WO2008120241A2

WO2008120241A2 - Novel alcohol solvates of perindopril erbumine

Info

Publication number: WO2008120241A2
Application number: PCT/IN2008/000202
Authority: WO
Inventors: Ashok Kumar; Satish Rajanikant Soudagar; Nalinnakshya Balaram Panda; Arpana Prashant Mathur
Original assignee: Ipca Laboratories Ltd
Current assignee: Ipca Laboratories Ltd
Priority date: 2007-03-29
Filing date: 2008-03-28
Publication date: 2008-10-09
Anticipated expiration: 2009-09-29
Also published as: WO2008120241A3

Abstract

The present invention discloses novel polymorphic forms of perindopril erbumine that are alcohol solvates, more particularly novel morphologically identical forms of perindopril erbumine salt characterized by powder X-ray diffraction pattern. The present invention further discloses processes for preparing such forms of perindopril erbumine and its use in industry.

Description

"NOVEL ALCOHOL SOLVATES OF PERINDOPRIL ERBUMINE"

Technical Field of invention:

The present invention relates to novel polymorphic forms of perindopril erbumine that are alcohol solvates. More particularly, it relates to novel morphologically identical forms of perindopril erbumine salt characterized by powder X-ray diffraction pattern. The present invention also relates to processes for preparing such forms 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) is chemically designated as (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 is 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 WOO 187835, WOO 187836 & 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 form of perindopril erbumine from organic solvents is not consistently reproducible. Patent application US20050250706 (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 2004/1 13293 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 structurally different forms, which are alcohol solvates. The alcohols solvates share a common physical morphology as characterized by their identical X-ray powder diffraction patterns. Thus the present invention provides a substantially pure morphologically identical forms of perindopril erbumine characterized by X-Ray diffraction analysis, which are perindopril erbumine alcohol solvates, hereinafter referred - to as the compound of the invention. These solvates can be obtained as a well defined compound or composition of matter and is herein after designated as Form A. Alcohol residue present in the novel solvates are preferably, 1-pentanol, 1-heptanol, 1-octanol, 1- hexanol, cyclopentanol, cyclohexanol or similar alcohols or their mixture thereof. The present invention also provides a process to obtain and a method of differentiating the novel solvates of perindopril erbumine from other forms of perindopril. The compound(s) of the present invention are appeared to be stable under normal conditions. The compound of the invention is also easier to characterize because it exists in a well defined state, with a common X-Ray diffraction pattern irrespective of the character of the alcohol residue present. 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 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.

Brief Description of the Drawings:

Fig.l shows representative X-Ray Powder Diffractogram of an exemplary batch of Form A of perindopril erbumine obtained in accordance with the invention. Fig 2. shows the Infra -Red spectra of Form A of perindopril erbumine cyclohexanol solvate 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.

"Perindopril erbumine" is a tertiary butyl amine salt of (2S, 3aS, 7aS)-l-[(2S)-2-[[( IS)-I- (ethoxycarbonyl) butyl] amino]- 1-oxopropyl] octahydro-lH-indole-2-carboxylic acid. It has the structural formula:

Formula IB

"Perindopril or perindopril free acid" is a free species of (2S, 3aS, 7aS)-l-[(2S)-2-[[(lS)- l-(ethoxycarbonyl) butyl] amino]- 1-oxopropyl] octahydro-lH-indole-2-carboxylic acid. It has the formula:

Formula IA

For the purposes of this description and claims of the present invention, the phrase "Perindopril erbumine 'Form A' refers to an alcohol 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. This phrase encompasses all alcohol solvates [or alcohol adduct] of perindopril erbumine that substantially possess the XRPD diagram disclosed in the present invention. As used herein, the phrase having "at least one characteristic of Form A¹, 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 was 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. 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 X'pertPRO X-Ray machine of Philips make. The X-ray powder diffraction patterns were recorded with Cu K alpha radiation source (voltage of 45kV; current: 40 mA). The step scan mode was performed with a step size of 0.008°, at a scan rate of 14.6 sec/step.

