Specification
CRYSTALLINE FORMS OF PERINDOPRIL ERBUMINE
INTRODUCTION TO THE INVENTION The present invention relates to crystalline forms of perindopril erbumine. More specifically it relates to crystalline Form t:, ("zeta") and Form ^ ("eta") of perindopril erbumine, their combination with pharmaceutically acceptable carriers and processes for their preparation.
Perindopril erbumine is the adopted name for a drug compound having the chemical name (2S,3aS,7aS)-1 -[(S)-N-[(S)-1 -carboxy-butyl]alanyl]hexahydro-2-indolinecarboxylic acid, 1-ethyl ester, compound with tert-butylamine, and being structurally represented by Formula I.
Formula I
Perindopril erbumine is the ethyl ester of a non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor useful for the treatment of hypertension and is commercially available under the brand name ACEON ™ as tablets in 2 mg, 4 mg and 8 mg strengths for oral administration.
U.S. Patent No. 4, 508,729 discloses perindopril and its derivatives and their pharmaceutically acceptable salts, pharmaceutical compositions containing them, processes for their preparation, and their use in the treatment of hypertension.
U.S. Patent No. 4,914,214 describes a process for the preparation of perindopril, and pehndopril erbumine.
International Application Publication Nos. WO 01/87835, WO 01/87836, and WO 01/58868 deschbe crystalline Forms a, s, and y of perindopril erbumine, processes for preparing them and pharmaceutical formulations containing the same.
International Application Publication No. WO 06/0063941 describes perindopril erbumine monohydrate and a process for its preparation.
Processes for the preparation of perindopril and its pharmaceutically acceptable salts have also been described in U.S. Patent Nos. 4,914,214 and 6,835,843, Internationa! Application Publication Nos. WO 05/037788, WO 04/113293, WO 04/046172, and WO 05/068425, and U.S. Patent Application Publication No. 2003/0186896.
Regulatory authorities throughout the world require that all possible crystalline forms of the same active drug compound be synthesized and characterized as completely as possible. There is thus a continuing need to prepare new polymorphic forms of pharmacologically active compounds of commercial interest such as perindopril or its salts, which provide the pharmaceutical formulation scientist with a broader spectrum of crystalline forms of an active ingredient to choose from, based on their differing physiochemical properties.
It is also important that the processes for the preparation of the polymorphic forms be robust and reproducible, so that the processes are easily scaled up in the plant.
The present invention provides crystalline forms of perindopril erbumine, their combinations with a pharmaceutically acceptable carrier, and processes for their preparation, which are robust and reproducible.
SUMMARY OF THE INVENTION The present invention relates to crystalline Form C, and Form r\ of
perindopril erbumine, their combinations with pharmaceutically acceptable
carriers, and processes for their preparation.
One aspect of the present invention provides crystalline Form C, and Form r|
of perindopril erbumine, and their combination with pharmaceutically acceptable
carriers characterized by their X-ray powder diffraction ("XRPD") patterns,
differential scanning calorimetry ("DSC") curves, and infrared ("IR") absorption
spectra.
Another aspect of the present invention provides processes for the
preparation of Form C, and Form r\ of perindopril erbumine and their combinations
with a pharmaceutically acceptable carrier. In an embodiment, a process for the preparation of Form ^ and Form TI of perindopril erbumine and their combination with a pharmaceutically acceptable carrier comprises:
a) providing a solution of perindopril erbumine either alone or in combination with a pharmaceutically acceptable carrier in a suitable solvent;
b) adding an anti-solvent to the solution obtained in step a); and
c) recovering the solid;
Another aspect of the present invention provides an alternative process for the preparation of crystalline Form C, of perindopril erbumine. In an embodiment, an alternative process for preparation of crystalline Form C, of perindopril erbumine comprises:
a) providing a solution of perindopril erbumine in an alcohol solvent; and
b) removing the solvent from the solution obtained in step a).
Yet another aspect of the present invention provides an alternate process for the preparation of Form r| of perindopril erbumine starting from Form C, with or without a pharmaceutically acceptable carrier by subjecting it to pressure.
In a still further aspect, the present invention provides a pharmaceutical composition comprising crystalline Form C^ or Form ri of perindopril erbumine with or without a pharmaceutically acceptable carrier and their combinations with one or more pharmaceutically acceptable carriers, excipients or diluents.
In an embodiment, the invention provides perindopril erbumine having crystalline Form zeta.
In another embodiment, the invention provides perindopril erbumine having crystalline Form eta.
An embodiment of the invention provides a process for preparing perindopril erbumine having crystalline form zeta, comprising removing solvent from a solution comprising perindopril erbumine and ethanol.
A furt:her emodiment of the invention provides a process for preparing perindopril erbumine having crystalline Form zeta, comprising adding an antisolvent to a solution comprising perindopril erbumine and ethanol.
In a further embodiment, the invention provides a process for preparing perindopril erbumine having crystalline Form eta, comprising adding an antisolvent to a solution comprising perindopril erbumine and isopropanol.
A still further embodiment of the invention provides perindopril erbumine having crystalline Form eta, in a molecular dispersion with a pharmaceutically acceptable hydrophobic carrier.
A yet further embodiment of the invention provides a process for preparing perindopril erbumine in a molecular dispersion with a pharmaceutically acceptable hydrophobic carrier, comprising removing solvent from a solution comprising perindopril erbumine and a pharmaceutically acceptable hydrophobic carrier.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is an X-ray powder diffraction pattern of crystalline Form ^ of perindopril erbumine prepared in Example 1.
Fig. 2 is a differential scanning calorimetric curve of crystalline Form C^ of perindopril erbumine prepared in Example 1.
Fig. 3 is an infrared absorption spectrum of crystalline Form ^ of perindopril erbumine prepared in Example 1.
Fig. 4 is an X-ray powder diffraction pattern of crystalline Form r| of perindopril erbumine prepared in Example 6.
Fig. 5 is a differential scanning calorimetric curve of crystalline Form r| of perindopril erbumine prepared in Example 6.
Fig. 6 is an infrared absorption spectrum of crystalline Form r\ of perindopril erbumine prepared in Example 6.
DETAILED DESCRIPTION OF THE INVENTION The present invention relates to crystalline Form C^ and Form r\ of perindopril erbumine, their combinations with pharmaceutically acceptable carriers, and processes for their preparation.
One aspect of the present invention provides crystalline Form C, and Form rj of perindopril and their combinations with pharmaceutically acceptable carriers characterized by their X-ray powder diffraction ("XRPD") patterns, differential scanning calorimetry ("DSC") curves, and infrared ("IR") absorption spectra.
The XRPD data reported herein were obtained using Cu Ka-1 radiation, having the wavelength 1.541 A, and were generated using a Brul
Documents
Application Documents
| # |
Name |
Date |
| 1 |
4031-chenp-2008 pct.pdf |
2011-09-04 |
| 2 |
4031-chenp-2008 form-5.pdf |
2011-09-04 |
| 3 |
4031-chenp-2008 form-3.pdf |
2011-09-04 |
| 4 |
4031-chenp-2008 form-1.pdf |
2011-09-04 |
| 5 |
4031-chenp-2008 drawings.pdf |
2011-09-04 |
| 6 |
4031-chenp-2008 description(complete).pdf |
2011-09-04 |
| 7 |
4031-chenp-2008 correspondence-others.pdf |
2011-09-04 |
| 8 |
4031-chenp-2008 claims.pdf |
2011-09-04 |
| 9 |
4031-chenp-2008 abstract.pdf |
2011-09-04 |