WO2005123721A2 - Formes amorphes et polymorphes de candesartan cilexetil - Google Patents

Formes amorphes et polymorphes de candesartan cilexetil Download PDF

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WO2005123721A2
WO2005123721A2 PCT/IB2005/001739 IB2005001739W WO2005123721A2 WO 2005123721 A2 WO2005123721 A2 WO 2005123721A2 IB 2005001739 W IB2005001739 W IB 2005001739W WO 2005123721 A2 WO2005123721 A2 WO 2005123721A2
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Prior art keywords
candesartan cilexetil
polymoφhic
amoφhous
candesartan
cilexetil
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WO2005123721A3 (fr
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Yatendra Kumar
Shantanu De
Swargam Sathyanarayana
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Ranbaxy Laboratories Ltd
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Ranbaxy Laboratories Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • 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
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives

Definitions

  • the present invention provides stable substantially pure amorphous forms of candesartan cilexetil.
  • the present invention further provides novel polymorphic forms of . candesartan cilexetil, processes for their preparation and pharmaceutical compositions thereof. Novel polymorphic forms are designated as Form A and Form B of candesartan cilexetil.
  • Candesartan cilexetil is chemically ( ⁇ )-l-[[(cyclohexyloxy)carbonyloxy)]ethyl 2- ethoxy-l-[[[2 , -(lH-tetrazole-5-yl)]l, -biphenyl-4yl-]methyl]-lH-benzimidazole-7- carboxylic acid (Formula I).
  • Candesartan cilexetil is a biphenyl tetrazole compound useful as an angiotensin II antagonist in treating cardiovascular conditions, for example, hypertension and cardiac arrest.
  • FORMULA I Three polymorphic forms of candesartan cilexetil, which are designated as Form I, Form II and amorphous, have been previously disclosed. All three polymo ⁇ hic forms are interconvertible by process modification, which is depicted in Figure 1, wherein transformation 1 represents crushing/grinding, transformation 2 represents recrystallization using acetone, and transformation 3 represents recrystallization using acetone-water (3:1 v/v), methanol, ethanol, isopropanol or acetonitrile.
  • the grinding process reported for preparing an amo ⁇ hous form from crystalline Form I or Form II involves repeated cycles of crushing or milling to obtain amo ⁇ hous powder, which is usually contaminated with crystalline forms.
  • candesartan cilexetil is heat sensitive and therefore grinding causes unwanted degradation and loss in purity.
  • a process for preparing candesartan free acid which involves evaporating solvent from a solution of candesartan to dryness to form amo ⁇ hous powder.
  • This amo ⁇ hous powder is unstable, decomposing even when stored at ambient temperature.
  • this amo ⁇ hous powder has significant residual solvent content and therefore is not acceptable for pharmaceutical use.
  • novel polymo ⁇ hic forms A and B of candesartan cilexetil are also provided herein.
  • an amo ⁇ hous form of candesartan cilexetil having less than about 600 ppm residual dichloromethane.
  • the amo ⁇ hous form of candesartan cilexetil can also have less than about 1000 ppm ethyl acetate, less than about 1500 ppm toluene, less than about 2000 ppm methanol, less than about 2000 ppm acetone or less than about 2000 ppm ethanol.
  • a storage-stable amo ⁇ hous form of candesartan cilexetil having a purity of about 99 %.
  • the storage-stable amo ⁇ hous form of candesartan cilexetil has a purity of about 99.4 %.
  • polymo ⁇ hic Form A of candesartan cilexetil is also provided.
  • This polymo ⁇ hic form can include one or more of the following embodiments.
  • polymo ⁇ hic Form A of candesartan cilexetil can have an X-ray powder diffraction pattern (XRPD) comprising 2 ⁇ values of about 7.3, 7.5, 14.7 or 15.1.
  • XRPD X-ray powder diffraction pattern
  • Polymo ⁇ hic Form A of candesartan cilexetil can also exhibit a Differential
  • polymo ⁇ hic Form A of candesartan cilexetil can exhibit a Fourier Transform Infrared (FTIR) spectrum comprising abso ⁇ tions at about 3430 cm “1 (br), 2940 cm “1 (s), 2860 cm “1 , 1750 cm “1 (s), 1730 cm “1 , 1550 cm “1 (s), 1430 cm “1 , 1355 cm “1 , 1280 cm “1 (s), 1245 cm “1 (s), 1080 cm “1 (s), 1040 cm “1 or 750 cm “1 .
  • FTIR Fourier Transform Infrared
  • polymo ⁇ hic Form B of candesartan cilexetil can include one or more of the following embodiments.
