WO2012044189A1 - Forme cristalline hydratée inédite de l'erbumine de périndopril, ses procédés de préparation et son utilisation dans des préparations pharmaceutiques - Google Patents

Forme cristalline hydratée inédite de l'erbumine de périndopril, ses procédés de préparation et son utilisation dans des préparations pharmaceutiques Download PDF

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Publication number
WO2012044189A1
WO2012044189A1 PCT/PT2011/000033 PT2011000033W WO2012044189A1 WO 2012044189 A1 WO2012044189 A1 WO 2012044189A1 PT 2011000033 W PT2011000033 W PT 2011000033W WO 2012044189 A1 WO2012044189 A1 WO 2012044189A1
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WO
WIPO (PCT)
Prior art keywords
perindopril erbumine
hydrated form
perindopril
erbumine
crystalline hydrated
Prior art date
Application number
PCT/PT2011/000033
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English (en)
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WO2012044189A8 (fr
Inventor
María Teresa Nogueira Leal da Silva DUARTE
Vânia Mafalda de Oliveira ANDRÉ
Luís Manuel Cunha SILVA
Pedro Paulo De Lacerda E Oliveira Santos
José Manuel Abecassis EMPIS
Original Assignee
Instituto Superior Técnico
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Publication date
Application filed by Instituto Superior Técnico filed Critical Instituto Superior Técnico
Publication of WO2012044189A1 publication Critical patent/WO2012044189A1/fr
Publication of WO2012044189A8 publication Critical patent/WO2012044189A8/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the invention concerns a new hydrated form of perindopril erbumine, as well as its preparation and its use in pharmaceutical preparations.
  • the invention is a new form of perindopril erbumine with formula I .
  • Perindopril with the chemical designation 2-methylpropane- 2-amine- ( 2 S , 3aS-7aS) -1- [ (2S) -2- [ [ (IS) -1-ethoxycarbonyl ) - butyl] amino] propanoyl] octahydro-lff-indole-2-carboxylic acid and of the formula II, is an important ACE (angiotensine conversion enzyme) inhibitor that is used as a successful drug for the treatment of hypertension.
  • ACE angiotensine conversion enzyme
  • Perindopril was first synthesised in 1981 and disclosed in EP49,658, US4,508,729 and PT73755. The synthesis is complex and a stereoisomer mixture is formed, which must be separated.
  • the coupling reagent involved in the formation of the peptide bond is DCC, N, N' -dicyclohexylcarbodiimide .
  • the substance as a pure (S,S,S,S,S) isomer is claimed therein as well as its acceptable pharmaceutical salts.
  • Perindopril is commercially available as a tertbutylamine (erbumine) salt of formula III that was described for the first time in 1988 in patents EP308,341 and PT88, 527. Both claim the synthesis of perindopril and its tertbutylamine (erbumine) salt.
  • Perindopril erbumine is usually commercialized in combination with a diuretic for the treatment of high blood pressure.
  • EPl, 296, 947, EPl, 294, 689/EPl, 676, 839, EP1,296, 948, WO2007/017894 and WO2008/050185 disclose processes of preparation of forms alpha, beta, gamma, eta and theta, respectively.
  • Other polymorphic forms are disclosed in EPl, 636, 185, WO2007/092758 and WO2008/114270.
  • EPl, 647, 547 discloses new crystalline forms of perindopril erbumine monohydrate, perindopril erbumine sesquihydrate and perindopril erbumine anhydrous and a process for their preparation thereof by dissolving perindopril erbumine in water or in water under the addition of a volatile water-miscible polar organic solvent, freezing and lyophilising.
  • WO2007/017893 discloses a new process for the preparation of the monohydrated form of perindopril erbumine.
  • O2005037788A1, O2005068425A1, WO2007020009A1 and WO2007092758 report other forms of perindopril erbumine.
  • the object of this invention is a new hydrated form of perindopril erbumine (1:1:1.25) characterized by different techniques, including powder and single crystal X-ray diffraction (PXRD and SCXRD, respectively) , being useful in the preparation of pharmaceutical products.
  • This new form may be obtained by crystallization from an alcoholic solution or directly by grinding other forms. All the processes described lead to the new form starting from any polymorphic form of perindopril erbumine.
  • the novel process for preparing this new crystalline form of perindopril erbumine hydrate is advantageous as a highly pure product is obtained whose crystal structure is determined by single-crystal X-ray diffraction data and with characteristic 2 ⁇ values in the X-ray powder diffractogram.
  • the final product is not hygroscopic and it is easy to use, facilitating its formulation. All the preparation steps are easy to execute, namely drying and filtration. Very high yields are achieved, close to 100%, occurring losses of product only in the materials used during the process.
  • the new hydrate of perindopril erbumine is obtained from grinding of forms alpha, beta or gamma of perindopril erbumine.
  • the X-ray generator was operated at 50 kV and 30 mA; the X-ray data collection was monitored by SMART program (Bruker, 2003) . All the data were corrected for Lorentzian, polarization and absorption effects using SAINT and SADABS (Bruker, 2003) programs.
  • SIR97 was used for structure solution and SHELXL-97 was used for full matrix least-squares refinement on ⁇ 2 .
  • the present invention as disclosed herein relates to a novel process that leads to the formation of a new hydrated form of the perindopril erbumine salt.