The present inventors have noted as indicated in the disclosure of WOOl 87835/36 applications, that perindopril was not obtained in a crystalline form in a consistent manner for pharmaceutical applications before. The new perindopril erbumine alcohol solvates 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(s) 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 with specific peaks. These characteristics are not exhibited by any other form of perindopril erbumine and accordingly, the alcohol solvate forms of the present invention are easily distinguishable from any other crystal form of the perindopril erbumine disclosed in prior art. The compound(s) of the invention is characterized as being amorphous or partly crystalline or highly crystalline solvate of perindopril erbumine with an alcohol. The alcohols forming the novel crystals and share common X- Ray diffraction pattern are selected from, but not limited to, linear or branched chain or cyclic alcohol having C₅-Cg carbons, such as 1 -pentanol, 1-hexanol, 1-heptanol, 1- octanol, cyclopentanol, cyclohexanol or similar alcohols or their mixture thereof . The most preferred alcohol is cyclohexanol.

Thus, the character of this new compound(s) (Form A) is confirmed by PXRD patterns and FT IR spectra obtained from a sample thereof which are provided as FIGS. 1 to 2 respectively. The representative 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 2Θ angles ± 0.30. More specifically, the XRPD pattern shows characteristic peaks at 5.62, 8.18, 8.70, 9.04, 11.22, 14.1 1, 16.38, 16.86, 17.45 19.69, 21.97, 22.55, and 23.55 ± 0.30 degrees 20 angles ± 0.30.

The novel compounds or forms of perindopril erbumine designated as Form A is further characterized by FT-IR spectra having peaks at about 3330, 1626, 1200, 1 173, and 1148 cm-1, which are characteristic for the present form A.

The new compounds of the present invention are selected from 1 -pentanol solvate of perindopril erbumine, 1-heptanol solvate of perindopril erbumine, 1 -octanol solvate of perindopril erbumine, 1-hexanol solvate of perindopril erbumine, cyclopentanol solvate of perindopril erbumine, cyclohexanol solvate of perindopril erbumine or mixture of said alcohol solvates. The X-Ray diffraction pattern, representative of the new compounds of the present invention is given in figure 1.

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 a linear or branched chain or cyclic alcohol having Cs-C₈ carbons, optionally in presence of an organic solvent to form a reaction solution at a suitable temperature for a suitable time; and ii) recovering respective novel alcohol solvate of perindopril erbumine from the reaction solution. Said alcohol may be selected from 1-pentanol, 1-heptanol, 1- octanol, 1-hexanol, cyclopentanol, cyclohexanol or similar alcohols or their mixture thereof. In a second process variant, preparation of perindopril erbumine comprises i) treating perindopril free acid with tertiary butyl amine in a linear or branched chain or cyclic alcohol having Cs-Cg carbons alcohol, in presence or absence of an organic solvent to form a reaction solution at a suitable temperature for a suitable time and ii) recovering respective novel alcohol solvate of perindopril erbumine from the reaction solution. Said alcohol may be selected from 1-pentanol, 1-heptanol, 1-octanol, 1-hexanol, cyclopentanol, cyclohexanol or similar alcohols or their mixture thereof.

The organic solvents may be selected from, but not limited to, hydrocarbon solvents, ester solvent, ketone solvent or an alcohol. Especially preferred hydrocarbon solvent is toluene; especially preferred ester is an acetate solvent such as ethyl 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 amount of alcohol is not very crucial and will depend on the process conversion & conditions desired. Equimolar quantities or excess of said alcohols such as cyclohexanol with respect to starting perindopril erbumine is especially preferred for obtaining a complete conversion, for example into a cyclohexanol solvate of perindopril erbumine.

The compound(s) of the present invention is recovered by conventional techniques such as solvent elimination or filtration or centrifugation. The process conditions are further illustrated in the Examples.

The compound is also useful as an intermediate for obtaining the stable alpha form of perindopril erbumine. The conversion process comprises treatment of the compounds of the present invention in presence of organic solvent. The preferred organic solvent is ethyl acetate. 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(s) which are alcohol solvates of perindopril erbumine designated as "Form A" 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 present invention encompasses any pharmaceutical composition comprising a representative copy of Powder X-Ray diffraction as disclosed in the present invention.

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 EP 1679072.

The examples provided below are illustrative and are not intended to limit the scope of the claimed invention.

Examples:

Example 1 : Perindopril erbumine cyclohexanol solvate: 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 ⁰C. 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 ⁰C to constant weight. Yield 4.2 gm. The XRPD & IR spectra of the sample were recorded and are reproduced in figure 1 to 2.

Example 2: Perindopril erbumine cyclohexanol solvate:

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 about 65 ⁰C. 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 ⁰C. to constant weight. Yield 3.7 gm. The XRPD of the sample was recorded and found matching with Form A.

