Claims:We claim:

1. Storage stable amorphous form of Ivabradine hydrochloride.

2. A process for preparing amorphous Ivabradine hydrochloride comprising,

a) condensing compound of Formula-1 with compound of Formula-2 or its pharmaceutically acceptable salts thereof; to yield compound of Formula-3,

Wherein X= Cl, Br, I

b) reducing compound of Formula-3 using suitable reducing agent to yield Ivabradine base of Formula-4,

c) converting Ivabradine base of Formula-4 into its pharmaceutically acceptable salts,
d) converting pharmaceutically acceptable salt of Ivabradine into its storage stable amorphous form.

3. The process according to claim 2, the reaction of step a) is carried in presence of a base and organic solvent.

4. The process according to claim 3, base used in step a) is selected from potassium carbonate, sodium carbonate or cesium carbonate and organic solvent used is N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide or N-methylpyrrolidone.

5. The process according to claim 2, the reaction of step b) the reducing agent used is palladium on carbon (Pd/C), palladium on barium sulfate (Pd/BaSO4), platinum on carbon (Pt/C) or tris(triphenylphosphine) rhodium chloride and organic solvent used in step b) is methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, tert-butanol, ethane-1,2-diol or propane-1,2-diol.

6. The process according to claim 2, the reaction step d) wherein conversion is done either by providing a solution or suspension of Ivabradine hydrochloride in one or more of organic solvents; and removing the solvent.

7. The process according to claim 6, organic solvent used is selected from acetonitrile, propionitrile, isobutyronitrile, methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, tert-butanol, ethane-1,2-diol, propane-1,2-diol, water and their mixtures.

8. The process according to claim 6, techniques used for the removal of solvents in comprises one or more of distillation, distillation under vacuum, spray drying, agitated thin film drying, freeze drying, filtration, decantation or centrifugation.

9. The process according to claim 8, the technique used for the removal of solvents is spray drying.

, Description:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of stable amorphous Ivabradine hydrochloride.

BACK GROUND OF THE INVENTION
Ivabradine, and addition salts thereof with a pharmaceutically acceptable acid, and more especially its hydrochloride, have very valuable pharmacological and therapeutic properties, especially bradycardic properties, making those compounds useful in the treatment or prevention of various clinical situations of myocardial ischaemia 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. It is chemically known as (S)-7,8-dimethoxy-3-{3-{N-[(4,5-dimethoxybenzocyclobut-1-yl)methyl]-N-(methyl)amino)propyl)-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one.

The molecule of the compound (I) has one chiral carbon atom in position 7. Ivabradine is the single (S) enantiomer.

The preparation and therapeutic use of Ivabradine and addition salts thereof with a pharmaceutically acceptable acid, and more especially its hydrochloride, have been described in the US patent specification US5296482A. In view of the pharmaceutical value of this compound, it has been of prime importance to obtain it with excellent purity and stability. It has also been important to be able to synthesise it by means of a process that can readily be converted to the industrial scale, especially in a form that allows rapid filtration and drying. Finally, that form had to be perfectly reproducible, easily formulated and sufficiently stable to allow its storage for long periods without particular requirements for temperature, light or oxygen level. The patent specification US5296482A describes a synthesis process for Ivabradine and its hydrochloride. However, that document does not specify the conditions for obtaining Ivabradine in a form that exhibits those characteristics in a reproducible manner. In the above mentioned process Ivabradine as a product was isolated by chromatographic techniques. The chromatographic technique for purification is cumbersome, tedious and difficult to utilize on an industrial scale.

The above mentioned drawbacks call for an alternative and improved process for the preparation of highly pure Ivabradine hydrochloride that would be commercially viable, reproducible on industrial scale and meets the needs of regulatory agencies. Subsequent US patent i.e. US7176197 reports alpha crystalline form of Ivabradine hydrochloride. Several other crystalline forms such as beta, gamma, delta, beta-d, gamma-d and delta-d are also reported by Les Laboratories.

Crystalline solids normally require a significant amount of energy for dissolution due to their highly organized, lattice like structures. For example, the energy required for a drug molecule to escape from a crystal is more than from an amorphous or a non-crystalline form. It is known that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form (Econno T., Chem. Phazm Bull., 1990; 38: 2003-2007). For some therapeutic indications, one bioavailability pattern may be favoured over another. Therefore, it is desirable to have amorphous forms of drugs with high purity to meet the needs of regulatory agencies and also highly reproducible processes for their preparation.

