Polymorphic forms of ivabradine hydrochloride

Abstract

Stable crystalline Form II and stable crystalline Form III of ivabradine hydrochloride and processes for their preparation are disclosed.

Claims

1. A crystalline Form II of ivabradine hydrochloride characterized by x-ray powder diffraction having characteristic peaks at about 15.50, 18.02, 19.00, 19.80, 22.42, 24.16, and 25.460.2 (2), substantially free from one or more of: (S)-1-(4,5-dimethoxy-1,2-dihydrocyclobutanbenzene-1-yl)-N-methylmethamine (S-methylamine); 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2-one (tetrahydrobenzazepine); (1S)-4,5-dimethoxy-1-(methylaminomethyl)benzocyclobutane hydrochloride (BCP condense); or (1S)-4,5-dimethoxy-1,2-dihydrocyclobutanebenzen-1-yl)-N-((4,5-dimethoxy-1,2-dihydrocyclobutanebenzen-1-yl)methyl-N-methyl-methamine (dimer impurity), as measured by area percentage of HPLC.

2. The crystalline ivabradine hydrochloride according to claim 1, wherein single individual impurity is not more than 0.15%, as measured by area percentage of HPLC.

3. The crystalline ivabradine hydrochloride according to claim 1, wherein the total impurities is not more than 0.15%, as measured by area percentage of HPLC.

4. The crystalline ivabradine hydrochloride according to claim 1, having a purity of about 99% or more, as measured by area percentage of HPLC.

5. The crystalline ivabradine hydrochloride according to claim 1, which is substantially free from known crystalline forms , , , or amorphous forms after storage for 6 months at 40 C. and a relative humidity of 75% or at 25 C. and a relative humidity of 60%.

6. The crystalline ivabradine hydrochloride according to claim 1, which is having particle size distributions wherein the 10th volume percentile particle size (D10) is less than about 50 m, the 50th volume percentile particle size (D50) is less than about 200 m, or the 90.sup.th volume percentile particle size (D90) is less than about 400 m, or any combination thereof.

7. The crystalline ivabradine hydrochloride according to claim 5, comprising a packaging which includes placing crystalline ivabradine hydrochloride under nitrogen atmosphere in a non-permeable bag or placing crystalline ivabradine hydrochloride in polyethylene bag, optionally containing oxygen busters and sealing it or placing crystalline ivabradine hydrochloride in a triple laminated bag, optionally containing oxygen busters and sealing it or placing crystalline ivabradine hydrochloride in triple laminated bag inside a high density polyethylene (HDPE) container.

8. A pharmaceutical composition comprising crystalline Form II of ivabradine hydrochloride characterized by x-ray powder diffraction having characteristic peaks at about 15.50, 18.02, 19.00, 19.80, 22.42, 24.16, and 25.460.2 (2)having purity of about 99% or more and substantially free from one or more of: (S)-1-(4,5-dimethoxy-1,2-dihydrocyclobutanbenzene-1-yl)-N-methylmethamine (S-methylamine); 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2-one (tetrahydrobenzazepine); (1S)-4,5-dimethoxy-1-(methylaminomethyl)benzocyclobutane hydrochloride (BCP condense); or (1S)-4,5-dimethoxy-1,2-dihydrocyclobutanebenzen-1-yl)-N-((4,5-dimethoxy-1,2-dihydrocyclobutane-benzen-1-yl)methyl-N-methyl-methamine (dimer impurity), as measured by area percentage of HPLC.

9. The pharmaceutical composition according to claim 8, wherein the crystalline ivabradine hydrochloride is crystalline Form II characterized by x-ray powder diffraction having characteristic peaks at about 15.50, 18.02, 19.00, 19.80, 22.42, 24.16, and 25.460.2 (2).

10. The crystalline ivabradine hydrochloride according to claim 1, is prepared by the process comprising: (a) providing a solution of ivabradine hydrochloride in one or more solvents by heating at about 30 C. to about 120 C.; (b) obtaining the crystalline Form II of ivabradine hydrochloride by the removal of the solvents; and (c) drying the crystalline Form II of ivabradine hydrochloride at about 40 C. to about 70 C., wherein the solvent is at least one member selected from the group consisting of methanol, ethanol, isopropanol, butanol, dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, methyl ethyl ketone, acetone, methyl isobutyl ketone, ethyl acetate, butyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, water and mixtures thereof.

