WO2008120241A2 - Nouveaux solvates alcooliques de périndopril erbumine - Google Patents

Nouveaux solvates alcooliques de périndopril erbumine Download PDF

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Publication number
WO2008120241A2
WO2008120241A2 PCT/IN2008/000202 IN2008000202W WO2008120241A2 WO 2008120241 A2 WO2008120241 A2 WO 2008120241A2 IN 2008000202 W IN2008000202 W IN 2008000202W WO 2008120241 A2 WO2008120241 A2 WO 2008120241A2
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WO
WIPO (PCT)
Prior art keywords
perindopril erbumine
perindopril
erbumine
alcohol
peaks
Prior art date
Application number
PCT/IN2008/000202
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English (en)
Other versions
WO2008120241A3 (fr
Inventor
Ashok Kumar
Satish Rajanikant Soudagar
Nalinnakshya Balaram Panda
Arpana Prashant Mathur
Original Assignee
Ipca Laboratories Limited
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Filing date
Publication date
Application filed by Ipca Laboratories Limited filed Critical Ipca Laboratories Limited
Publication of WO2008120241A2 publication Critical patent/WO2008120241A2/fr
Publication of WO2008120241A3 publication Critical patent/WO2008120241A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Periodopril 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:
  • Periodopril 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:
  • 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.
  • the phrase having "at least one characteristic of Form A 1 refers to a crystalline form of perindopril erbumine that possesses one of the PXRD peaks or peaks in Infra Red spectrum provided herein.
  • 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.
  • FT-IR Fourier Transform Infrared
  • 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 C 5 -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.
  • 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 2 ⁇ 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.
  • 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-C 8 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.
  • 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.
  • hydrocarbon solvent is toluene; especially preferred ester is an acetate solvent such as ethyl acetate.
  • a suitable temperature is meant a temperature which induces the transformation of starting material to product without decomposing any of these compounds.
  • suitable temperatures include, but are not limited to, room temperature and above.
  • 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
  • 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.
  • Form A 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.
  • 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.
  • 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 0 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 0 C to constant weight. Yield 4.2 gm. The XRPD & IR spectra of the sample were recorded and are reproduced in figure 1 to 2.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Peptides Or Proteins (AREA)
  • Indole Compounds (AREA)

Abstract

La présente invention concerne de nouvelles formes polymorphes de périndopril erbumine qui sont des solvates alcooliques, plus particulièrement de nouvelles formes morphologiquement identiques du sel de périndopril erbumine caractérisées par leur motif de diffraction de rayons X sur poudres. La présente invention concerne également des procédés de préparation de telles formes de périndopril erbumine et leurs utilisations dans l'industrie.
PCT/IN2008/000202 2007-03-29 2008-03-28 Nouveaux solvates alcooliques de périndopril erbumine WO2008120241A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN597/MUM/2007 2007-03-29
IN597MU2007 2007-03-29

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WO2008120241A2 true WO2008120241A2 (fr) 2008-10-09
WO2008120241A3 WO2008120241A3 (fr) 2010-11-11

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001083439A2 (fr) * 2000-07-06 2001-11-08 Les Laboratoires Serviers NOUVELLE FORME CRISTALLINE η DU SEL DE TERT-BUTYLAMINE DU PERINDOPRIL, SON PROCEDE DE PREPARATION, ET LES COMPOSITIONS PHARMACEUTIQUES QUI LA CONTIENNENT
WO2001087836A1 (fr) * 2000-07-06 2001-11-22 Les Laboratoires Servier Nouvelle forme cristalline $g(b) du sel de tert-butylamine du perindopril, son procede de preparation, et les compositions pharmaceutiques qui la contiennent
WO2001087835A1 (fr) * 2000-07-06 2001-11-22 Les Laboratoires Servier FORME CRISTALLINE α DU SEL DE TERT-BUTYLAMINE DU PERINDOPRIL
EP1647547A1 (fr) * 2004-10-15 2006-04-19 Diagen Smartno pri Ljubljani, d.o.o. Perindopril erbumine sous forme crystalline hydrate, procédé pour leur préparation et formulations pharmacéutiques leur contenant
WO2007017893A2 (fr) * 2005-05-05 2007-02-15 Arch Pharmalabs Limited Preparation d'une nouvelle forme cristalline de perindopril erbumine monohydrate

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001083439A2 (fr) * 2000-07-06 2001-11-08 Les Laboratoires Serviers NOUVELLE FORME CRISTALLINE η DU SEL DE TERT-BUTYLAMINE DU PERINDOPRIL, SON PROCEDE DE PREPARATION, ET LES COMPOSITIONS PHARMACEUTIQUES QUI LA CONTIENNENT
WO2001087836A1 (fr) * 2000-07-06 2001-11-22 Les Laboratoires Servier Nouvelle forme cristalline $g(b) du sel de tert-butylamine du perindopril, son procede de preparation, et les compositions pharmaceutiques qui la contiennent
WO2001087835A1 (fr) * 2000-07-06 2001-11-22 Les Laboratoires Servier FORME CRISTALLINE α DU SEL DE TERT-BUTYLAMINE DU PERINDOPRIL
EP1647547A1 (fr) * 2004-10-15 2006-04-19 Diagen Smartno pri Ljubljani, d.o.o. Perindopril erbumine sous forme crystalline hydrate, procédé pour leur préparation et formulations pharmacéutiques leur contenant
WO2007017893A2 (fr) * 2005-05-05 2007-02-15 Arch Pharmalabs Limited Preparation d'une nouvelle forme cristalline de perindopril erbumine monohydrate

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WO2008120241A3 (fr) 2010-11-11

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