FIELD OF THE INVENTION
The present invention relates to crystalline ivabradine hydrochloride of formula I and process for the preparation thereof.

Particularly, the present invention relates to process for the preparation of crystalline ivabradine hydrochloride.
BACKGROUND OF THE INVENTION
Ivabradine Hydrochloride of formula I, marketed under the trade name Corlanor® or Procoralan® which is used as a hyperpolarization-activated cyclic nucleotide-gated channel blocker that reduces the spontaneous pacemaker activity of the cardiac sinus node, resulting in heart rate reduction with no effect on ventricular repolarization and no effects on myocardial contractility. It is useful in many cardiovascular diseases such as angina pectoris, myocardial infarction, and associated rhythm disturbances.
Ivabradine hydrochloride is chemically known as 3-(3-{[((7S)-3,4-Dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7¬ yl)methyl] methyl amino}propyl)-1,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-benzazepin-2-one, hydrochloride.
Ivabradine and its pharmaceutically acceptable salts were first disclosed in US Patent 5,296,482 (US’482). The US’482 describes list of acid addition salts for ivabradine; especially, in the mineral series hydrochloric, hydrobromic, sulphuric, nitric, and phosphoric acid, and in the organic series acetic, propionic, maleic, fumaric, tartaric, oxalic, isethionic, benzenesulphonic, benzoic, and methanesulphonic acids.
US’482 has also disclosed preparation of ivabradine hydrochloride by treating the free base with hydrochloric acid and then crystallizing from acetonitrile. However, disclosure of the patent is silent about the preparation of ivabradine hydrochloride from ivabradine oxalate.
Ivabradine Hydrochloride exists in several polymorphic forms which are described below:
The a (alpha) polymorphic form of ivabradine hydrochloride, has been described in EP Patent 1589005 (EP’005); which is prepared by addition of hydrochloride of the (7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine in 3-[2-(1,3-dioxolan-2-yl)ethyl]-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one in the presence of ethanol and water to isolate ivabradine hydrochloride.
The resultant product is crystallized in the presence of toluene / 1-methyl-2-pyrrolidinone mixture. The Ivabradine hydrochloride is thereby obtained in a yield of 85%.
EP Patent 1707562 (EP’562) has disclosed ?-crystalline form of ivabradine hydrochloride prepared from mixture of ivabradine hydrochloride and 2-ethoxyethanol; a mixture of ivabradine hydrochloride, 2-ethoxyethanol and water; or a mixture of ivabradine hydrochloride and ethanol. Further water is heated until dissolution is complete and is then cooled until, and the resulting product is isolated by filtration.
The d (delta) crystalline form of ivabradine hydrochloride and a method for its preparation has been described in EP Patent 1775288 (EP’288); which is prepared by preheating of acetonitrile or a mixture of acetonitrile and water, followed by addition of ivabradine hydrochloride.
PCT Publication 2008146308 (WO’308) has described a process for the preparation of ivabradine hydrochloride by treating ivabradine with alcoholic hydrogen chloride, and the amorphous form of ivabradine hydrochloride. WO’308 has also described amorphous form of ivabradine hydrochloride.
EP Patent 2781509 (EP’509) has described e (epsilon) form of ivabradine hydrochloride, which has been prepared by mixing anhydrous ivabradine hydrochloride in C4-C7 ketone at a temperature between -10 and 50 °C or by solubilizing free base ivabradine in a C4-C7 ketone and further treating with hydrogen chloride.
Other polymorphic forms of ivabradine hydrochloride, designated as form I, is described in PCT Publication 2008/065681(WO’681); which has been prepared by treatment of ivabradine in acetonitrile with a saturated solution of HCI in isopropanol.
In addition to above discussed polymorphs of ivabradine, several other polymorphic form of ivabradine hydrochloride and processes for the preparation thereof have also been described, such as: ß form in US7361649; ßd form in US7361652; ?d form in US7361651; dd-crystalline form in US738493; form Z, form K, and form X in EP2534135; form zeta in IN2375/MUM/2010; form IV in US9139531; form II and form III in WO2013/102919; form A in IN316755; form Zy-I in IN21/MUM/2010; omega form in CN101805289; crystal S in CN103864690; form-L in IN 201841038102 etc.
It is always desired that all crystalline forms of the same active compound should be synthesized and characterized as completely as possible. It is also required that the commercial product should not contain traces of any of the other form as a contamination or, if present, the percentages of each of the forms should be well characterized to avoid any changes in the dissolution and efficacy.