11. The process according to claim 10, wherein the removal of the solvent comprises one or more of filtration, filtration under vacuum, decantation, centrifugation, distillation and distillation under vacuum.

12. A process for preparing crystalline ivabradine hydrochloride according to claim 1, the process comprising: (a) contacting ivabradine base with hydrogen chloride in one or more first solvents to obtain ivabradine hydrochloride; (b) obtaining a solution of ivabradine hydrochloride in one or more second solvents; (c) optionally adding water to the solution, heating the solution and cooling to obtain the ivabradine hydrochloride wet-cake; and (d) treating the wet-cake with one or more of first solvents to obtain the crystalline of ivabradine hydrochloride.

13. The process according to claim 12, wherein the first is at least one member selected from the group consisting of methanol, ethanol, isopropanol, butanol, dimethylformamide, dimethyl acetamide, dimethylsulfoxide, N-methylpyrrolidone, methyl ethyl ketone, acetone, methyl isobutyl ketone, ethyl acetate, butyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, water, or mixtures thereof.

14. The process according to claim 12, wherein the second solvent comprises one or more of dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, water, or mixtures thereof.

15. A pharmaceutical composition comprising a crystalline ivabradine hydrochloride according to claim 1 having one or more pharmaceutically acceptable carriers, excipients, or diluents.

16. The pharmaceutical composition according to claim 8 having one or more pharmaceutically acceptable carriers, excipients, or diluents.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is an X-ray powder diffraction pattern of crystalline ivabradine hydrochloride Form II.

(2) FIG. 2 is a Differential Scanning Calorimetry analysis of crystalline ivabradine hydrochloride Form II.

(3) FIG. 3 is an X-ray powder diffraction pattern of crystalline ivabradine hydrochloride Form III.

DETAILED DESCRIPTION OF THE INVENTION

(4) The inventors have found new polymorphic forms of ivabradine hydrochloride and, in particular, the crystalline forms are designated as Form II and Form III of ivabradine hydrochloride. The new forms are characterized by their respective X-ray powder diffraction pattern as well as differential scanning calorimetry thermogram, as shown in FIGS. 1, 2, and 3.

(5) The inventors also have developed a process for the preparation of the crystalline Form II of ivabradine hydrochloride, by providing solution of ivabradine hydrochloride in one or more solvents to obtain ivabradine hydrochloride solution; and obtaining crystalline Form II of ivabradine hydrochloride by the removal of solvents.

(6) The inventors have also developed a process for the preparation of the crystalline Form III of ivabradine hydrochloride, by contacting ivabradine hydrochloride with a preheated one or more suitable solvent to obtain ivabradine hydrochloride solution; and obtaining the crystalline Form III of ivabradine hydrochloride by the removal of solvents.

(7) 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.

(8) 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.

(9) The inventors have found that the crystalline Form II of ivabradine hydrochloride is stable and is substantially free from known crystalline forms , , , or amorphous form. The stable crystalline Form II of ivabradine hydrochloride has no detectable quantity of crystalline , , , or amorphous forms after storage for 6 months at 40 C. and a relative humidity of 75% or at 25 C. and a relative humidity of 60%.

(10) The inventors have found that the crystalline Form III of ivabradine hydrochloride is stable and is substantially free from known crystalline forms , , , or amorphous form. The stable crystalline Form III of ivabradine hydrochloride has no detectable quantity of crystalline , , , or amorphous forms after storage for 6 months at 40 C. and a relative humidity of 75% or at 25 C. and a relative humidity of 60%.

(11) All ranges recited herein include the endpoints, including those that recite a range between two values. The 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 the very least, a degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

(12) Thus, the advantage of the present invention is to provide storage stable crystalline forms of ivabradine hydrochloride which doesn't change to amorphous form and doesn't tend to decrease the water content.

(13) 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.

(14) As used herein, stable crystalline Form II 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 six months does not contain peaks at about 6.8, 11.9, and 15.9 2 and having less than about 5% of known crystalline forms like or or crystalline forms. In particular, it may contain less than about 1% crystalline forms like or or crystalline forms, for example, it may not contain any detectable amount of forms like or or crystalline forms.

