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:
"Novel alcohol solvate of Perindopril erbumine"
2. APPLICANT
(a) NAME: IPCA LABORATORIES LIMITED
(b) NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: 48, Kandivli Industrial Estate, Mumbai - 400 067,
Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention.

Technical field:
The present invention relates to a novel polymorphic form of perindopril erbumine that is an alcohol solvate. More particularly, it relates to novel cyclohexanol solvate form of perindopril erbumine salt. The present invention also relates to processes for preparing such form of perindopril erbumine and its use in industry. Perindopril erbumine is a drug falls in a -
class of medications called angiotensin-converting enzyme (ACE) inhibitors.
Background of the Invention
Perindopril (Formula IA), chemical name is (2S,3aS,7aS)-((2-(l-(ethoxycarbonyl)-(S)-butylamino)-(S)-propionyl)octahydro-indole-2- carboxylic acid 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 literature 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 & WO0183439 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 form of perindopril erbumine from organic solvents is not consistently reproducible. Patent application US20050250706
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(Glenmark pharmaceuticals) discusses various alternative solvents for preparation of perindopril erbumine in alpha form. Other forms are reported in EP 1294689 A, EP 1296948 and WO 2004/113293 patent applications which are designated beta gama, delta and omega forms respectively. EP 1647547 patent application discloses hydrated forms of perindopril erbumine. The stability data of the reported forms are not reported. Therefore there is a need in the art to search new forms of perindopril erbumine, which are stable to storage and handling.
Summary of the Invention:
The prior art processes presents substantial difficulties in producing the crystal forms such as alpha, beta and gamma forms of perindopril erbumine in structurally pure form in a consistent manner. It has now surprisingly been found that the Perindopril erbumine occurs in a structurally different form, which is an alcohol solvate. Thus the present invention provides a substantially pure perindopril erbumine cyclohexanol solvate, preferably a cyclohexanol monosolvate, hereinafter referred to as the compound of the invention. This cyclohexanol solvate can be obtained as a well defined compound and is herein after designated as Form A. The compound of the present invention can exists in amorphous, partly crystalline or completely crystalline forms. Partly crystalline or highly crystalline form is especially preferred. The present invention also provides a process to obtain and a method of differentiating the cyclohexanol solvate of perindopril erbumine from other forms of perindopril. The compound of the invention is advantageous because it is more stable and well defined than the corresponding morphologically different perindopril erbumine compounds in prior art and is therefore easier to handle and store. The compound of the invention is also easier to characterize because it exists in a well defined state. Additionally, the compound of the invention is easier to synthesize in a reproducible manner and thereby easier to handle in a full scale production. The compound is also useful as an intermediate for obtaining the most stable alpha form of perindopril. The compounds are useful for pharmaceutical application and thus the invention includes pharmaceutical compositions containing the compound of the present invention.
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Brief Description of the Drawings:
Fig.l shows an X-Ray Powder Diffractogram of an exemplary batch of Form A of perindopril erbumine obtained in accordance with the invention.
Fig. 2 shows Infra -Red spectra of Form A of perindopril erbumine obtained in accordance with the invention.
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.
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 of the invention being isolated in the specified form.
The term "separating from a solvent" with respect to the 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 things being treated.
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The term "forming a solution" means obtaining a solution of a substance in a solvent in any manner. It encompasses partial solutions.
The term 'stable' as used herein, refers to the tendency to remain substantially in the same physical form for at least a month, preferably at least 6 months, more preferably at least a year, still more preferably at least 3 years, even still more preferably at least 5 years, when stored under ambient conditions (20 °C/60% RH) without external treatment. Substantially the same physical form in this context means that at least 70%, preferably at least 80% and more preferably at least 90% of the crystalline form remains.
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-(ethoxycarbonyl) butyl] amino]-1-oxopropyl] octahydro-l//-indole-2-carboxylic acid. It has the structural formula:

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"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 the formula:


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).