There is a need to provide improved methods for preparation of polymorphic forms of ivabradine hydrochloride which are substantially free of impurities, shows higher stability, reproducibility, and purity so that it can be used as active ingredient for formulation.
Present invention full fills the need in the prior art and provides pure, reproducible, and stable polymorphic form of ivabradine hydrochloride and process for preparation thereof.
OBJECT OF THE INVENTION
The main object of present invention is to provide an improved process for the preparation of crystalline ivabradine HCl.
Another object of present invention is to provide a process for preparation of crystalline ivabradine HCl substantially free from chiral impurity.
Another object of present invention is to provide substantially pure, reproducible, and stable polymorphic form of ivabradine hydrochloride.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a process for the preparation of crystalline ivabradine HCl.
In another aspect, the present invention provides a process for the preparation of substantially pure crystalline ivabradine hydrochloride.
In an embodiment, the present invention provides a process for the preparation of crystalline ivabradine hydrochloride substantially free from chiral impurity.
In another aspect, the present invention provides a process for the preparation of crystalline ivabradine hydrochloride from ivabradine oxalate.
In another aspect, the present invention provides a process for the preparation of crystalline ivabradine hydrochloride, comprising:
a) reacting ivabradine oxalate with a suitable base in presence of a suitable solvent to obtain ivabradine base;
b) adding hydrochloric acid in the resulting ivabradine base of step (a);
c) stirring the mixture of step b) for a suitable time to obtain ivabradine hydrochloride;
d) adding a suitable solvent to the ivabradine hydrochloride obtained in step c), and stirring it for a suitable time; and
e) isolating crystalline ivabradine hydrochloride.
In another aspect, the present invention provides a process for the preparation of crystalline ivabradine hydrochloride, comprising:
a) reacting ivabradine oxalate with hydrochloric acid in a suitable solvent to obtain a reaction mixture;
b) stirring the reaction mixture of step (a) for a suitable time to obtain ivabradine hydrochloride; and
e) isolating crystalline ivabradine hydrochloride.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows an X-ray powder diffraction (XRPD) pattern of a (alpha) crystalline form of ivabradine hydrochloride of formula I prepared according to process of present invention.
Figure 2 shows an X-ray powder diffraction (XRPD) pattern of ? (gamma) crystalline form of ivabradine hydrochloride of formula I prepared according to process of present invention.
Figure 3 shows an X-ray powder diffraction (XRPD) pattern of d (delta) crystalline form of ivabradine hydrochloride of formula I prepared according to process of present invention.
Figure 4 shows an X-ray powder diffraction (XRPD) pattern of e (epsilon) form of ivabradine hydrochloride of formula I prepared according to process of present invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to polymorph of ivabradine hydrochloride and process for preparation thereof.
However, prior to discussing this invention in further detail, the following definitions are set forth to illustrate the meaning and scope of various terms used to describe the invention herein.
The term “polymorph” or “solid state form” or “polymorph of ivabradine hydrochloride” or “crystalline ivabradine hydrochloride” used herein means a crystal modification of ivabradine hydrochloride, which can be characterized by analytical methods such as X-ray powder diffraction pattern, infra-red spectrum (IR), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), or by other techniques.
An XRPD pattern is an x-y graph with diffraction angle on the x-axis and intensity on the y-axis. The peak within the pattern may be used to characterize a crystalline solid form.
A crystal (or polymorph) form may be referred to herein as substantially free of any other crystalline (or polymorphic) form. As used herein, the term “substantially free” mean that the crystalline form contains 20% or less, 10% or less, 5% or less, 2% or less, or 1% or less of any other form of the subject compound.
The polymorphic forms of ivabradine hydrochloride of the present invention have advantageous properties selected from at least one of the following: solubility, purity, flowability, storage stability, stability to dehydration, stability to polymorphic conversion, low content of residual solvents, and low hygroscopicity.
As used herein, and unless otherwise specified, the term "Alkyl" refers to a mono-radical of a branched or unbranched saturated hydrocarbon chain that can be substituted or unsubstituted.
As used herein, and unless otherwise specified, the term "substantially free" is meant that the crystalline ivabradine hydrochloride of formula I contain about 2% (w/w) or less, about 1% (w/w) or less, about 0.5% (w/w) or less, or about 0.2% (w/w) or, or about 0.1% (w/w) less of a specified or unspecified impurity.
