FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"A new method for preparation of Perindopril Erbumine in alpha crystalline form"
2. APPLICANT (S)
(a) NAME: IPCA LABORATORIES LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956 (c) ADDRESS: 48, Kandivli Industrial Estate, Mumbai-400 067
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.

Technical field:
The present invention relates to processes for the production of alpha crystalline form of
i
perindopril erbumine, which is in a class of medications called angiotensin-converting enzyme (ACE) inhibitors
Background of the Invention
Perindopril (Formula IA) and its pharmaceutically acceptable salts, especially the tert. butylamine salt (Formula IB), is an inhibitor of the enzyme that converts angiotensin I (or kininase II), a precursor for formation of angiotensin II enzyme, thereby enables on the one hand prevention of the conversion of the decapeptide angiotensin I to the octapeptide angiotensin II (vasoconstrictor) and on the other hand prevention of the degradation of bradykinin (vasodilator) to inactive peptide. These two actions contribute to the beneficial effects of perindopril or its salts in cardiovascular disorders, especially arterial hypertension and cardiac insufficiency. The use of perindopril in these therapies demands high purity of the final compound in a manufacturing operation.
Perindopril, its preparation and its therapeutic use were first described in European Patent Specification No. 0049658. There are ample literatures available for the preparation of perindopril and its erbumine salt exploring various synthetic alternatives. However there are only a few reports on the production of a stable crystalline form of perindopril erbumine. Among them WO0187835, WO0187836 & WOO 183439 patents disclose that perindopril erbumine can exist in three different polymorphic forms (designated as Form alpha and Form beta and Form gamma) and provides analytical characterization for those polymorphs. Here it is worth mentioning that at least two of these polymorphs, (alpha & beta) were isolated from the same, solvent - ethyl acetate, however, by applying different processing conditions. However it is also reported that preparation of specific alpha form of perindopril erbumine from ethyl acetate is hot consistently reproducible. Patent application Nr. US20050250706 (Glenmark pharmaceuticals) discusses various alternative solvents for preparation of
2

perindopril erbumine in alpha form. This patent makes use of mainly ketonic solvents or its mixture with nitriles for the preparation of alpha form.
Summary of the Invention
The present inventors had discovered that the prior art processes present substantial difficulties in producing alpha crystal form of perindopril erbumine in a consistent manner. The invention, therefore, aims to provide an improved process for making Form alpha of perindopril erbumine.
In accordance with one aspect, the invention provides a process for preparation of crystalline Form alpha of perindopril erbumine, which process includes crystallizing perindopril erbumine in crystalline "Form alpha" from a solvent selected from C 5 - CIO hydrocarbon solvents (aromatic or aliphatic) or its mixtures with esters like ethyl acetate, primary or secondary or tertiary alcohols and mixture of esters with alcohols like 1-butanol. Preferably the solvent for isolation is benzene, toluene, xylene or mixture of toluene & ethyl acetate or mixture of ethyl acetate & benzene under suitable conditions.
Detailed Description of the Invention
Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials, are described.
To describe the invention^ certain terms are defined herein specifically as follows.
3

Unless stated to the contrary, any of the words "including," "includes," "comprising," and "comprises" mean "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims.
The term "isolating" is used to indicate separation or collection or recovery of the compound being isolated in the specified crystalline form.
The term "separating from a solvent" with respect to the crystalline solids described herein means obtaining a solid of specified characteristics from a solution or a partial solution.
The term "treating" means adding or combining or mixing the stated reagent or materials to the thing being treated.
The term "forming a solution" means obtaining a solution of a substance in a solvent in any manner.
The term "inoculating" has the same meaning as the term "seeding," and means adding previously obtained solid to facilitate crystallization. Thus, the term "seeding crystals" with respect to claimed process means crystals/powder of previously obtained crystalline Form alpha of perindopril erbumine.
The term "hydrocarbon" means a solvent containing hydrocarbons. The term does not exclude solvents containing insignificant amounts of other solvents. "Perindopril erbumine" is a tertiary butyl amine salt of (2S, 3aS, 7aS)-l-[(2S)-2-[[(lS)-l-
4

(ethoxycarbonyl) butyl] amino]- 1-oxopropyl] octahydrb-l//rindole-2-carboxylic acid. It has the structural formula:

"Perindopril or perindopril.free acid" is a free species of (2S, 3aS, 7aS)-l-[(2S)-2-[[(lS)-l-
/ -\ .'.
(ethoxycarbonyl) butyl], amino]-1-oxopropyl] octahydro-l//-indole-2-carboxylic acid. It has
*--,<-.■ •■ « i .
the formula:


;—COOH

It should be understood that there exists equilibrium between a free species and salt form of a compound capable of forming salt with bases/acids (e.g., by virtue of having a carboxylic acid functionality in the molecule).
Polymorphic forms of perindopril erbumine are known. See, e.g., PCT applications WO No. WO0187835, WO0187836 & WO01834395. These patents disclose and characterize three polymorphic forms of the drug: Form alpha, Form beta and Form gamma. The WOO 187835 patent describes that the perindopril was not obtained in a stable crystalline form consistently for pharmaceutical applications before.
For the purposes of this description and claims of the present invention, the term "crystalline Form alpha of perindopril erbumine" is the polymorphic form denoted as Form alpha in the WOO 187835 publication. The ' WOO 187835 patent publication is herein also incorporated by reference specifically for the purposes of providing the reference -analytical information
5

