EP1660451A2 - Nouvelles formes cristallines de carvedilol - Google Patents

Nouvelles formes cristallines de carvedilol

Info

Publication number
EP1660451A2
EP1660451A2 EP04775682A EP04775682A EP1660451A2 EP 1660451 A2 EP1660451 A2 EP 1660451A2 EP 04775682 A EP04775682 A EP 04775682A EP 04775682 A EP04775682 A EP 04775682A EP 1660451 A2 EP1660451 A2 EP 1660451A2
Authority
EP
European Patent Office
Prior art keywords
carvedilol
crystalline carvedilol
ethyl acetate
carvedilol form
crystalline
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04775682A
Other languages
German (de)
English (en)
Inventor
Rok Zupet
Marija Grcman
Matej Smrkolj
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
KRKA dd
Original Assignee
KRKA Tovarna Zdravil dd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by KRKA Tovarna Zdravil dd filed Critical KRKA Tovarna Zdravil dd
Publication of EP1660451A2 publication Critical patent/EP1660451A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system

Definitions

  • the invention relates to the field of physical and synthetic organic chemistry. It relates to the process for crystallization of novel solid crystalline modification of carvedilol or solvate thereof, having an excellent efficacy as pharmaceuticals.
  • Carvedilol ( ⁇ )- 1 -(9H-carbazolyl-4-oxy)-3-[[2-(2-methoxyphenoxy) ethyl]amino]-2-propanol, is a non selective ⁇ -adrenergic blocker with ⁇ l-blocking activity.
  • Solid drug formulations are useful in the treatment of hypertension, congestive heart failure and angina. It is used in pharmaceutical compositions as a racemic mixture of both enantiomers, having structural formula:
  • Carvedilol possesses lively polymorphic behaviour. Depending to the method of isolation, several different solid crystalline modifications are identified. Several stable modifications and some stable and semi stable hydrates, solvates and salts of the drug were discovered and characterized by many development groups. The solid polymorphs, pseudo polymorphs, hydrates, solvates and salts are well analytically characterized. Materials could be successfully distinguished comparing their IR, Raman, XRPD, DSC or solid NMR spectra and melting points.
  • EP 0 893 440 Al discloses the crystallization of carvedilol from methanol. Thermodynamically more stable modification I was isolated.
  • WO 02/00216 and WO 03/005970 describe stable modification HI of carvedilol. According to the experiments disclosed in the cited applications, polymorph HI could be prepared by crystallization from water or precipitation from organic solvent by addition of water used as anti-solvent.
  • WO 02/00216 describes also new solid modifications of carvedilol, designated as forms IV and V, which could be prepared by isolation from organic solvents with precipitation by addition of cyclohexane or hexane.
  • WO 03/029214 Al describes new modification of carvedilol, which is hemihydrate and prepared by dissolving spray congealed material in water or methanol/water as crystallization media.
  • WO 03/059807 A2 describes a crystalline solid of carvedilol solvate, designated as form VI.
  • Figure 1 FT-IR spectrum of crystalline form VII.
  • Figure 2 DSC curve of crystalline form VH.
  • Figure 3 XRPD pattern of crystalline form VII.
  • Figure 4 FT-IR spectrum of crystalline form LX.
  • Figure 5 DSC curve of crystalline form IX.
  • Figure 6 XRPD pattern of crystalline form LX.
  • DSC scans were recorded on Perkin Elmer DSC 7 Scanning calorimeter. Samples of approx. 3 mg were scanned between 30 and 130°C at heating rate of 10°C/min under nitrogen atmosphere in aluminium DSC open pans.
  • X-ray powder diffraction patterns were obtained by Phillips PW3040/60 X'Pert PRO diffractometer equipped by X'Celerator detector; CuK ⁇ radiation 1,541874A. The 2 ⁇ range was 4-30°, and step size was 0,0167°. Detailed description of the invention
  • a process for the preparation of crystalline carvedilol is performed in ethyl acetate as a crystallization solvent or ethyl acetate with added water in miscible mixtures, as a crystallization solvent.
  • the present invention further provides processes for crystallization, comprising dissolving carvedilol in concentrations from 1-40% w/w in heated solvents, as ethyl acetate or ethyl acetate/water mixtures, and cooling the crystallization mixtures to lower temperatures than the boiling point of the crystallization mixtures to provoke crystallization of carvedilol solid crystalline modifications.
  • Carvedilol could be successfully crystallized from ethyl acetate using the difference in solubility of the drug, which is higher in warm or boiling ethyl acetate and lower in cooled ethyl acetate, where at the temperature lower than 0°C, the solubility of carvedilol is lower than 0.5% w/w.
  • Crystallization of solid crystalline drug from solutions containing 25-30% w/w of carvedilol starts at temperatures higher than 60°C.
  • Crystallization of solid crystalline drug from solutions containing 2-10% w/w of carvedilol starts at temperatures from 20-40°C.