  • the water is in a 1.25 to 1 proportion relatively to the perindopril anion and erbumine cation.
  • This new form is prepared by perindopril erbumine form alpha commercially available or obtainable, for example through the techniques described in patent WO 01/87835 or in patent applications WO 2005/059609 and WO 2005/108365, by dissolution in alcohols containing between one and four carbon atoms.
  • the use of other perindopril erbumine polymorphic forms to synthesize the novel hydrate is also possible.
  • the alcoholic solution of any of these forms is stirred for a few minutes for complete dissolution and left to crystallize by slow evaporation in an open vessel, at room temperature. Crystals are formed after one day.
  • the crystallization process can also be performed by partial removal of the crystallization solvent or by distillation, or by variable temperature, or by addition of a non-solvent, or by seeding or by the combination of any of the techniques mentioned.
  • the new form can be synthesized by mechanochemistry starting from different perindopril erbumine polymorphic forms.
  • echanochemical synthesis consists of grinding perindopril erbumine form a, in the presence of small amounts of ethanol, to obtain the pure new form in a fast and quantitative way. This experimental technique was successfully used in the synthesis of the new hydrated form starting from other crystalline forms.
  • the novel hydrate of perindopril erbumine hydrate thus obtained by the different synthetic pathways previously described exhibits characteristic XRPD pattern with the main peaks observed at the following angles 2 ⁇ : 9.508, 15.315, 15.497, 15.676, 16.102, 21.064, 21.429, 21.677° (only main peaks with intensity higher than 30% are listed) .
  • the asymmetric unit is represented in Figure 2, depicting the relative positioning of the atoms.
  • the determination of the number of hydration water was done by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and confirmed by SCXRD.
  • thermogravimetric analysis was carried out using a Shimadzu TGA 50 apparatus, from room temperature to ca . 300 °C, with a heating rate of 2°C/min, under a continuous nitrogen stream with a flow rate of 20 cm 3 /min; differential scanning calorimetry (DSC) study was performed in a Shimadzu DSC 50 equipment between the room temperature and ca . 160 °C, and using a heating rate of 2°C/min; hot-stage microscopy (HSM) experiments were carried out using a Linkam TP94 device connected to a Linkam LTS350 platinum plate.
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • HSM hot-stage microscopy
  • FIGS 5, 6 and 7 represent the DSC, TGA and HSM results, respectively.
  • TGA ( Figure 6) shows a loss of approximately 5% in the range of 60-120°C and thus the ratio of 1 mol of salt to 1.25 mol of water is confirmed.
  • the release of the crystallization water molecules can be verified in Figure 7 where water starts releasing at 84°C.
  • Stability tests to the form claimed here were performed using slurry techniques with ethanol. After 48 hours the product was identical to the starting material as verified by comparing both powder patterns. The same tests were performed to polymorphic forms alpha, beta and gamma and after 48 hours the product obtained was the new hydrated form claimed here (1:1:1.25), that remained unchangeable after 48 hours.
  • Figure 1 represents the XRPD diffractogram of the claimed perindopril erbumine hydrated form.
  • Figure 2 represents the molecular diagram of the claimed perindopril erbumine hydrated form (stoichiometry 1:1:1.25), obtained from SCXRD.
  • Figure 3 represents ATR-FT-IR spectra of the claimed perindopril erbumine hydrated form.
  • Figure 4 represents the Raman-FT spectra of the claimed perindopril erbumine hydrated form.
  • Figure 5 represents the DSC data for the claimed perindopril erbumine hydrated form.
  • Figure 6 represents the TGA data for the claimed perindopril erbumine hydrated form.
  • Figure 7 represents the HSM images for the claimed perindopril erbumine hydrated form.
  • Figure 8 represents the diffractograms obtained before (a) and after (b) of the slurry experiments using the new hydrated form of perindopril erbumine.
  • Figure 9 represents the powder patterns of the new hydrated of perindopril erbumine after the synthesis (a) and after 12 months in the shelf (b) .
  • Figure 10 represents the perindopril erbumine hydrated form.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne une forme hydratée inédite de l'erbumine de périndopril (I), caractérisée par différentes techniques, dont la diffraction des rayons X sur poudre et la diffraction des rayons X sur un cristal unique. Ladite forme hydratée inédite peut être utilisée dans le cadre de la préparation de composés pharmaceutiques. Elle peut être obtenue par cristallisation à partir d'une solution alcoolique ou directement par broyage d'autres formes cristallines. Toutes les voies de synthèse décrites permettent l'obtention de ladite forme inédite à partir de l'une quelconque des formes polymorphes de l'erbumine de périndopril.
PCT/PT2011/000033 2010-09-29 2011-09-26 Forme cristalline hydratée inédite de l'erbumine de périndopril, ses procédés de préparation et son utilisation dans des préparations pharmaceutiques WO2012044189A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PT105315 2010-09-29
PT105315A PT105315B (pt) 2010-09-29 2010-09-29 Uma nova forma cristalina hidratada de erbumina de perindopril, métodos para a sua preparação e sua utilização em preparações farmacêuticas