Apart from that, US patent i.e. US 8212026 first time disclosed the amorphous form and its process for the preparation. The amorphous form prepared according to the process provided found to be unstable.

Further, lot of patent literature has been published such as WO2011098582, WO2012025940, WO2008125006, CN101768117 and many more on crystalline forms of Ivabradine as either hydrochloride salts or other acid addition salts to overcome the prior art drawbacks.

Though many crystalline forms for Ivabradine hydrochloride are reported in literature and quest to find a stable polymorphic form remained unanswered. Thus based on all above mentioned drawbacks, the applicant has now found that amorphous form of particular salt of Ivabradine, the hydrochloride, can be obtained which is well defined and that exhibits valuable characteristics of stability and processability than any other crystalline as well as amorphous form reported earlier.

OBJECTS OF THE INVENTION
The main objective of the present invention is to provide a simple and efficient process for the preparation of a “Storage stable amorphous form”; which is well defined and has valuable characteristics in terms of filtration, drying, stability, processability and ease of formulation.

SUMMARY OF THE INVENTION
In one aspect of the present invention, the inventors have proceeded with extensive research to provide a Ivabradine hydrochloride as a storage stable amorphous form.

In second aspect of the present invention is to provide an improved process for preparing storage stable amorphous Ivabradine hydrochloride.

BRIEF DESCRIPTION OF FIGURES:
Figure 1 illustrates PXRD pattern of amorphous Form of Ivabradine hydrochloride

DETAILED DESCRIPTION
The instant invention relates to an efficient and industrially advantageous process for the preparation of highly pure storage stable Ivabradine hydrochloride as amorphous form.

In first embodiment the present invention provides Ivabradine hydrochloride as a pure storage stable amorphous form. Pure storage stable amorphous form of Ivabradine hydrochloride of present invention is further characterized by complete absence of other polymorphic forms and shows no crystalline material even after keeping for longer duration of time.

The prior art discloses various process for the preparation of amorphous Ivabradine hydrochloride. However, the amorphous compound obtained using these processes are found to be unstable by inventors of the present invention and converted to crystalline form during stability. Thus, inventors of the present invention have developed an industrially feasible process for preparing storage stable amorphous Ivabradine hydrochloride.

In particular, the storage stable amorphous form of Ivabradine hydrochloride does not show any change in the XRD pattern after storage for six months at 25°C and 60% relative humidity.

More particularly, the storage stable amorphous Ivabradine hydrochloride has no detectable quantities of crystalline Ivabradine hydrochloride after storage for six months at 25°C and 60% relative humidity.

As used herein, storage stable refers to retention of the original size and shape of the amorphous Ivabradine hydrochloride, as well as the pharmacological activity of the active agent over a period of at least one month.

In second embodiment of the present invention provides an optimized process for preparing storage stable amorphous Ivabradine hydrochloride comprising,

a) condensing compound of Formula-1 with compound of Formula-2 or its pharmaceutically acceptable salts thereof; to yield a compound of Formula-3

Wherein X= Cl, Br, I

b) reducing compound of Formula-3 using suitable reducing agent to yield Ivabradine base of Formula-4.

c) converting Ivabradine base of Formula-4 into its pharmaceutically acceptable salts

d) converting pharmaceutically acceptable salt of Ivabradine into its amorphous form.

In an embodiment, X used in step a) is preferably Cl, I; more preferably I.

The reaction of step a) is carried by condensing compound of Formula-1 with compound of Formula-2 or its pharmaceutically acceptable salts thereof; in presence of a base and organic solvent.

In an embodiment, base used in step a) is selected from organic and inorganic bases; preferably selected from inorganic base, more preferably selected from metal carbonates, most preferably is potassium carbonate.

In an embodiment, the solvent used in step a) is polar-aprotic solvents, preferably is N,N-dimethylformamide.

In an embodiment, the reaction of step b) is carried out by reducing compound of Formula-3 using suitable reducing agent to yield Ivabradine base of Formula-4 in an organic solvent.

In an embodiment, the reducing agent used in step b) is selected from palladium catalysts, preferably palladium on carbon (Pd/C).

In an embodiment, the solvent used in step b) is selected from alcohol solvents, preferably methanol.

In an embodiment, the reaction of step c) comprises converting Ivabradine base of Formula-4 into its pharmaceutically acceptable salts, preferably hydrochloride salt.