(15) As used herein, stable crystalline Form III 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 six months does not contains peaks at about 6.8 2 and having less than about 5% of known crystalline forms like or or crystalline forms. In particular, it may contain less than about 1% crystalline forms like or or crystalline forms, for example, it may not contain any detectable amount of forms like or or crystalline forms.

(16) As used herein, stable crystalline Form II 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 six months is having less than about 5% of amorphous form. In particular, it may contain less than about 1% amorphous form, for example, it may not contain any detectable amount of amorphous form.

(17) As used herein, stable crystalline Form III 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 six months is having less than about 5% of amorphous form. In particular, it may contain less than about 1% amorphous form, for example, it may not contain any detectable amount of amorphous form.

(18) As used herein, the term obtaining may include filtration, filtration under vacuum, centrifugation, and decantation to isolate product. 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.

(19) 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.

(20) In one general aspect, the invention provides a novel crystalline Form II of ivabradine hydrochloride characterized by X-ray powder diffraction pattern having characteristics peaks at about 15.50, 18.02, 19.00, 19.80, 22.42, 24.16, and 25.46 (2).

(21) The crystalline Form II of ivabradine hydrochloride is further characterized by X-ray powder diffraction pattern having peaks substantially as depicted in FIG. 1. The crystalline Form II of ivabradine hydrochloride is further characterized by X-ray powder diffraction pattern having characteristic peaks at degrees 2 substantially as depicted in Table-1 as herein below.

(22) TABLE-US-00001 TABLE 1 Characteristic X-ray Powder Diffraction Pattern Peaks (expressed in 2 0.2 2) and Relative Intensities of Diffraction Lines for Form II of Ivabradine Hydrochloride Degree 2 0.2 2 I/Io 8.05 6.6 8.69 4.7 9.00 2.0 9.83 3.2 11.17 2.0 12.11 6.2 12.73 1.3 14.68 1.4 15.50 100.0 16.18 16.8 17.08 19.4 17.35 8.7 18.02 21.9 19.00 31.8 19.80 34.3 20.96 18.6 21.72 20.5 22.42 32.4 23.07 3.2 23.78 8.3 24.16 40.8 24.46 26.8 25.14 11.1 25.46 21.6 26.16 3.0 26.60 7.1 27.36 12.7 27.85 9.3 28.57 4.1 29.83 2.9 30.82 5.5 31.32 6.8 31.70 5.2 32.76 4.1 33.72 4.8 34.58 2.0 34.95 1.9 35.61 3.0 37.25 2.2 37.81 3.1

(23) The crystalline Form II of ivabradine hydrochloride is further characterized by differential scanning calorimetry substantially as depicted in FIG. 2. It is further characterized by having one or more of endothermic peaks in the range of 73 C.-78 C., in the range of 152 C.-159 C., and in the range of 197 C.-199 C.

(24) In another general aspect, the invention provides a novel crystalline Form III of ivabradine hydrochloride characterized by X-ray powder diffraction pattern having characteristics peaks at about 15.48, 16.18, 19.00, 19.78, 24.12, 24.41 (2).

(25) The crystalline Form III of ivabradine hydrochloride is further characterized by X-ray powder diffraction pattern having peaks substantially as depicted in FIG. 3.

(26) The crystalline Form III of ivabradine hydrochloride is further characterized by X-ray powder diffraction pattern having characteristic peaks at degrees 2 substantially as depicted in Table-2 as herein below.