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WO2012044189A1 true WO2012044189A1 (fr) 2012-04-05
WO2012044189A8 WO2012044189A8 (fr) 2014-10-16

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016178591A2 (fr) 2015-05-05 2016-11-10 Gene Predit, Sa Marqueurs génétiques et traitement de l'obésité masculine

Citations (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT73755A (fr) 1980-10-02 1981-11-01 Science Union & Cie Procede de preparation d'imino diacides substitues
US4508729A (en) 1979-12-07 1985-04-02 Adir Substituted iminodiacids, their preparation and pharmaceutical compositions containing them
PT88527A (pt) 1987-09-17 1988-10-01 Adir Procede de synthese industrielle du perindopril et des principaux intermediaires de synthese
WO2001087835A1 (fr) 2000-07-06 2001-11-22 Les Laboratoires Servier FORME CRISTALLINE α DU SEL DE TERT-BUTYLAMINE DU PERINDOPRIL
EP1294689A1 (fr) 2000-07-06 2003-03-26 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
EP1296948A2 (fr) 2000-07-06 2003-04-02 Les Laboratoires Servier Nouvelle forme cristalline gamma du sel de tert-butylamine du perindopril, son procede de preparation, et les compositions pharmaceutiques qui la contiennent
WO2005037788A1 (fr) 2003-10-21 2005-04-28 Lupin Ltd. Nouvelle methode de preparation de perindopril erbumine cristalline
WO2005059609A1 (fr) 2003-12-16 2005-06-30 Nitto Denko Corporation Procede de production d'un film birefringent, film optique et dispositif d'affichage d'image dans lequel il est utilise
WO2005068425A1 (fr) 2004-01-14 2005-07-28 Lek Pharmaceuticals D.D. Nouvelle forme cristalline de perindopril
WO2005108365A1 (fr) 2004-05-07 2005-11-17 Glenmark Pharmaceuticals Limited Procedes de preparation d'une forme polymorphe alpha du perindopril erbumine
EP1636185A1 (fr) 2003-06-24 2006-03-22 Azad Pharmaceutical Ingredients AG Nouvelles formes cristallines de perindopril erbumine
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
WO2007017894A2 (fr) 2005-05-05 2007-02-15 Arch Pharmalabs Limited Preparation d'une nouvelle forme cristalline $g(h)(eta) de perindopril erbumine
WO2007020009A1 (fr) 2005-08-12 2007-02-22 Sandoz Ag Nouvelle forme cristalline de perindopril erbumine
WO2007092758A2 (fr) 2006-02-03 2007-08-16 Dr. Reddy's Laboratories Ltd. Formes cristallines de périndopril erbumine
WO2008050185A2 (fr) 2006-10-26 2008-05-02 Glenmark Pharmaceuticals Limited Nouveaux polymorphes de la périndopril erbumine
WO2008114270A1 (fr) 2007-03-22 2008-09-25 Aarti Healthcare Limited Procédé de préparation d'un sel de périndopril erbumine et son ou ses nouveaux polymorphes