In an embodiment, the reaction of step d) Ivabradine hydrochloride salt is then converted to storage stable amorphous form by either making a solution or suspending in one or more of organic solvents; and then removing the solvents.
The solution or suspension can be obtained by known methods which includes either direct use of a reaction mixture containing Ivabradine hydrochloride is obtained in the course of its synthesis; or dissolving Ivabradine hydrochloride in one or more of solvents or mixture thereof

In an embodiment, solvent used herein is nitriles, alcohols and polar solvents and their mixtures, preferably methanol.

In an embodiment, the techniques which may be used for the removal of solvents herein comprises one or more of distillation, distillation under vacuum, spray drying, agitated thin film drying (“ATFD”), freeze drying (lyophilization), filtration, decantation, and centrifugation. The solvent may also be removed, optionally, at reduced pressure and/or at elevated temperature as known in the art.

In a particular embodiment, the most preferably technique used for the removal of solvents is spray drying.

Further, as used herein the term “Reducing agent” used in current invention refers to reducing single carbon-carbon, using standard techniques that are well known to those skilled in the art. For example, reduction of the double bond may be effected with hydrogen gas (H2), using catalysts such as palladium on carbon (Pd/C), palladium on barium sulfate (Pd/BaSO4), platinum on carbon (Pt/C), tris(triphenylphosphine) rhodium chloride (Wilkinson's catalyst) and like.

“Base” used in the synthesis include both organic and inorganic bases. Organic bases include but not limited to pyridine, DMAP (4-dimethylaminopyridine), triethylamine, DIEA (N,N-diisopropylethylamine), N-methylpiperidine, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DABCO (1,4-diazabicyclo[2.2.2]octane), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), N-methylmorpholine and like.

Inorganic bases include but not limited to alkali metal hydrides like sodium hydride, potassium hydride and lithium hydride etc; metal carbonates like potassium carbonate, sodium carbonate, caesium carbonate etc; bicarbonates such as potassium hydrogen carbonate, sodium hydrogen carbonate etc; alkali metal alkoxides such as potassium ethoxide, sodium ethoxide, potassium tertiary butoxide, sodium tertiary butoxide; and hydroxides such as, sodium hydroxide, potassium hydroxide and lithium hydroxide etc; and like.

“Organic solvent” used in present invention refers but not limited to "ester solvents" such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents" such as N,N-dimethylacetamide, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcohol solvents" such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, tert-butanol, ethane-1,2-diol, propane-1,2-diol and the like; "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane, anisole and the like; "polar solvents" such as water; and their mixtures.

“Phase transfer catalyst” used in the reaction is selected from tetra butyl ammonium chloride (TBAC), tetra butyl ammonium bromide (TBAB), benzyl tri butyl ammonium chloride (BTBAC), benzyl triethyl ammonium chloride (BTAC), tetra ethyl ammonium bromide (TEAB), tetra ethyl ammonium chloride (TEAC), tetra propyl ammonium bromide (TPAB), cetyl trimethyl ammonium bromide (CTAB), cetyl trimethyl ammonium chloride solution 50% (CTAC) and like.

“Pharmaceutically acceptable salts” refers to carboxylic acid and sulphonic acid salts, more specifically salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; acetic acid, propionic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, oxalic acid, salicylic acid, benzoic acid, methansulfonic acid, isethionic acid, benzenesulfonic acids and like.

PXRD
X-ray powder diffraction (XRPD) was performed on X-Ray powder diffractometer: PanAlytical X'pert Pro powder diffractometer, CuKa radiation, ? = 1.5405980 A. X’Celerator detector active length (2 theta) = 3.3473mm, laboratory temperature 22-25 °C. Zero background sample-holders. Prior to analysis, the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The ground sample was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a microscopic glass slide.

The present invention also provides pharmaceutical compositions comprising the storage stable Ivabradine hydrochloride as amorphous form. In a preferred embodiment, the composition comprises a therapeutically effective amount of amorphous Form of Ivabradine hydrochloride of the present invention with one or more pharmaceutically acceptable carriers, excipients, or diluents. In particular, the compositions comprise the storage stable amorphous form of Ivabradine hydrochloride that do not show any change in the XRD pattern after storage for six months at 25°C and 60% relative humidity. More particularly, the compositions comprise storage stable amorphous Ivabradine hydrochloride that has no detectable quantities of crystalline Ivabradine hydrochloride after storage for six months at 25°C and 60% relative humidity.