  • polymo ⁇ hic Form B of candesartan cilexetil can exhibit an X-ray powder diffraction pattern (XRPD) comprising 2 ⁇ values of about 7.2, 14.2, 14.6 or 15.8.
  • XRPD X-ray powder diffraction pattern
  • Polymo ⁇ hic Form B of candesartan cilexetil can also exhibit a Differential
  • polymo ⁇ hic Form B of candesartan cilexetil can exhibit a Fourier Transform Infrared (FTIR) spectrum comprising abso ⁇ tions at about 3430 cm “1 (br), 2940 cm “1 (s), 2860 cm “1 , 1755 cm “1 (s), 1730 cm “1 , 1550 cm “1 (s), 1430 cm “1 , 1355 cm “1 , 1280 cm “1 (s), 1245 cm “1 (s) 1080 cm “1 (s) 1040 cm “1 or 745 cm* "1 .
  • FTIR Fourier Transform Infrared
  • Also provided are processes to prepare storage-stable, substantially pure amo ⁇ hous form of candesartan cilexetil comprising the steps of: a) dissolving candesartan cilexetil in one or more organic solvents to form a solution, b) removing the solvent from the solution by spray-drying to form amo ⁇ hous form of candesartan cilexetil, and c) optionally drying the amo ⁇ hous form of candesartan cilexetil.
  • the processes can include one or more of the following embodiments.
  • drying the amo ⁇ hous form of candesartan cilexetil can be carried out by passing air or an inert gas.
  • the inert gas can be nitrogen, argon and carbon dioxide.
  • the gas inlet temperature can range from about 40 °C to about 150 °C and outlet temperature can range from about 20 °C to about 80 °C.
  • the organic solvent can be one or more lower alcohols, one or more ketones, one or more nitriles, one or more chlorinated hydrocarbons, one or more dipolar aprotic solvents, one or more esters, one or more cyclic ethers, or mixtures thereof.
  • Also provided are processes to prepare storage-stable, substantially pure amo ⁇ hous form of candesartan cilexetil comprising the steps of: a) dissolving candesartan cilexetil in a first organic solvent and adding a second organic solvent, wherein candesartan cilexetil is slightly soluble, sparingly soluble or insoluble in the second organic solvent, and b) isolating the precipitated amo ⁇ hous form.
  • the first organic solvent can comprise a single organic solvent or a mixture of organic solvents in which candesartan cilexetil is soluble at ambient temperature or upon slight heating.
  • the first organic solvent can be one or more lower alcohols, one or more ketones, one or more nitriles, one or more chlorinated hydrocarbons, one or more dipolar aprotic solvents, one or more esters, one or more cyclic ethers, or mixtures thereof.
  • the second organic solvent can be water, cyclohexane, diethyl ether, diisopropyl ether, hexane, petroleum ether or mixtures thereof.
  • Also provided are processes to prepare polymo ⁇ hic Form A of candesartan cilexetil comprising the steps of: a) suspending candesartan cilexetil in one or more solvents selected from one or more mono- or di-(C 1 -C 8 )alkyl ethers to form a suspension, b) stirring the suspension for sufficient time to effect conversion of candesartan cilexetil to polymo ⁇ hic Form A of candesartan cilexetil, and c) isolating polymo ⁇ hic Form A of candesartan cilexetil from the suspension.
  • These processes can include one or more of the following embodiments.
  • the one or more mono- or di-(C 1 -C 8 )alkyl ethers can be ethylene glycol, propylene glycol, diethyl ether, methyl t-butyl ether, diisopropyl ether or mixtures thereof.
  • stirring can be carried out at a temperature of about -25 °C to 55 °C.
  • Also provided are processes to prepare polymo ⁇ hic Form B of candesartan cilexetil comprising the steps of: a) suspending candesartan cilexetil in one or more solvents to form a suspension, wherein the one or more solvents are selected from aromatic hydrocarbons, aliphatic hydrocarbons or mixtures thereof, b) stirring the suspension for sufficient time to effect conversion to polymo ⁇ hic Form B of candesartan cilexetil, and c) isolating polymo ⁇ hic Form B of candesartan cilexetil from the suspension.
  • stirring can be carried out at a temperature of about -25 °C to 55 °C.
  • Also provided are processes to prepare polymo ⁇ hic Form A of candesartan cilexetil comprising the steps of: a) heating polymo ⁇ hic Form B of candesartan cilexetil to a temperature of about 35 °C or above under vacuum for sufficient time to convert it to polymo ⁇ hic Form A of candesartan cilexetil, b) isolating polymo ⁇ hic Form A of candesartan cilexetil.
  • various pharmaceutical compositions comprising a storage-stable amo ⁇ hous form of candesartan cilexetil having less than about 600 ppm residual dichloromethane.