For the purposes of this description and claims of the present invention, the phrase "Perindopril erbumine 'Form A' refers to a cyclohexanol solvate form of perindopril erbumine, wherein the letter 'A', is referring to a crystalline form of Perindopril erbumine that one of skill in the art can identify as a distinct entity distinguishable from other crystalline forms of perindopril erbumine based on the characterization details provided herein with the present invention. As used herein, the phrase having "at least one characteristic of Form A', refers to a crystalline form of perindopril erbumine that possesses one of the PXRD peaks or peaks in Infra Red spectrum provided herein. For example, a single or a combination of PXRD peaks which is not found in another crystalline form of perindopril is enough to show at least one of the characteristics of Form 'A' of perindopril erbumine, the compound of the present invention. A single or a combination of peaks in an FT IR spectrum provided herein with this invention may also serve the same purpose.
Identification of solids obtained by the present invention can be made by methods known in the art per se such as X-Ray powder diffraction, Fourier Transform Infrared (FT-IR) spectra and 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 FTIR and XRPD methods used for the identification and characterization of the novel form of perindopril erbumine are described below:
a) FT-IR spectral analysis
FTIR spectra of novel form were recorded directly on untreated powder by means of spectrometer. Spectra was recorded at room temperature from 4000 cm-1 to 650 cm-1, for each sample 32 scans were collected at a resolution of 4 cm-1.
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b) X-ray powder diffraction studies.
Analytical characterization of the compound according to 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 step scan mode was performed with a step width of 0.02 °, at a scan rate of 0.5 step/s
The present inventors have noted as indicated in the disclosure of WO0187835/36 applications, that perindopril was not obtained in a crystalline form in a consistent manner for pharmaceutical applications before. The perindopril erbumine cyclohexanol solvate obtained according to the present invention is substantially stable and free from other forms of perindopril erbumine such as those described in prior art.
The compound of the invention is characterized by the positions of the major peaks in the X-ray powder diffractogram, but may also be characterized by conventional FT-IR spectroscopy and OVI (Organic volatile impurities). These characteristics are not exhibited by any other form of perindopril erbumine and accordingly, the cyclohexanol solvate form of the present invention is easily distinguishable from any other crystal form of the perindopril erbumine disclosed in prior art. The compound of the invention is characterized as being amorphous or partly crystalline or highly crystalline solvate of perindopril erbumine with cyclohexanol in about 1:1 ratio of individual molecules arranged in the unit cell.
Thus, the character of this new form (Form A) is confirmed by PXRD patterns and FT IR spectra obtained from a sample thereof which are provided as Figures 1 to 2 respectively. The PXRD pattern shows at least one characteristic and exclusive peak at about 5.62 degrees 2 theta. More particularly the PXRD pattern shows characteristic and exclusive peaks at 5.62, 11.22, 16.38, 16.86, 19.69 and 21.97 degrees 20 angles. More specifically, the XRPD pattern shows characteristic peaks at 5.62, 8.18, 8.7, 9.04, 11.22, 14.11, 15.93, 16.38, 16.86, 17.45 19.69,21.97,22.55,23.17, and 23.55 degrees 20 angles.
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The novel form of perindopril erbumine Form A is further characterized by FT-IR spectra having peaks at 3330, 1626, 1200, 1173, and 1148 cm-1, which are characteristic for the present form A.
The novel form of perindopril erbumine 'Form A' is further characterized by the content of cyclohexanol as analyzed by OVI. The cyclohexanol content is found to be in the range of about 18-19% by weight of perindopril erbumine. Especially preferred compound of the present invention is cyclohexanol monosolvate of perindopril erbumine having a PXRD pattern as substantially given in figure 1.
The main peaks, with positions and relative intensities, have been extracted from the diffractogram in FIG. 1 and are given below in table 1. The relative intensities are less reliable and some additional very weak peaks found in the diffractogram have been omitted from table 1.
Table 1

2q values in degrees d spacing Percentage relative intensity
5.62 15.70 79.12
8.18 10.79 38.28
8.70 10.14 46.76
9.04 9.77 45.20
11.22 7.87 67.08
14.11 6.26 30.23
15.93 5.55 46.88
16.38 5.40 32.29
16.86 5.25 100
17.45 5.07 33.82
19.69 4.50 31.74
21.97 4.04 81.59
22.55 3.93 46.71
23.17 3.83 28.99
23.55 3.77 31.42
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In a further aspect, the present invention provides processes for the preparation of the perindopril erbumine Form A which comprises; i) contacting perindopril erbumine of any form with cyclohexanol or in an organic solvent containing cyclohexanol to form a reaction solution at a suitable temperature for a suitable time and ii) recovering cyclohexanol solvate of perindopril erbumine from the reaction solution.