Certain specific aspects and embodiments of this invention are described in further detail by the examples given below, which are provided only for the purpose of illustration and are not intended to limit the scope of the invention in any manner.

EXAMPLES
Preparation of N-(2,2-dimethoxyethyl)-2-(3,4-dimethoxyphenyl)acetamide
3,4-Dimethoxy phenyl acetic acid (10 g) was taken in dimethylforamide (30 ml) to get a clear solution and cooled to 0-5 0C. To this 1-Hydroxy benzotriazole (13 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (14 g) was added followed by addition of aminoacetaldehyde dimethyl acetal solution (6 g) in N,N-dimethylformaldehyde (10 ml). After sometime, triethylamine was added drop wise (21 ml) to the solution and stirred for 4-6 h. The resultant mass was charged with water (180 ml) and the product was extracted using dichloromethane (40 ml) and the organic layer was distilled and dried under vacuum to yield title compound.

Preparation of 7,8-dimethoxy-1,3-dihydro-2H-benzazepin-2-one
Acetic acid (40 ml) and N-(2,2-dimethoxyethyl)-3,4-dimethoxyphenylacetamide (10 g) was charged into a round bottomed flask and sulphuric acid (6 ml) was added followed by temperature of the reaction mass was raised to 55 0C. After 2-4 h, the reaction mass was diluted with water (200 ml), filtered and dried and purified using acetone (20 ml) to yield 7,8-dimethoxy-1,3-dihydro-2H-benzazepin-2-one.

Preparation of 7,8-dimethoxy-3-(3-chloropropyl)-1,3-dihydro-2H-3-benzazepin-2-one
In a round bottomed flask, 7,8-dimethoxy-1,3-dihydro-2H-benzazepin-2-one (10 g) and dimethyl sulfoxide (50 ml) and potassium hydroxide (3 g) was taken and slowly added 1-bromo-3-chloro propane solution (8 g in 3 ml of dimethyl sulfoxide). After 4-6 h, the resultant mixture was diluted with water (280 ml), filtered the resultant solid, dried to yield the title compound.

Preparation of 7,8-dimethoxy-3-[3-iodopropyl]-l,3-dihydro-2H-3-benzazepin-2-one
Methyl isobutyl ketone (50 ml) and 7,8-dimethoxy-3-(3-chloropropyl)-1,3-dihydro-2H-3-benzazepin-2-one (10 g) and sodium iodide (6 g) was taken in to a round bottom flask and temperature was raised to 95-100 0C. After 5-7 h, the reaction mass was distilled under reduced pressure and purified using acetonitrile (60 ml) to yield title compound.
Preparation of compound of Formula-3
DMF (35 ml), (S)-N-[(4,5-dimethoxybenzocyclobut-1-yl)-methyl]-N-(methyl)amine hydrochloride (6 g) and potassium carbonate (10 g ) was charged into a RBF. To which slowly added 7,8-dimethoxy-3-[3-iodopropyl]-l,3-dihydro-2H-3-benzazepin-2-one (10 g). After 7-9 h, reaction mass was diluted with water (175 ml) and the product was extracted using ethyl acetate (100 ml), distilled the organic layer and dried to yield compound of Formula-3.

Preparation of Ivabradine Base
Methanol (100 ml), compound of Formula-3 (10 g) and 10% Pd/C (2 g) were taken in an autoclave. The reaction was carried under hydrogen pressure and temperature (55-600C) for 5-7 h. The after completion of reaction the reaction mass was filtered, washed with methanol (40 ml). The organic layer obtained was distilled to yield an oily residue of Ivabradine base.

Preparation of Ivabradine hydrochloride
Ivabradine base (10 g) obtained in earlier step was dissolved in aqueous HCl solution (2 g of Con HCl in 20 ml of water) and filtered. The product was extracted using dichloromethane (40 ml), distilled. The residue obtained was further purified using acetonitrile (20 ml) to yield Ivabradine hydrochloride API.

Preparation of Storage stable amorphous Ivabradine hydrochloride
Methanol (25 ml) and Ivabradine hydrochloride (5 g) was taken in round bottomed flask. The clear solution obtained was spray dried using the conditions i.e. Inlet temperature of 110-140 0C, Aspirator flow rate of 45N M3/hr, Nitrogen Pressure of 1.4-1.5Kg/cm2, Feed Rate (Solution) of 2-10 ml/min, Outlet temperature of 45-60 0C to get the material which on drying gave storage stable amorphous Ivabradine hydrochloride.