As used herein, and unless otherwise specified, the term "substantially pure" relates to compounds having a purity of about 95% or more. In other words, the term relates a compound, having a purity, measured as % area normalization by HPLC, of about 95% or more. In other embodiments, the term relates to compounds having a purity of about more than 97% area normalization by HPLC. In preferred embodiments, the term relates to compounds having a purity of about more than 98% (by HPLC; area normalization).
As used herein, the modifier term "about" should be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression "from about 5 to about 10" also discloses the range "from 5 to 10." When used to modify a single number, the term "about" may refer to plus or minus 10% of the indicated number and includes the indicated number e.g., "about 10%" may indicate a range from 9% to 11%, and "about 1" may be from 0.9-1.1.
A reaction mixture may be characterized herein as being at or allowed to come to ‘room temperature’ or ‘ambient temperature’, also abbreviated as ‘RT’. Room temperature means that the temperature of the reaction mass or reaction mixture is close to, or the same as, that of the space in which the reaction mass or reaction mixture is located. Generally, RT is from about 20°C to about 30°C.
As used herein, and unless otherwise specified, the term "isolated" in reference to the compounds of the present invention, their salts or solid-state forms thereof corresponds to compounds that are physically separated from the reaction mixture in which they are formed.
The term “comprising” or “comprises” used herein refers to the composition and methods include the recited elements, but not exclude other materials of steps that do not materially affect the basic and novel characteristic(s) of the invention.
In an aspect, the present invention provides a process for the preparation of substantially pure crystalline ivabradine hydrochloride.
In an embodiment, the present invention provides a process for the preparation of crystalline ivabradine hydrochloride substantially free from chiral impurity.
In another aspect, the present invention provides a process for the preparation of crystalline ivabradine hydrochloride having chiral impurity below 0.15%.
In another aspect, the present invention provides a process for the preparation of crystalline ivabradine hydrochloride from ivabradine oxalate.
In another aspect, the present invention provides a process for the preparation of crystalline ivabradine hydrochloride, comprising:
a) reacting ivabradine oxalate with a suitable base in presence of a suitable solvent to obtain ivabradine base;
b) treating hydrochloric acid with the resulting ivabradine base of step (a) to get a mixture;
c) stirring the mixture of step b) for a suitable time to obtain ivabradine hydrochloride;
d) adding a suitable solvent to the ivabradine hydrochloride obtained in step c), and stirring it for a suitable time; and
e) isolating crystalline ivabradine hydrochloride.
The suitable base in step (a) may be selected from, but not limited to, aqueous ammonia, ammonium carbonate, ammonium bicarbonate, alkyl amines, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, or the like, or a mixture thereof.
Preferably, alkyl amine is dimethylamine and triethylamine. Most preferably, the suitable base in step (a) is aqueous ammonia.
The suitable solvent in step (a) may be selected from, but not limited to, methylene dichloride, methyl isobutyl ketone (MIBK), 2-butanone, 3-pentanone, ethyl acetate, toluene, heptane, cyclohexane, acetonitrile, or the like, or a mixture thereof. Most preferably, the solvent is methylene dichloride.
The hydrochloric acid employed in step (b) may be methanolic hydrochloride, aqueous HCl or gaseous HCl. More preferably, methanolic hydrochloride acid is selected.
The step (c) is carried out for about 30-60 minutes at a temperature from about 0°C to about 50°C, preferably at about 2°C to about 40°C, and most preferably at about 20°C to about 30°C or at room temperature.
The ivabradine hydrochloride obtained in step (c) may or may not be isolated.
The suitable solvent in step (d) may be selected from, but not limited to, MIBK, 2-butanone, 3-pentanone, ethyl acetate, cyclohexane, acetonitrile, or the like, or a mixture thereof. Preferably, acetonitrile is employed to obtain delta form; MIBK, 2-butanone, 3-pentanone, or cyclohexane is employed to obtain epsilon form; 2-butanone is employed to obtain gamma form; and ethyl acetate is employed to obtain alfa form.
The step (d) is carried out for about 24-30 hours at a temperature from about 0°C to about 50°C, preferably at about 2°C to about 40°C, and most preferably at about 20°C to about 30°C or at room temperature.
In another aspect, the present invention provides a process for the preparation of crystalline ivabradine hydrochloride, comprising:
a) reacting ivabradine oxalate with hydrochloric acid in a suitable ketone solvent to obtain a reaction mixture;
b) stirring the reaction mixture of step (a) for a suitable time to obtain ivabradine hydrochloride; and
c) isolating crystalline ivabradine hydrochloride.