Example 3: Perindopril erbumine cyclohexanol solvate from perindopril free acid:

2.0 grams of perindopril free acid was taken in 30 ml ethylacetate at room temperature. To this 0.44 gm tertiary butyl amine and 6 ml cyclohexanol were added and the mixture was then heated until complete dissolution at 70 ⁰C. The solution was then cooled to about 30 degrees and the precipitated crystals were filtered and dried under vacuum at 40 ⁰C. to constant weight. Yield 1.8 gm. The XRPD of the sample was recorded and found matching with that of figure 1.

Example 4. Perindopril erbumine octanol solvate:

2.0 grams of perindopril erbumine was taken in a mixture of 15 ml of ethyl acetate and 5 ml of 1-octanol at room temperature. It was then heated until complete dissolution at about 60 ⁰C. The solution was then cooled to about 30 degrees and the precipitated crystals were filtered and dried to constant weight. Yield 1.8 gm. The XRPD of the sample was recorded and found matching with Form A. Example 5. Perindopril erbumine heptanol solvate:

2.0 grams of perindopril erbumine was taken in a mixture of 5 ml of toluene and 5 ml of 1 -heptanol at room temperature. It was then heated until complete dissolution at about 55 ⁰C. The solution was then cooled to about 10 degrees and the precipitated crystals were filtered and dried to constant weight. Yield 0.7 gm. The XRPD of the sample was recorded and found matching with Form A.

Example 6. Perindopril erbumine pentanol solvate:

2.0 grams of perindopril erbumine was taken in a mixture of 5 ml of ethyl acetate and 5 ml of 1 -pentanol at room temperature. It was then heated until complete dissolution at 60 ⁰C. The solution was then cooled to about 30 degrees and the precipitated crystals were filtered and dried to constant weight. Yield 1.8 gm. The XRPD of the sample was recorded and found matching with Form A.

Claims

We Claim,

1. Perindopril erbumine alcohol solvates.

2. Perindopril erbumine having a powder X-Ray diffraction pattern (PXRD) containing peaks at about 5.62, 11.22, 16.38, 16.86, 19.69 and 21.97 degrees 2Θ angles ± 0.30.

3. Perindopril erbumine according to claim 1 to 2, wherein a powder X-Ray diffraction pattern (PXRD) of said perindopril erbumine possess characteristic peaks at 5.62, 8.18, 8.70, 9.04, 1 1.22, 14.1 1, 16.38, 16.86, 17.45 19.69, 21.97, 22.55, and 23.55 ± 0.30 degrees 2Θ angles ± 0.30.

4. Perindopril erbumine according to any one of the preceding claim, wherein the perindopril is further characterized by peaks in an Infra-Red spectrum at about 3330, 1626, 1200, 1 173, and 1 148 cm- 1.

5. Perindopril erbumine according to any one of the preceding claim is designated as "Form A".

6. Perindopril erbumine according to any one of the preceding claim, wherein the alcohol is selected from a linear or branched chain or cyclic alcohol having C₅-C₈ Carbon atoms.

7. Perindopril erbumine according to claim 6, wherein the alcohol is 1-pentanol, 1- heptanol, 1-octanol, 1-hexanol, cyclopentanol, and cyclohexanol.

8. A crystalline perindopril erbumine as claimed in claims 1 to 7 made by a process comprising the steps of: a. contacting perindopril or its erbumine salt in a linear or branched chain or cyclic alcohol having C₅-C₈ Carbon atoms; b. optionally adding tertiary butyl amine to step a) mixture c. agitating the mixture for suitable period; and d. separating said perindopril erbumine.

9. The process as claimed in claim 8, wherein the processing is in presence of an organic solvent.

10. The process as claimed in claim 9, wherein said organic solvent is selected from, hydrocarbon solvents, ester solvent, ketone solvent or an alcohol.

1 1. A process to prepare Alpha form of perindopril erbumine comprising subjecting the compounds according to claim 1 to 2 to processing in presence of an organic solvent.

12. A process according to claim 10, wherein the organic solvent is ethyl acetate.

13. A pharmaceutical composition comprising perindopril erbumine exhibiting a powder X-Ray diffraction pattern (PXRD) containing one or more peaks at near 5.62, 11.22, 16.38, 16.86, 19.69 and 21.97 degrees 2Θ ± 0.30.