(XRD) for Forms alpha, beta and gamma. Identification of solids obtained by the process of the invention can be made by comparing with the reference analytical information provided in the WOO 187835 patent application. Of course, it should be understood that operator, instrument and other similar issues may result in some margin of error with respect to analytical characterization of the solid.
The WOO 187835 patent application describes isolation of crystalline Form alpha of perindopril by dissolution of perindopril erbumine in ethyl acetate by heating until complete dissolution, filter the solution followed by gradual cooling of the ethyl acetate solution to about 60 °C with a cooling rate of about 5-10 °C per hour and thereafter cooled to room temperature that leads to precipitation of the perindopril erbumine salt in alpha crystal form. To obtain Form Beta from the same solvent, a rapid cooling was applied. The inventors of the present invention had found that the use of ethyl acetate does not provide a reliable, consistent methodology to prepare Form alpha. The inventors had recognized that in using ethyl acetate small changes in manufacturing parameters might lead to contamination of the desired solid Form alpha with Form beta impurities.
The inventors, on exploring various process alternatives, for a reliable process solution have found that the use of hydrocarbons or its mixture with ethyl acetate and alcohols or mixtures of ethyl acetate and dioxane as a solvent for isolation permits reliable preparation of Form alpha of perindopril erbumine. Especially preferred hydrocarbons are toluene, benzene and xylene and alcohol is n-butanol. Among ester, ethyl acetate is preferred to be used in combination with hydrocarbons.
Thus, Form alpha of perindopril erbumine may be obtained; from a solution of perindopril erbumine in benzene or toluene or xylene or ethylacetate-toluene or ethylacetate-benzene or ethylacetate - n-butanol or benzene - n-butanol, toluene-n-butanol or any similar cross combinations. The solution of perindopril erbumine may be prepared by mixing perindopril erbumine in the solvent of choice and stirring for dissolution. Preferably a solution is formed under heating at a temperature from ambient temperature to reflux temperature of the solvent.
6

The solution is then allowed to cool to precipitate' the_ perindopril erbumine in alpha crystalline form which can be separated from the solvent by filtration. Alternately, the perindopril erbumine solution may be formed by dissolving perindopril free acid in the solvent and the solution may then be filtered to remove any particulate matter. Once the solution of the perindopril acid is obtained, tertiary butyl amine is added to form the perinopril erbumine salt. The mass may be heated till complete dissolution. The mass is then cooled until crystallization of the solid is complete. The solid is filtered, washed, and dried. In the process, optionally, either before or after tertiary butyl amine addition, the solution may be seeded with previously obtained crystals of the Form alpha. The process conditions are further illustrated in the Examples.
The starting perindopril free acid or perindopril erbumine may be obtained by following any known process disclosed in the literature. The present inventors used samples obtained as per the process disclosed in EP1679072.
Analytical characterization:of the solid(s) obtained in accordance with the process of the invention was carried out by using X-ray powder diffraction using a PANALYTICAL XpertPRO X-Ray machine of Philips make. The X-ray powder diffraction patterns were recorded with Cu K alpha-1 radiation source (voltage of 50 kV; current: 25 mA). The analytical data obtained for the solids were compared with data provided in the WOO 187835 patent application.
The examples provided below are illustrative and are not intended to limit the scope of the claimed invention.
Example 1.
2.0 grams of perindopril erbumine was taken in 18 ml benzene at room temperature. It was then heated until complete dissolution at 65 °C. The solution was then cooled to about 30 degrees and the precipitated crystals were filtered and washed with fresh benzene and dried
7

under vacuum at 30 °C. to constant weight. Yield 1.9 gm. The XRPD of the sample was recorded and found matching with Form alpha.
Example 2.
2.0 grams of perindopril erbumine was taken in a mixture of 30 ml ethyl acetate and 8 ml 1-butanol at room temperature. It was then heated until complete dissolution at 75 °C. The solution was then cooled to about 10 degrees and the precipitated crystals were filtered and washed "with fresh ethyl acetate and dried under vacuum at 25-30 °C. to constant weight. Yield 1.9 gm. The XRPD of the sample was recorded and found matching with Form alpha. Yield 1.2 gm.
Example 3.
2.0 grams of perindopril erbumine was taken in 14 ml toluene at room temperature. It was then heated until complete dissolution at 75 °C. The solution was then cooled to about 30 degrees and the precipitated crystals were filtered and washed with fresh toluene and dried under vacuum at 30 °C. to constant weight. Yield 1.9 gm. The XRPD of the sample was recorded and found matching with Form alpha. Yield 1.9 gm.
Dated this 6th day of November 2006
Dr. Gopakumar G. Nair Agent for the Applicant