Preferably, the hydrochloric acid in step (a) is aqueous HCl.
The stirring in (b) is carried out for about 12-15 hours at a temperature from about 0°C to about 50°C, preferably at about 2°C to about 40°C, and most preferably at about 20°C to about 30°C or at room temperature.
The ketone solvent used in step a) is selected from 2-butanone, 3-pentanone, methyl isobutyl ketone, cyclohexanone.
Optionally, the reaction mixture is seeded with desired crystalline ivabradine hydrochloride.
Crystalline ivabradine hydrochloride of the present invention is isolated as solid by any method known in the prior art, preferably by filtration. Preferably, the isolation by filtration is performed at room temperature.
Crystalline ivabradine hydrochloride of the present invention isolated as solid is dried by any conventional method known in the prior art at a suitable temperature. Preferably, the drying is performed at a temperature in the range of about 40°C-80°C.
In yet another aspect, the present invention provides pharmaceutical compositions of crystalline ivabradine hydrochloride prepared according to present disclosure.
In yet another aspect, the crystalline ivabradine hydrochloride prepared according to present invention can be used to prepare other solid state forms of ivabradine hydrochloride.
The solid forms of Ibrutinib are confirmed by pattern and data of X-ray powder diffraction (XRPD) performed on XRPD instrument PAN alytical X’Pert Pro.
The following examples are provided to describe the invention in further detail.
EXAMPLES:
Example 1: Preparation of d (delta) crystalline form of ivabradine hydrochloride
Ivabradine Oxalate (25 g, 0.0448 mol) was taken in MDC (125.0 ml) and neutralized using aq. Ammonia. The reaction mixture was extracted with MDC (50 ml). In the organic layer, methanolic HCl (10.0 ml) was added. Reaction mass is allowed to stir for 2.0 hours. Thereafter, solvent was distilled off and degassed. In the degas mass, acetonitrile (50 ml) was added and degassed further. Finally, acetonitrile (100 ml) was added and stirred at 20-30ºC for 2 hours. The solid was filtered and wet material was dried at 40-50ºC affording 20.0 g of Ivabradine Hydrochloride (20. g, yield: 88%).

Example 2: Preparation of e (epsilon) form of ivabradine hydrochloride
5.0 g (0.0099 mol) of Ivabradine Hydrochloride was taken in 3-pentanone (50.0 ml) and stirred for 6.0 hours at 20-30ºC. Reaction mass was filtered and dried at 40-50ºC to get epsilon form of Ivabradine Hydrochloride (4.2 g, yield: 91%).
Example 3: Preparation of e (epsilon) form of ivabradine hydrochloride
5.0 g (0.0099 mol) of Ivabradine Hydrochloride was taken in 2-butanone (40-60 ml) and moisture was adjusted between 0.2-0.9% followed by seeding with epsilon form. Reaction mass was stirred for 18.0 hours at 20-30ºC. Reaction mass was filtered and dried at 40-50ºC to get epsilon form of Ivabradine Hydrochloride (4.0 g, yield:88.0%
Example 4: Preparation of e (epsilon) form of ivabradine hydrochloride
3.0 g (0.0059 mol) of Ivabradine Hydrochloride was taken in methyl isobutyl ketone (30.0 ml). Reaction mass was stirred for 24.0 hours at 20-30ºC. Reaction mass was filtered and dried at 40-50ºC to get epsilon form of Ivabradine Hydrochloride (3.8 g, yield: approx. 88.0%).
Example 5: Preparation of e (epsilon) form of ivabradine hydrochloride
3.0 g (0.0059 mol) of Ivabradine Hydrochloride was taken in cyclohexanone 15.0ml). Reaction mass was stirred for 24.0 hours at 20-30ºC. Reaction mass was filtered and dried at 40-50ºC to get epsilon form of Ivabradine Hydrochloride (3.8 g, yield: 84%).
Example 6: Preparation of e (epsilon) form of ivabradine hydrochloride
Ivabradine Oxalate (5.0 g, 0.099 mol) was taken in methylene dichloride (25.0 ml) and neutralized using aq. Ammonia. The reaction mixture was extracted with methylene dichloride (50 ml). Organic layer was distilled and degassed. In degassed mass, 2-butanone (10 ml) was added which was further distilled and degassed to get Ivabradine base. Ivabradine base was taken in 2-butanone (40-60 ml) and moisture was adjusted between 0.2-0.9% followed by purging of dry HCl gas. Thereafter, seeding with epsilon form was done and reaction mass was stirred for18.0 hours at 20-30ºC. The solid was filtered and dried at 40-50ºC to get epsilon form of Ivabradine Hydrochloride (3.6 g, yield: 80.0%).
