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. A process for the preparation of polymorphic form γ of Perindopril (L)-Arginine comprising the steps of:
a) dissolving Perindopril free acid in water,
b) adding L-Arginine,
c) removing the water, and
d) isolating polymorphic form γ of Perindopril (L)-Arginine.
2. The process according to claim 1 , wherein the water is removed by freeze drying or spray drying.
3. A process for the preparation of polymorphic, form γ of Perindopril (L)-Arginine comprising the steps of:
a) dissolving Perindopril L-Arginine in a solvent,
b) adding an antisolvent, and
c) isolating polymorphic form γ of Perindopril (L)-Arginine.
4. The process according to claim 3 , wherein the solvent is selected from the group consisting of alcohols, ethers, and polar solvents.
5. The process according to claim 3 , wherein the antisolvent is selected from the group consisting of ester solvents, ketone solvents, and ether solvents.
6. A process for the preparation of polymorphic form γ of Perindopril (L)-Arginine comprising the steps of:
a) suspending Perindopril free acid and L-Arginine in a solvent,
b) heating the reaction mass to the reflux temperature of the solvent,
c) adding an anti-solvent, and
d) isolating polymorphic form γ of Perindopril (L)-Arginine.
7. The process according to claim 6 , wherein the solvent for suspension is selected from the group consisting of hydrocarbons, alcohols, and mixtures thereof.
8. The process according to claim 6 , wherein the antisolvent is selected from the group consisting of acetonitrile, ethers, and mixtures thereof.
9. The process according to claim 4 , wherein the solvent is selected from the group consisting of methanol, 1,4-dioxane, pyridine, and N-methyl pyrrolidone.
10. The process according to claim 5 , wherein the antisolvent is selected from the group consisting of ethyl acetate, acetone, and isopropyl ether.
11. The process according to claim 7 , wherein the solvent for suspension is selected from the group consisting of toluene, methanol, ethanol, isopropanol, butanol, and mixtures thereof.
12. The process according to claim 8 , wherein the antisolvent is selected from the group consisting of acetonitrile, isopropyl ether, diethyl ether, and mixtures thereof.