  • Carvedilol prepared by crystallization from 2% w/w carvedilol ethyl acetate solution contains
  • the solvated form is well stable in suspension, and as well could be isolated and characterized. At ambient temperature it is only temporarily stable and in a week time it re crystallizes to more stable solid modifications.
  • meta-stable solvated form is transformed to modification ⁇ , HI or to a mixture of both modifications.
  • the present invention further provides the novel crystalline solid modification of carvedilol, non-solvated form, designated as form VH.
  • the non-solvated crystalline form VII is characterized by the melting point 68.8-72.4°C.
  • the form VII exhibits IR spectrum, Figure 1, with characteristic absorption bands at: 3469.2 cm “1 , 3393.5 cm “1 , 3345.5 cm “1 , 3278.1 cm “1 , 3054.5 cm “1 , 3009.0 cm “1 , 2909.8 cm “1 , 2871.2 cm “1 , 2836.5 cm “1 , 1736.2 cm “1 , 1625.8 cm “1 , 1606.3 cm “1 , 1589.1 cm “1 , 1507.6 cm '1 , 1452.7 cm “1 , 1441.4 cm “1 , 1383.1 cm “1 , 1347.5 cm “1 , 1332.7 cm “1 , 1305.0 cm “1 , 1284.5 cm “1 , 1255.6 cm “1 , 1226.9 cm “1 , 1215.0 cm “1 , 1178.8 cm “1 , 1151.6 cm “1 , 1123.6 cm “1 , 1095.8 cm “1 , 1040.0 cm “1
  • the most characteristic absorption bands of the form VII are at: 3469.2 cm “1 , 3278.1 cm '1 , 2871.2 cm “1 , 1123.6 cm “1 , 1095.8 cm “1 , 745.0 cm “1 , 722.9 cm “1 .
  • the form VII is further characterized by DSC analysis, Figure 2.
  • the DSC curve shows two endotherms; the first endotherm with the peak temperature at about 73°C and the second one with the peak temperature at about 114°C.
  • the first endotherm is due to the polymo ⁇ hic transition from form VII to more stable form II, the second endotherm is the melting of form ⁇ .
  • the crystalline form VII is further identified by XRPD analysis, Figure 3.
  • the X-ray powder diffraction pattern of the form VII shows characteristic two-theta values at: 6.42, 6.78, 10.94, 11.58, 12.90, 13.62, 16.79, 17.51, 17.90, 18.81, 19.42, 20.83, 21.19, 21.93, 23.30, 24.49, 25.27, 26.09, 27.20, 29.21 ⁇ 0.1.
  • the most characteristic diffractions of the form VEt are at: 6.42, 6.78, 10.94, 11.58, 12.90, 13.62, 16.79, 17.51, 17.90, 23.30 and 27.20 ⁇ 0.1 two-theta degrees.
  • modification II is isolated in pure crystalline mo ⁇ hological form.
  • modification IQ in pure form or in mixtures with modification II is formed.
  • the mixtures of modification HI and new polymo ⁇ hic modification LX could be isolated using ethyl acetate with 2-3% w/w of water for re crystallization of carvedilol.
  • the pure new polymo ⁇ hic modification LX of carvedilol is prepared using ethyl acetate and water in a miscible mixture as a solvent for crystallization.
  • the miscible mixture of ethyl acetate and water contains preferably more than 3% w/w of water and most preferably more than 4% w/w of water.
  • the preferred concentration of carvedilol is from 8-25% w/w.
  • the present invention further provides the novel crystalline solid modification of carvedilol, designated as form LX.
  • the form LX is characterized by the melting point 94.5-96.2°C.
  • the form LX exhibits IR spectrum, Figure 4, with characteristic abso ⁇ tion bands at: 3568.0 cm “1 , 3339.1 cm “1 , 3287.9 cm “1 , 3201.4 cm “1 , 3052.8 cm 2976.3 cm “1 , 2942.9 cm
  • the form LX is further characterized also by DSC analysis.
  • the DSC curve of form LX ( Figure 5), exhibits the minor endotherm at the peak temperature of about 80°C and the major endotherm at the peak temperature of about 99°C and the onset temperature of about 95°C.
  • the semi hydrated modification LX releases water from the crystal lattice at temperatures higher than 60°C (the first endotherm exhibits from DSC curve), and there formed non- hydrated modification, which is characterized by the second DSC endotherm. Up to the melting point the non-hydrated material retains the same crystalline lattice. Exposing the non- hydrated modification to the normal ambient environment and temperatures lower than 60°C, reversible hydratation of the anhydrous form occurs and the semi hydrated modification is obtained.
  • the form LX is also analyzed by XRPD analysis, Figure 6.
  • the X-ray powder diffraction pattern of the form IX shows characteristic two-theta values at: 6.16, 6.46, 8.39, 10.88, 11.39, 12.35, 12.98, 13.62, 14.72, 16.86, 17.42, 18.26, 19.28, 19.58, 21.88, 23.15, 24.61, 25.58, 26.06, 27.40, 27.63, 29.01, 29.55 ⁇ 0.1.
  • the most characteristic diffractions of the form LX are at 6.16, 6.46, 11.39, 12.35, 13.62, 14.72, 16.86, 19.28, 19.58 and 23.15 ⁇ 0.1 two-theta degrees.
  • Carvedilol ethyl acetate solvate was dried at reduced pressure 10-20 mmHg at maximum 50°C to evaporate the solvent and after loss of weight for 12 tol5% in 6-8 hours, non- solvated carvedilol of mo ⁇ hological form VH with the melting point 68.8-72.4°C was isolated.
  • Crystalline carvedilol form II was obtained by drying carvedilol form VII at temperature 70- 80°C for 6-8 hours.
  • Example 4