Patent Citations (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4508729A (en) 1979-12-07 1985-04-02 Adir Substituted iminodiacids, their preparation and pharmaceutical compositions containing them
EP0049658A1 (fr) 1980-10-02 1982-04-14 Adir Iminodiacides substitués, leur préparation et compositions pharmaceutiques les contenant
PT73755A (fr) 1980-10-02 1981-11-01 Science Union & Cie Procede de preparation d'imino diacides substitues
PT88527A (pt) 1987-09-17 1988-10-01 Adir Procede de synthese industrielle du perindopril et des principaux intermediaires de synthese
EP0308341A1 (fr) 1987-09-17 1989-03-22 Adir Et Compagnie Procédé de synthèse industrielle du périndopril et de ses principaux intermédiaires de synthèse
WO2001087835A1 (fr) 2000-07-06 2001-11-22 Les Laboratoires Servier FORME CRISTALLINE α DU SEL DE TERT-BUTYLAMINE DU PERINDOPRIL
EP1294689A1 (fr) 2000-07-06 2003-03-26 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
EP1296947A1 (fr) 2000-07-06 2003-04-02 Les Laboratoires Servier Forme cristalline alpha du sel de tert-butylamine du perindopril
EP1296948A2 (fr) 2000-07-06 2003-04-02 Les Laboratoires Servier Nouvelle forme cristalline gamma du sel de tert-butylamine du perindopril, son procede de preparation, et les compositions pharmaceutiques qui la contiennent
EP1296947B1 (fr) * 2000-07-06 2004-02-04 Les Laboratoires Servier Forme cristalline alpha du sel de tert-butylamine du perindopril
EP1676839A2 (fr) 2000-07-06 2006-07-05 Les Laboratoires Servier Nouvelle forme cristalline bêta du sel de tert-butylamine du perindopril, son procédé de préparation et les compositions pharmaceutiques qui la contiennent
EP1636185A1 (fr) 2003-06-24 2006-03-22 Azad Pharmaceutical Ingredients AG Nouvelles formes cristallines de perindopril erbumine
WO2005037788A1 (fr) 2003-10-21 2005-04-28 Lupin Ltd. Nouvelle methode de preparation de perindopril erbumine cristalline
WO2005059609A1 (fr) 2003-12-16 2005-06-30 Nitto Denko Corporation Procede de production d'un film birefringent, film optique et dispositif d'affichage d'image dans lequel il est utilise
WO2005068425A1 (fr) 2004-01-14 2005-07-28 Lek Pharmaceuticals D.D. Nouvelle forme cristalline de perindopril
WO2005108365A1 (fr) 2004-05-07 2005-11-17 Glenmark Pharmaceuticals Limited Procedes de preparation d'une forme polymorphe alpha du perindopril erbumine
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
WO2007017894A2 (fr) 2005-05-05 2007-02-15 Arch Pharmalabs Limited Preparation d'une nouvelle forme cristalline $g(h)(eta) de perindopril erbumine
WO2007020009A1 (fr) 2005-08-12 2007-02-22 Sandoz Ag Nouvelle forme cristalline de perindopril erbumine
WO2007092758A2 (fr) 2006-02-03 2007-08-16 Dr. Reddy's Laboratories Ltd. Formes cristallines de périndopril erbumine
WO2008050185A2 (fr) 2006-10-26 2008-05-02 Glenmark Pharmaceuticals Limited Nouveaux polymorphes de la périndopril erbumine
WO2008114270A1 (fr) 2007-03-22 2008-09-25 Aarti Healthcare Limited Procédé de préparation d'un sel de périndopril erbumine et son ou ses nouveaux polymorphes

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016178591A2 (fr) 2015-05-05 2016-11-10 Gene Predit, Sa Marqueurs génétiques et traitement de l'obésité masculine

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Publication number Publication date
PT105315A (pt) 2012-03-29
PT105315B (pt) 2013-01-16
WO2012044189A8 (fr) 2014-10-16

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