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

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

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• 2003
  • 2003-09-02 SI SI200300218A patent/SI21616A/sl not_active IP Right Cessation
• 2004
  • 2004-09-01 WO PCT/SI2004/000029 patent/WO2005021504A2/en active Application Filing
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