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouvelles formes cristallines VII and IX de carvédilol et des processus de préparation de celle-ci. Cette invention concerne en particulier des processus d'isolation de carvédilol, via un acétate éthyle utilisé comme solvant.
EP04775682A 2003-09-02 2004-09-01 Nouvelles formes cristallines de carvedilol Withdrawn EP1660451A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SI200300218A SI21616A (sl) 2003-09-02 2003-09-02 Nove kristalne oblike karvedilola
PCT/SI2004/000029 WO2005021504A2 (fr) 2003-09-02 2004-09-01 Nouvelles formes cristallines de carvedilol

Publications (1)

Publication Number Publication Date
EP1660451A2 true EP1660451A2 (fr) 2006-05-31

Family

ID=34271325

Family Applications (1)

Application Number Title Priority Date Filing Date
EP04775682A Withdrawn EP1660451A2 (fr) 2003-09-02 2004-09-01 Nouvelles formes cristallines de carvedilol

Country Status (3)

Country Link
EP (1) EP1660451A2 (fr)
SI (1) SI21616A (fr)
WO (1) WO2005021504A2 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1245974C (zh) 2000-06-28 2006-03-22 特瓦制药工业有限公司 卡维地洛
CA2472377A1 (fr) 2002-01-15 2003-07-24 Teva Pharmaceutical Industries Ltd. Corps solides cristallins de carvedilol, et leurs procedes d'elaboration
US20070043099A1 (en) * 2005-06-09 2007-02-22 Igor Lifshitz Crystalline forms of carvedilol and processes for their preparation
WO2007043938A1 (fr) * 2005-10-07 2007-04-19 Astrazeneca Ab Nouvelle forme cristalline de 3,5-dibromo-n-[(2s)-2-(4-fluorophenyl)-4-(3-morpholin-4-ylazetidin-1-yl)butyl]-n-methylbenzamide, modification b
WO2008002683A2 (fr) 2006-06-28 2008-01-03 Teva Pharmaceutical Industries Ltd. Carvédilol phosphate

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0893440A1 (fr) * 1997-07-22 1999-01-27 Roche Diagnostics GmbH Une modification thermodynamique stabilisée de 1-(4-carbazolyloxy)-3[2-(2-methoxyphenoxy)ethylamino]- 2-propanole, un procédé pour sa préparation et une composition pharmaceutique qui la contient
CN1245974C (zh) * 2000-06-28 2006-03-22 特瓦制药工业有限公司 卡维地洛
ATE328595T1 (de) * 2001-07-13 2006-06-15 Smithkline Beecham Corp Carvedilolpolymorph
BR0212927A (pt) * 2001-09-28 2004-10-13 Hoffmann La Roche Formas pseudopolimórficas de carvedilol
CA2472377A1 (fr) * 2002-01-15 2003-07-24 Teva Pharmaceutical Industries Ltd. Corps solides cristallins de carvedilol, et leurs procedes d'elaboration
EP1562552A1 (fr) * 2002-11-08 2005-08-17 Egalet A/S Compositions de carvedilol a liberation commandee
SK285547B6 (sk) * 2002-11-08 2007-03-01 Zentiva, A. S. Spôsob prípravy Carvedilolu
US7482471B2 (en) * 2003-06-20 2009-01-27 Sun Pharmaceutical Industries Limited Process for preparation of 1-[9H-carbazol-4-yloxy]-3-[{2-(2-(-methoxy)phenoxy)-ethyl}-amino]-propan-2-ol

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2005021504A3 *

Also Published As

Publication number Publication date
SI21616A (sl) 2005-04-30
WO2005021504A3 (fr) 2005-06-02
WO2005021504A2 (fr) 2005-03-10

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