Ivabradine hydrochloride form iv

Abstract

Ivabradine hydrochloride Form IV, its pharmaceutical composition, process for its preparation, and its use as therapeutically active ingredient and pharmaceutical compositions containing Ivabradine hydrochloride Form IV.

1 . Ivabradine hydrochloride Form IV with a powder X-ray diffraction comprising the following degrees 2 theta (±0.2) peaks: 8.74, 15.55, 17.17, 19.89, and 24.29, wherein the X-ray diffraction is measured using a CuKα radiation. 
     
     
         2 . Ivabradine hydrochloride Form IV according to  claim 1 , with a powder X-ray diffraction comprising the following degrees 2 theta (±0.2)peaks: 8.11, 8.74, 15.55, 17.17, 19.18, 19.89, 21.82, 22.49, 24.29 and 24.53, where in the X-ray diffraction is measured using a CuKα radiation. 
     
     
         3 . Ivabradine hydrochloride Form IV according to  claim 1 , with a powder X-ray diffraction essentially as depicted in  FIG. 1 . 
     
     
         4 . Ivabradine hydrochloride Form IV according to  claim 1 , having a Differential Scanning calorimetry thermogram which shows one endothermic peak from 153° C. to 157° C. 
     
     
         5 . Ivabradine hydrochloride Form IV according to  claim 1 , having a Differential Scanning calorimetry thermogram essentially as depicted in  FIG. 2 . 
     
     
         6 . A process for preparing ivabradine hydrochloride Form IV according to  claim 1 , which comprises the step of:
 a) slurrying ivabradine hydrochloride in a solvent system, wherein the solvent system comprises toluene, ethanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate and mixtures thereof.   
     
     
         7 . The process according to  claim 6 , wherein the temperature of step (a) is lower than 60° C. 
     
     
         8 . The process according to  claim 6 , wherein the reaction time for performing step (a) is less than 48 h. 
     
     
         9 . The process according to  claim 6 , wherein the proportion in step (a) of liter of the solvent system versus kilogram of ivabradine hydrochloride Form IV is from 5 to 50. 
     
     
         10 . The process according to  claim 6 , further comprising the step of:
 b) isolation of ivabradine hydrochloride Form IV, and   c) drying the isolated ivabradine hydrochloride Form IV under vacuum pressure and at a temperature between 45° C. and 70° C.   
     
     
         11 . A process for preparing ivabradine hydrochloride Form IV according to  claim 6  comprising the steps of:
 i) stirring a solution of ivabradine free base in a solvent system, wherein the solvent system comprises toluene, ethanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate and mixtures thereof; 
 ii) maintaining the solution at a temperature lower than 60° C.; 
 iii) adding a solution of hydrochloric acid to obtain ivabradine hydrochloride; 
 iv) seeding with the ivabradine hydrochloride Form IV; 
 v) isolating the ivabradine hydrochloride Form IV and 
 vi) drying the isolated ivabradine hydrochloride Form IV under vacuum pressure and at a temperature between 45° C. and 70° C. 
 
     
     
         12 . A pharmaceutical composition comprising ivabradine hydrochloride Form IV according to  claim 1 , and at least a pharmaceutically acceptable excipient. 
     
     
         13 . The pharmaceutical composition according to  claim 12  wherein the said composition is in the form of a tablet for oral administration. 
     
     
         14 . The pharmaceutical composition according to  claim 12 , wherein the coating agent is selected from derivatives of cellulose, derivatives of Poly(methylmethacrylate), Polyvinyl alcohol and derivates of Polyvinyl alcohol. 
     
     
         15 . The pharmaceutical composition according to  claim 12 , wherein said composition contains from about 5 mg to about 9 mg of ivabradine hydrochloride Form IV. 
     
     
         16 . A process for the manufacture of the composition according to  claim 12 , characterized in that said process comprises using direct compression, dry granulation and/or wet granulation techniques. 
     
     
         17 . The process, according to  claim 16 , characterized in that the wet granulation process comprises using organic solvents. 
     
     
         18 . A method for the treatment of a disease in a subject in need comprising administering to said subject in need an effective amount of ivabradine hydrochloride Form IV according to  claim 1 . 
     
     
         19 . A method for the treatment of a disease in a subject in need comprising administering to said subject in need an effective amount of a pharmaceutical composition according to  claim 12 . 
     
     
         20 . A method for the treatment of bradycardics, myocardial ischaemia, supraventricular rhythm disturbances, chronic stable angina pectoris in coronary artery disease adults with normal sinus rhythm, myocardial infarct, heart failure and associated rhythm disturbances in a subject in need comprising administering to said subject an effective amount of ivabradine hydrochloride Form IV according to  claim 1 . 
     
     
         21 . A method for the treatment of bradycardics, myocardial ischaemia, supraventricular rhythm disturbances, chronic stable angina pectoris in coronary artery disease adults with normal sinus rhythm, myocardial infarct, heart failure and associated rhythm disturbances in a subject in need comprising administering to said subject an effective amount of a pharmaceutical composition according to  claim 12 .