(27) TABLE-US-00002 TABLE 2 Characteristic X-ray Powder Diffraction Pattern Peaks (expressed in 2 0.2 2) and Relative Intensities of Diffraction Lines for Form III of Ivabradine Hydrochloride Degree 2 0.2 2 I/Io 4.08 2.6 8.02 9.6 8.70 5.1 9.79 2.8 10.49 1.0 11.16 2.5 12.12 7.7 12.34 5.2 12.72 1.3 13.20 11.2 14.33 2.9 14.69 1.1 15.48 100.0 16.18 26.9 16.84 8.7 17.03 13.6 17.33 5.8 17.98 21.7 19.00 25.7 19.78 33.1 20.92 24.9 21.70 15.7 22.38 24.4 24.12 39.8 24.41 26.2 25.44 16.9 26.14 7.0 26.56 4.8 27.38 10.2 27.81 13.0 28.56 3.3 29.29 2.2 29.82 4.0 30.79 5.6 31.36 8.4 31.68 6.9 32.82 4.5 33.73 5.4 34.60 2.2 34.89 2.0 35.58 2.3 37.19 2.2 37.83 3.3 38.49 1.5

(28) In another aspect, the present invention provides a process for the preparation of crystalline Form II of ivabradine hydrochloride. The process comprising: (a) providing solution of ivabradine hydrochloride in one or more suitable solvents to obtain ivabradine hydrochloride solution; and (b) obtaining the crystalline Form II of ivabradine hydrochloride by the removal of the solvents.

(29) In general, the suitable solvent as in step (a) comprises one or more of methanol, ethanol, isopropanol, butanol, dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, methyl ethyl ketone, acetone, methyl isobutyl ketone, ethyl acetate, butyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 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.

(30) The solution of ivabradine hydrochloride is provided in a mixture of methyl ethyl ketone and tetrahydrofuran from about ambient temperature to about reflux temperature of mixture. In particular, the solution may be heated at about 30 C. to about 120 C., more particularly from about 35 C. to about 80 C. followed by cooling. The cooled solution is subjected to removal of solvents by the know techniques as disclosed herein above.

(31) In another general aspect, the present invention provides a process for the preparation of crystalline Form III of ivabradine hydrochloride. The process comprising: (a) contacting ivabradine hydrochloride with a preheated one or more suitable solvent to obtain ivabradine hydrochloride solution; and (b) obtaining the crystalline Form III of ivabradine hydrochloride by the removal of the solvents.

(32) In general, the suitable solvent as in step (a) comprises one or more of dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, acetone, methyl ethyl ketone, methyl isobutyl ketone, 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.

(33) 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 II of ivabradine hydrochloride prior to the initiation of product crystallization or the slurry may be cooled prior to filtration.

(34) According to further embodiments, the process further comprising additional drying of the ivabradine hydrochloride obtained. The drying is carried out under for example in a hot air oven, tray drier, dried under vacuum and/or in a Fluid Bed Drier. 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. The drying may be done at about 40 C. to about 70 C. The process may include further forming of the product so obtained into a finished dosage form.

(35) In another aspect, the present invention provides a process for the preparation of crystalline Form II of ivabradine hydrochloride, the process comprising: (a) contacting ivabradine base with hydrogen chloride in one or more first solvents to obtain ivabradine hydrochloride; (b) obtaining the solution of ivabradine hydrochloride in one or more second solvents to obtain ivabradine hydrochloride solution; and (c) obtaining the crystalline Form II of ivabradine hydrochloride by the removal of second solvents.

(36) In general, the process includes contacting ivabradine base with hydrogen chloride in one or more first solvents. The first solvent comprises one or more of methanol, ethanol, isopropanol, butanol, dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, methyl ethyl ketone, acetone, methyl isobutyl ketone, ethyl acetate, butyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, water, or mixtures thereof.

(37) In general, the second solvent comprises one or more of dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, water, or mixtures thereof.

(38) According to another aspect, the present invention provides storage stable crystalline Form II and Form III of ivabradine hydrochloride.

(39) In general, the storage stable crystalline Form II of ivabradine hydrochloride is substantially free from known crystalline forms , , or . Further, the storage stable crystalline Form II of ivabradine hydrochloride is substantially free from amorphous form.

(40) In general, the storage stable crystalline Form III of ivabradine hydrochloride is substantially free from known crystalline forms , , or . Further, the storage stable crystalline Form II of ivabradine hydrochloride is substantially free from amorphous form.

(41) According to another aspect, the present invention provides stable crystalline Form II of ivabradine hydrochloride, wherein the Form II of ivabradine hydrochloride is having water content from about 2.0% to about 4.0% w/w.

(42) In another aspect, the present invention provides a process for packaging crystalline ivabradine hydrochloride, the process comprising: (a) placing crystalline 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,
wherein crystalline ivabradine hydrochloride comprises of Form II or Form III.

