim 8, further comprising additional drying of the ivabradine hydrochloride obtained.

12. The process as claimed in claim 11, wherein the drying is carried out under controlled humidity conditions.

13. The process as claimed in claim 12, wherein the controlled humidity is a relative humidity of less than about 60%.

14. The process as claimed in claim 13, wherein the controlled humidity is a relative humidity of from about 20% to about 50%.

15. The process as claimed in claim 1 1, wherein the drying comprises drying at a temperature of above about 40°C in hot air oven for about 1 hour to about 12 hours; and drying under control humidity at a temperature of less than about 40°C.

16. A process for the preparation of crystalline Form Zeta "ζ" of ivabradine hydrochloride, the process comprising:

17. The process as claimed in claim 16, wherein the suitable solvent comprises one or more of dimethylformamide, dimethylacetamide, dimethylsulfoxide, N- methylpyrrolidone, acetonitrile, water, or mixtures thereof.

18. Storage stable crystalline Form Zeta "ζ" of ivabradine hydrochloride.

19. The stable crystalline Form Zeta "ζ" of ivabradine hydrochloride as claimed in claim 18 which is substantially free from known crystalline forms β, δ, or γ.

20. The stable crystalline Form Zeta "ζ" of ivabradine hydrochloride as claimed in claim 18 which is substantially free from amorphous form.

21. The stable crystalline Form Zeta "ζ" of ivabradine hydrochloride as claimed in claim 18, wherein the Zeta "ζ" form of ivabradine hydrochloride is having a water content from about 2.0% to about 8.0% w/w.

22. The stable crystalline Form Zeta "ζ" of ivabradine hydrochloride as claimed in claim 18, wherein the Zeta "ζ" form of ivabradine hydrochloride has 5% or less of crystalline β, δ, γ, or amorphous forms after storage for 3 months at 40°C and a relative humidity of 75% or at 25 °C and a relative humidity of 60%.

23. The stable crystalline Form Zeta "ζ" of ivabradine hydrochloride as claimed in claim 18, wherein the Zeta "ζ" form of ivabradine hydrochloride has no detectable quantity of crystalline β, δ, γ, or amorphous forms after storage for 3 months at 40°C and a relative humidity of 75% or at 25 °C and a relative humidity of 60%.

24. A process of packaging crystalline Form Zeta "ζ" of ivabradine hydrochloride, the process comprising:

(c) placing the bag of step (b) inside a triple laminated bag, optionally containing oxygen busters and sealing it; and

(d) placing the sealed triple laminated bag inside a high density polyethylene (HDPE) container and sealing it.

25. A pharmaceutical composition comprising a therapeutically effective amount of crystalline Form Zeta "ζ" of ivabradine hydrochloride and one or more pharmaceutically acceptable carriers, excipients, or diluents.

26. A pharmaceutical composition comprising a therapeutically effective amount of a storage stable crystalline Form Zeta "ζ" of ivabradine hydrochloride having no detectable quantity of crystalline β, δ, γ, or amorphous forms, and one or more pharmaceutically acceptable carriers, excipients, or diluents.

27. Crystalline Form Zeta "ζ" of ivabradine hydrochloride having particle size distributions wherein the 10th volume percentile particle size (D10) is less than about 50 um, the 50th volume percentile particle size (D50) is less than about 200 um, or the 90th volume percentile particle size (D90) is less than about 400 um, or any combination thereof.