Polymorphic form of lercanidipine hydrochloride and process for the preparation thereof

1. Lercanidipine hydrochloride substantially in polymorph form V, exhibiting characteristic peaks (expressed in degrees 2θ±0.2°θ) at about 15.1595, about 17.2752, about 19.8836, about 20.7967, and about 21.4870.

2. The lercanidipine hydrochloride substantially in polymorph form V of claim 1 , exhibiting characteristic peaks (expressed in degrees 2θ±0.2°θ) at about 7.5567, about 10.8095, about 12.9422, and about 22.5097; and exhibiting a predominant endotherm peak at about 179.5° C.

3. The lercanidipine hydrochloride substantially in polymorph form V of claim 1 , further characterized by exhibiting characteristic peaks (expressed in degrees 2θ±0.2°θ) at about 11.5702 and about 24.6309.

4. The lercanidipine hydrochloride substantially in polymorph form V of claim 1 , having a purity of equal to or greater than about 98.5%.

5. A pharmaceutical composition comprising a therapeutically effective amount of the lercanidipine hydrochloride substantially in polymorph form V of claim 1 .

6. The pharmaceutical composition of claim 5 , wherein the lercanidipine hydrochloride substantially in polymorph form V is a micronized lercanidipine hydrochloride substantially in polymorph form V having a particle size of less than about 400 microns.

7. A process for the preparation of lercanidipine hydrochloride substantially in polymorph form V, the process comprising:

(a) dissolving lercanidipine hydrochloride in a C 1 -C 12 aliphatic alcohol solvent to obtain a solution;

(b) adding a C 2 -C 12 aliphatic ester solvent to the solution; and

(c) recovering lercanidipine hydrochloride substantially in polymorph form V.

8. The process of claim 7 , wherein the recovering step comprises crystallizing the solution to produce lercanidipine hydrochloride crystals; and drying the lercanidipine hydrochloride crystals to obtain lercanidipine hydrochloride substantially in polymorph form V.

9. The process according of claim 8 , wherein the lercanidipine hydrochloride substantially in polymorph form V is thereafter converted to lercanidipine hydrochloride in an amorphous form.

10. Lercanidipine hydrochloride substantially in polymorph form V, prepared by the process of claim 7 .

11. A process for the preparation of substantially pure lercanidipine hydrochloride substantially in form V, the process comprising:

(a) reacting a solution comprising butanoic acid, 2-[(3-nitrophenyl)methylene]-3-oxo-2-[(3,3-diphenyl propyl)methylamino]-l,l-dimethyl ethyl ester hydrochloride and methylene dichloride, with methyl 3-amino crotonate and n-propanol and adjusting the pH of the solution to about 8 to about 9 with a base;

(b) distilling out n-propanol to obtain a residue;

(c) dissolving the residue in isopropyl acetate;

(d) treating the solution containing isopropyl acetate with a clarifying agent to form a clarified solution;

(e) concentrating the clarified solution to form a concentrated clarified solution; (f) dissolving the concentrated clarified solution in methanol and isopropyl acetate; (g) seeding the solution with a lercanidipine hydrochloride substantially in polymorph form V, and

(h) recovering the lercanidipine hydrochloride substantially in polymorph form V.

12. The process of claim 11 , further comprising:

cooling the reaction mass to a temperature of about 50° C. to about 55° C.;

distilling out n-propanol to obtain a first residue;

dissolving the first residue in n-propanol,

adjusting the pH of the reaction mass using n-propanol/HC1 and distilling off n-propanol to obtain a second residue;

dissolving the second residue in isopropyl acetate and washing with water to obtain a solution;

charcoalizing the solution and distilling off the isopropyl acetate to obtain a third residue;

dissolving the third residue in methanol and isopropyl acetate,

seeding the solution with lercanidipine hydrochloride polymorph form V and filtering the solids; and

drying the solids to obtain lercanidipine hydrochloride substantially in polymorph form V.

13. Lercanidipine hydrochloride substantially in polymorph form V, substantially free of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylic acid 2-[N-(3,3-diphenyl propyl)-N-methylamino]-l,1-dimethyl ethyl propyl di-ester.

14. The pharmaceutical composition of claim 5 , wherein the crystalline form of the lercanidipine hydrochloride is a micronized crystalline form of the lercanidipine hydrochloride having a particle size distribution equal to or less than about 200 microns.

15. The pharmaceutical composition of claim 5 , wherein the crystalline form of the lercanidipine hydrochloride is a micronized crystalline form of the lercanidipine hydrochloride having a particle size distribution equal to or less than about 50 microns.

16. The pharmaceutical com 52position of claim 5 , wherein the crystalline form of the lercanidipine hydrochloride is a micronized crystalline form of the lercanidipine hydrochloride having a particle size distribution equal to or less than about 15 microns.