Novel polymorphic forms of perindopril (l)-arginine and process for the preparation thereof

Abstract

The present invention relates to novel and stable polymorphic forms of Perindopril (L)-Arginine designated as Form γ and amorphous form and processes for their preparation. The present invention also provides the novel polymorph Form γ with greater stability to heat and humidity and can be prepared on large scale by an efficient, economic and reproducible process.

1 . Amorphous form of Perindopril (L)-Arginine. 
     
     
         2 . The amorphous form of Perindopril (L)-Arginine according to  claim 1 , having a powder X-ray diffraction pattern as shown in  FIG. 2 . 
     
     
         3 . The amorphous form of Perindopril (L)-Arginine according to  claim 1  characterized by a glass transition temperature (Tg) at about 96° C. in DSC as shown in  FIG. 3 . 
     
     
         4 . A process for the preparation of amorphous Perindopril (L)-Arginine comprising the steps of:
 a) dissolving polymorphic form γ of Perindopril (L)-Arginine in a solvent,   b) removing the solvent and   c) isolating the amorphous Perindopril (L)-Arginine.   
     
     
         5 . The process according to  claim 4 , wherein the solvent is an alcohol. 
     
     
         6 . The process according to  claim 4 , wherein the solvent is methanol. 
     
     
         7 . The process according to  claim 4 , wherein the solvent is removed by distillation. 
     
     
         8 . A process for the preparation of amorphous Perindopril (L)-Arginine comprising the steps of:
 a) suspending Perindopril free acid in a solvent or mixture of solvents,   b) adding (L)-Arginine and heating the reaction mass to reflux temperature,   c) cooling the solution to 20-30° C. and   d) removing the solvent and isolating amorphous Perindopril (L)-Arginine.   
     
     
         9 . The process according to  claim 8 , wherein the solvent is selected from the group consisting of lower alcohols, dichloromethane, water and mixtures thereof. 
     
     
         10 . The process according to  claim 9 , wherein the lower alcohol is selected from the group consisting of methanol, ethanol and isopropyl alcohol. 
     
     
         11 . The process according to  claim 8 , wherein the solvent is removed by spray drying or by freeze drying. 
     
     
         12 . A process for the preparation of polymorphic form γ of Perindopril (L)-Arginine comprising the steps of:
 a) suspending the amorphous Perindopril (L)-Arginine according to  claim 1  in a solvent, 
 b) distilling the suspension azeotropically at a temperature of about 80-110° C., 
 c) adding an antisolvent and 
 d) isolating polymorphic form γ of Perindopril (L)-Arginine. 
 
     
     
         13 . A process for the preparation of polymorphic form γ of Perindopril (L)-Arginine comprising exposing the amorphous form of Perindopril (L)-Arginine according to  claim 1  to a relative humidity of about 90% for several hours.