In a second process variant, preparation of perindopril erbumine comprises i) treating perindopril free acid with tertiary butyl amine in cyclohexanol or in an organic solvent containing cyclohexanol to form a reaction solution at a suitable temperature for a suitable time and ii) recovering cyclohexanol solvate of perindopril erbumine from the reaction solution.
The organic solvents may be selected from, but not limited to, hydrocarbon solvents, ester solvent, ketone solvent or an alcohol. An especially preferred hydrocarbon solvent is toluene; especially preferred ester is an acetate solvent such as ethyl acetate or butyl acetate.
By a suitable temperature is meant a temperature which induces the transformation of starting material to product without decomposing any of these compounds. Examples of such suitable temperatures include, but are not limited to, room temperature and above. By a suitable time is meant a time that results in high conversion of the starting material into product without causing any decomposition of either compounds, i.e. results in a good yield. This suitable time will vary depending on the temperature used in a way well known to people in the art. The higher the temperature, the shorter time is needed to give the desired conversion. The amount of cyclohexanol is not crucial and will depend on the process conversion & conditions desired. Equimolar quantities or in excess of cyclohexanol with respect to starting perindopril erbumine is especially preferred for obtaining a complete conversion to cyclohexanol monosolvate of perindopril erbumine.
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The cyclohexanol solvate is recovered by conventional techniques such as solvent elimination or filtration or centrifugation. The process conditions are further illustrated in the Examples.
Perindopril erbumine has been indicated for use in the following indications: hypertension, cardiovascular diseases and acute myocardial infarction. It may be used alone or concomitantly with other classes of antihypertensive agents (ACE inhibitors or calcium channel blockers) like amlodipine or its pharmaceutical salts
In a further aspect the invention thus provides new compound which is cyclohexanol solvate of perindopril erbumine for use in treating hypertension, congestive heart failure and acute myocardial infarction. In the practice of the invention, the most suitable route of administration as well as the magnitude of a therapeutic dose of perindopril erbumine Form A in any given case will depend on the nature and severity of the disease to be treated. The dose, dose frequency may also vary according to the age, body weight and response of the individual patient.
The invention thus provides pharmaceutical compositions containing perindopril erbumine Form A which may optionally contain other crystalline forms and/or other active pharmaceutical drugs such as ACE's. In addition to the active ingredient(s), the pharmaceutical compositions of the present invention can contain one or more commonly used pharmaceutical excipients. Excipients are added to the composition for a variety of purposes.
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.
The examples provided below are illustrative and are not intended to limit the scope of the claimed invention.
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Example:
Example 1
5.0 grams of perindopril erbumine was taken in 50 ml cyclohexanol at room temperature. It was then heated until complete dissolution at about 60 °C. The solution was then cooled to about 30 degrees and the precipitated crystals were filtered and washed with fresh cyclohexanol and dried under vacuum at 40 °C. to constant weight. Yield 4.2 gm. The XRPD & IR spectra of the sample were recorded and are reproduced in figure 1 to 3.
Example 2
4.0 grams of perindopril erbumine was taken in a mixture of 36 ml of toluene and 4 ml of cyclohexanol 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 5 ml cyclohexanol/toluene mixture and dried under vacuum at 40 °C. to constant weight. Yield 3.7 gm. The XRPD of the sample was recorded and found matching with Form A.
Example 3
2.0 grams of perindopril free acid was taken in 30 ml ethylacetate at room temperature. To this 0.44 ml teriary butyl amine and 6 ml cyclohexanol were added and the mixture was then heated until complete dissolution at 70 °C. The solution was then cooled to about 30 degrees and the precipitated crystals were filtered and dried under vacuum at 40 °C. to constant weight. Yield 1.8 gm. The XRPD of the sample was recorded and found matching with that of figure 1.
Dated this 29th day of March, 2007
Dr. Gopakumar G. Nair Agent for the applicant
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