NOVEL POLYMORPHIC FORMS OF PERINDOPRIL (L)-ARGININE AND PROCESS FOR THE PREPARATION THEREOF
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.