Example 7: Preparation of ? (gamma) crystalline form of ivabradine hydrochloride
Ivabradine Oxalate (5.0 g, 0.099 mol) was taken in 2-butanone (40.0 ml), and conc. HCl (1.3 g) was charged in the suspension. Thereafter, reaction mass was stirred for 24.0 hours at 20-30ºC. The solid was filtered and dried at 40-50ºC to get gamma form of Ivabradine Hydrochloride (3.6 g, yield: 80.0%).
Example 8: Preparation of a (alpha) crystalline form of ivabradine hydrochloride
Ivabradine Oxalate (60.0 g, 0.107 mol) was taken in methylene dichloride (300.0 ml) and neutralized using aq. Ammonia. The reaction mixture was extracted with methylene dichloride (120.0 ml.) In the organic layer, methanolic HCl (24.0 ml) was added. Reaction mass was allowed to stir for 2.0 hours. Thereafter, solvent was distilled and degassed. In the degassed mass, acetonitrile (120 ml) was added and degassed further. Again, acetonitrile (240.0 ml) was added and stirred for 2.0 hrs at raised temperature of 70-82°C. Temperature of the reaction mass was then cooled to 20-30ºC and maintained for 2 hours followed by filtration. Wet material was taken in ethylacetate (720.0 ml) and heated to 75 to 80°C with stirring for 1.0 hour. Thereafter, 120.0 ml ethyl acetate is distilled off. Reaction mass was then cooled to 25-35°C and stirred for 2.0 hrs. The solid was filtered, and wet material was dried at 70-80ºC affording 51.6 g Ivabradine Hydrochloride (51.6 g, yield: 95.0%). HPLC-purity 99.9% Chiral below 0.15%.

CLAIMS:

WE CLAIM
Claim 1. A process for the preparation of crystalline ivabradine hydrochloride, comprising:
a) reacting ivabradine oxalate with a base in presence of solvent to obtain ivabradine base;
b) treating hydrochloric acid with the resulting ivabradine base of step (a) to get a mixture;
c) stirring the mixture of step b) to obtain ivabradine hydrochloride;
d) adding a solvent to the ivabradine hydrochloride obtained in step c), and stirring for a suitable time; and
e) isolating crystalline ivabradine hydrochloride.
Claim 2. The process as claimed in claim 1, wherein in step (a) the base is selected from aqueous ammonia, ammonium carbonate, ammonium bicarbonate, alkyl amines, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide or a mixture thereof.
Claim 3. The process as claimed in claim 1, wherein in step (a) the solvent is selected from methylene dichloride, methyl isobutyl ketone (MIBK), 2-butanone, 3-pentanone, ethyl acetate, toluene, heptane, cyclohexane, acetonitrile or a mixture thereof.
Claim 4. The process as claimed in claim 1, wherein in step (b) hydrochloric acid is in the form of methanolic hydrochloride, aqueous hydrochloride or gaseous hydrochloric acid.
Claim 5. The process as claimed in claim 1, wherein in step (c) ivabradine hydrochloride is optionally isolated.
Claim 6. The process as claimed in claim 1, wherein in step (d) the suitable solvent is selected from MIBK, 2-butanone, 3-pentanone, ethyl acetate, cyclohexane, acetonitrile or a mixture thereof.

Claim 7. The process as claimed in claim 1, wherein in step (d) the solvent is stirred at a temperature from 0°C to 50°C and preferably at 2°C to 40°C for 24-30 hours.
Claim 8. A process for the preparation of crystalline ivabradine hydrochloride, comprising:
a) reacting ivabradine oxalate with hydrochloric acid in a ketone solvent to get a reaction mixture;
b) stirring the reaction mixture of step (a) to obtain ivabradine hydrochloride; and
c) isolating crystalline ivabradine hydrochloride.
Claim 9. The process as claimed in claim 8, wherein in step (a) ketone solvent is selected from 2-butanone, 3-pentanone, methyl isobutyl ketone and cyclohexanone.
Claim 10. The process as claimed in claim 1 and claim 8, the isolated crystalline ivabradine hydrochloride having chiral impurity below 0.15%.