(43) In another general aspect, the storage stable crystalline Form-II of ivabradine hydrochloride may be characterized by atleast 6 months stability results as outline in Table-III which is representative for one of the batch.

(44) TABLE-US-00003 TABLE III 1 2 3 6 Month Months Months Months 40 C. 2 C./ 40 C. 2 C./ 40 C. 2 C./ 40 C. 2 C./ Sr. Initial 75% 5% 75% 5% 75% 5% 75% 5% No. Tests Specifications RH RH RH RH 1. Description White to slightly White White White White White yellow powder Powder Powder Powder Powder Powder 2. Water by KF (% Not more than 4.0% 2.1 2.0 2.0 2.1 2.0 w/w) 3. Impurity Profile (i) Tetrahydro Not more than 0.15 BDL BDL BDL BDL BDL benzazepine (ii) (S)-methyl Not more than 0.15 BDL BDL BDL BDL BDL amino Compd. (iii) Benzocylco Not more than 0.15 BDL BDL BDL BDL BDL butane Compd. (iv) Dimer Impurity Not more than 0.15 BDL BDL BDL BDL BDL (v) Single Ind. Not more than 0.15 0.04 0.02 0.02 0.03 0.03 (vi) Total Imp. Not more than 0.15 0.09 0.05 0.03 0.08 0.09 4. Polymorph Form-II Form-II Form-II Form-II Form-II Form-II BDL = Below Detection Limit

(45) In another general aspect, the present invention accordingly provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline Form II of ivabradine hydrochloride and one or more pharmaceutically acceptable carriers, excipients or diluents.

(46) In another general aspect, the storage stable crystalline Form III of ivabradine hydrochloride may be characterized by atleast 6 months stability results as outline in Table-IV which is representative for one of the batch.

(47) TABLE-US-00004 TABLE IV 1 2 3 6 Month Months Months Months 40 C. 2 C./ 40 C. 2 C./ 40 C. 2 C./ 40 C. 2 C./ Sr. Initial 75% 5% 75% 5% 75% 5% 75% 5% No. Tests Specifications RH RH RH RH 1. Description White to slightly White White White White White yellow powder Powder Powder Powder Powder Powder 2. Impurity Profile (i) Tetrahydro Not More than 0.15 BDL BDL BDL BDL BDL benzazepine (ii) (S)-methyl Not more than 0.15 BDL BDL BDL BDL BDL amino Compd. (iii) Benzocylco Not more than 0.15 BDL BDL BDL BDL BDL butane Compd. (iv) Dimer Impurity Not more than 0.15 BDL BDL BDL BDL BDL (v) Single Ind. Not more than 0.15 0.04 0.04 0.03 0.04 0.03 (vi) Total Imp. Not more than 0.15 0.09 0.07 0.06 0.08 0.09 4. Polymorph Form-III Form-III Form-III Form-III Form-III Form-III BDL = Below Detection Limit

(48) In another general aspect, the present invention accordingly provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline Form III of ivabradine hydrochloride and one or more pharmaceutically acceptable carriers, excipients or diluents.

(49) In further aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a storage stable crystalline Form II of ivabradine hydrochloride having no detectable quantity of crystalline , , , or amorphous forms, and one or more pharmaceutically acceptable carriers, excipients, or diluents.

(50) In further aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a storage stable crystalline Form III of ivabradine hydrochloride having no detectable quantity of crystalline , , , or amorphous forms, and one or more pharmaceutically acceptable carriers, excipients, or diluents.

(51) An aspect of the present application provides a pharmaceutical compositions comprising therapeutically effective amount of a crystalline Form II or Form III of ivabradine hydrochloride substantially free of one or more its corresponding impurities as measured by HPLC.

(52) 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: (1S)-4,5-Dimethoxy-1-(methylaminomethyl)benzocyclobutane hydrochloride. Dimer impurity: 1-(4,5-Dimethoxy-1,2-dihydrocyclobutanebenzen-1-yl)-N-((4,5-dimethoxy-1,2-dihydrocyclobutanbenzen-1-yl)methyl-N-methylmethamine.