  • compositions comprising a storage-stable amo ⁇ hous form of candesartan cilexetil having a purity of 99 %. Also provided are pharmaceutical compositions comprising polymo ⁇ hic Form A of candesartan cilexetil optionally containing one or more pharmaceutically acceptable diluents, excipients or carriers. Also provided are pharmaceutical compositions comprising polymo ⁇ hic Form B of candesartan cilexetil optionally containing one or more pharmaceutically acceptable diluents, excipients or carriers. Also provided herein are methods of antagonizing angiotensin II in a mammal.
  • one method comprises administering to the mammal in need thereof a therapeutically effective amount a storage stable amo ⁇ hous form of candesartan cilexetil having less than about 600 ppm residual dichloromethane.
  • Another method comprises administering to the mammal in need thereof a therapeutically effective amount of a storage-stable amo ⁇ hous form of candesartan cilexetil having a purity of 99 %.
  • Another method comprises administering to the mammal in need thereof a therapeutically effective amount of polymo ⁇ hic Form A of candesartan cilexetil.
  • Yet another method comprises administering to the mammal in need thereof a therapeutically effective amount of polymo ⁇ hic Form B of candesartan cilexetil.
  • Figure 1 depicts the interconversion among polymo ⁇ h forms.
  • Figure 2 depicts an X-ray diffractogram of amo ⁇ hous form of candesartan cilexetil.
  • Figure 3 depicts FTLR spectrum of amo ⁇ hous form of candesartan cilexetil.
  • Figure 4 depicts DSC thermogram of amo ⁇ hous form of candesartan cilexetil.
  • Figure 5 depicts an X-ray diffractogram of Form A of candesartan cilexetil.
  • Figure 6 depicts DSC thermogram of Form A of candesartan cilexetil.
  • Figure 7 depicts FTIR spectrum of Form A of candesartan cilexetil.
  • Figure 8 depicts an X-ray diffractogram of Form B of candesartan cilexetil.
  • Figure 9 depicts DSC thermogram of Form B of candesartan cilexetil.
  • Figure 10 depicts FTLR spectrum of Form B of candesartan .cilexetil.
  • Figure 11 depicts X-ray diffractogram of "Type C" crystals of candesartan cilexetil.
  • Figure 12 depicts DSC thermogram of "Type C" crystals of candesartan cilexetil.
  • Figure 13 depicts FTLR spectrum of "Type C" crystals of candesartan cilexetil.
  • Powder XRD diffractograms were determined by using an X-Ray Difractometer, Rigaku Co ⁇ oration, RU-H3R, Goniometer CN2155A3, X-Ray tube with Cu target anode, Divergence slits 10, Receiving slit 0.15mm, Scatter slit 1°, Power: 40 KN, 100 mA, Scanning speed: 2 deg/min step: 0.02 deg, Wave length: 1.5406 A.
  • FTIR spectra were obtained using a Perkin Elmer FTIR, 16 PC, SCAN: l ⁇ scans, 4.0 cm "1 , according to the USP 25, general test methods page 1920, infrared abso ⁇ tion spectrum by potassium bromide pellet.
  • DSC thermograms were recorded using DSC821 e, Mettler Toledo, Sample weight: 3-5 mg, Temperature range: 50-350 °C, Heating rate: 20 °C/min, Nitrogen 80.0 mL/min, Number of holes in the crucible: 1.
  • a storage-stable amo ⁇ hous form of candesartan cilexetil having residual solvents as per the regulatory requirements.
  • such storage-stable amo ⁇ hous candesartan cilexetil can comprise less than about 600 ppm dichloromethane, less than about 1000 ppm ethyl acetate, less than about 1500 ppm toluene, less than about 2000 ppm methanol, less than about 2000 ppm acetone or less than about 2000 ppm ethanol.
  • the storage-stable amo ⁇ hous form of candesartan cilexetil is substantially pure, i.e., the storage-stable amo ⁇ hous candesartan cilexetil can be about 98.5 % pure, preferably about 99 % pure, more preferably about 99.4 % pure, and most preferably about 99.5 % or greater pure as determined by HPLC.
  • a novel polymo ⁇ hic Form A of candesartan cilexetil can exhibit a characteristic X-ray powder diffraction pattern (XRPD) comprising 2 ⁇ values of, for example, about 7.3, 7.5, 8.2, 14.7 or 15.1.
  • XRPD characteristic X-ray powder diffraction pattern
  • Form A of candesartan cilexetil can also exhibit a characteristic Differential Scanning Calorimetric (DSC) thermogram as depicted in Figure 6 having an exothermic peak at about 135.5 °C (e.g., Integral -212.3 mJ, Onset 123.2 °C, Peak Height 2.8 mW, Peak Width 11.3 °C).