(53) According to one aspect there is provided a pharmaceutical composition comprising a therapeutically effective amount of crystalline forms Form II or Form III of ivabradine hydrochloride substantially free from residual methyl ethyl ketone.

(54) An aspect of the invention provides crystalline Form II of ivabradine hydrochloride having particle size distributions wherein the 10th volume percentile particle size (D10) is less than about 50 m, the 50th volume percentile particle size (D50) is less than about 200 m, or the 90th volume percentile particle size (D90) is less than about 400 m, or any combination thereof.

(55) An aspect of the invention provides crystalline Form III of ivabradine hydrochloride having particle size distributions wherein the 10th volume percentile particle size (D10) is less than about 50 m, the 50th volume percentile particle size (D50) is less than about 200 m, or the 90th volume percentile particle size (D90) is less than about 400 m, or any combination thereof.

(56) In another aspect, the invention provides a process for the preparation of ivabradine hydrochloride which may be used starting material.

(57) In general, the process for preparation of ivabradine hydrochloride includes a mixing ivabradine hydrochloride with one or more of suitable solvent comprises tetrahydrofuran (THF), dimethylsulfoxide (DMSO), dimethylformamide, diethylether, dimethylether, water or a mixture thereof.

(58) Embodiments of the process includes providing mixture of ivabradine hydrochloride, tetrahydrofuran (THF) and water under heating conditions until dissolution is complete and the solution may be further cooled until crystallization is complete, and the product may be collected by filtration. The product thus obtain may be dried to obtain of ivabradine hydrochloride or used as such for the further process steps to obtain crystalline Form II or Form III.

(59) The novel crystalline forms of ivabradine hydrochloride can be characterized by any of the analytical technique like PXRD, DSC, IR as follows: (a) Characterization by PXRD

(60) 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/40 kv/40 mA 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)

(61) 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.

(62) The present invention is further illustrated by the following examples which are 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)

(63) 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)

(64) 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 Form-II or Form-III.

EXAMPLE 3

Preparation of Crystalline Form II of Ivabradine Hydrochloride (I)

(65) 20 g of ivabradine hydrochloride wet-cake and 200 mL of methyl ethyl ketone and tetrahydrofuran (10 mL) were heated at 75-80 C. for 15 minutes to get a clear solution. The reaction mixture was stirred for further 60 minutes and cooled to 25 C. gradually. The reaction mixture was stirred for 2 hours and filtered. The wet-cake was washed with methylethyl ketone and dried under vacuum at 40 C. to 45 C. for 12 hours. The X-ray powder diffraction discloses Form-II. (FIG. 1) and DSC (FIG. 2).

EXAMPLE 4

Preparation of Crystalline Form II of Ivabradine Hydrochloride (I)

(66) 25 g of ivabradine hydrochloride wet-cake and 250 mL of methyl ethyl ketone and 12.5 mL tetrahydrofuran were heated at 40 C. for 15 minutes to obtain solution. The reaction mixture was stirred for further 60 minutes and cooled to 25 C. gradually. The reaction mixture was stirred for 2 hours and filtered. The wet-cake was washed with methylethyl ketone and dried under vacuum at 40 C. to 45 C. for 12 hours. The X-ray powder diffraction discloses Form-II. (FIG. 1) and DSC (FIG. 2).

EXAMPLE 5

Preparation of Crystalline Form III of Ivabradine Hydrochloride (I)

(67) 200 mL of methyl ethyl ketone was charged in a round bottom flask and the temperature was raised to 50-60 C. 20.0 g of ivabradine hydrochloride was added and subsequently stirred for about 15 min at 50-60 C. The reaction mixture was then refluxed at 75-80 C. to obtain clear solution. The reaction mixture was allowed to cool gradually and stirred for 2 hours and filtered. The wet-cake was washed with 20 mL of methyl ethyl ketone and dried under vacuum at 40 C. to 45 C. for 12 hours. The X-ray powder diffraction discloses Form-III. (FIG. 3).

EXAMPLE 5

Packing of Crystalline FormsForm II & Form III of Ivabradine Hydrochloride (I)

(68) The crystalline polymorph Form II & Form III of ivabradine hydrochloride obtained as per example-3 and 4 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.

(69) 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.