  • DSC Differential Scanning Calorimetric
  • Form A of candesartan cilexetil also can exhibit a characteristic Fourier Transform Infrared (FTIR) spectrum as depicted in Figure 7 (which can comprise peaks at, for example, about 3430 cm “1 (br), 2940 cm “1 (s), 2860 cm “1 , 1750 cm “1 (s), 1730 cm “1 , 1550 cm “1 (s), 1430 cm “1 , 1355 cm “1 , 1280 cm “1 (s), 1245 cm “1 (s), 1080 cm “1 (s), 1040 cm “1 or 750 cm “1 . Also provided is a novel polymo ⁇ hic Form B of candesartan cilexetil.
  • FTIR Fourier Transform Infrared
  • Form B can exhibit a characteristic X-ray powder diffraction pattern (XRPD) as depicted in Figure 8, and in particular, can comprise 20 values of about 7.2, 8.1, 14.2, 14.6, 15.8 or 25.20.
  • Form B of candesartan cilexetil can exhibit a characteristic Differential Scanning Calorimetric (DSC) thermogram comprising two exothermic peaks at about 109.5 °C (e.g., Integral -32.7 mJ, Onset 101.8 °C, Peak Height 0.58 mW, Peak Width 7.33 °C) and 138.3 °C (e.g., Integral -134.9 mJ, Onset 128.7 °C, Peak Height 2.55 mW, Peak Width 7.9 °C).
  • DSC Differential Scanning Calorimetric
  • Form B of candesartan cilexetil can also exhibit a characteristic Fourier Transform Infrared (FTIR) spectrum comprising peaks at, for example, about 3430 cm “1 (br), 2940 cm “1 (s), 2860 cm “1 , 1755 cm “1 (s), 1730 cm “1 , 1550 cm “1 (s), 1430 cm “1 , 1355 cm “1 , 1280 cm “1 (s), 1245 cm “1 (s), 1080 cm “1 (s), 1040 cm “1 or 745 cm “1 .
  • FTIR Fourier Transform Infrared
  • Also provided are processes to prepare storage-stable, substantially pure amo ⁇ hous form of candesartan cilexetil wherein the processes comprise dissolving candesartan cilexetil in a suitable organic solvent, removing the solvent from the solution by spray-drying, and optionally followed by drying the resultant amo ⁇ hous form.
  • Solutions of candesartan cilexetil may be obtained by dissolving candesartan cilexetil in one or more suitable organic solvents.
  • Candesartan cilexetil when used as a starting material, may be in any crystalline form or mixtures thereof, particularly Form I or Form II. Crystalline forms can be obtained by methods known in the art such as processes disclosed in U.S. Patent No.
  • Suitable solvent includes any solvent or solvent mixture in which candesartan cilexetil is soluble at ambient temperature or upon slight heating (i.e., about 15 °C to about 65 °C, about 20 °C to about 50 °C, and even about 25 °C to about 40 °C).
  • suitable solvents include lower alcohols (e.g., methanol, ethanol, isopropanol, propanol, and the like, or mixtures thereof); ketones (e.g., acetone, ethyl methyl ketone, methyl isobutyl ketone or mixtures thereof); nitriles (e.g., acetonitrile, benzonitrile or mixtures thereof); chlorinated hydrocarbons (e.g., methylene chloride, chloroform, carbon tetrachloride, ethylene dichloride or mixtures thereof); dipolar aprotic solvents (e.g., dimethylsulphoxide, dimethylacetamide, dimethylformamide or mixtures thereof); esters (e.g., ethyl acetate, ethyl formate, methyl formate, methyl acetate, n-propyl acetate, isopropyl acetate or mixtures thereof); cyclic ethers (e.g.
  • the spray drying may be accomplished by using a spray dryer, which operates on the principle of nozzle spraying in a parallel flow, i.e., the sprayed product and the drying gas flow in the same direction.
  • the drying gas can be air, one or more inert gases (e.g., nitrogen, argon, carbon dioxide or mixtures thereof), or mixtures thereof.
  • Gas inlet temperatures may range from about 40 °C to about 150 °C and outlet temperatures may range from about 20 °C to about 80 °C.
  • Also provided are processes to prepare storage-stable, substantially pure amo ⁇ hous form of candesartan cilexetil wherein the processes comprise dissolving candesartan cilexetil in a first organic solvent or first organic solvent mixture and adding a second organic solvent or second organic solvent mixture.
  • candesartan cilexetil is slightly soluble or sparingly soluble or insoluble in the second organic solvent or second organic solvent mixture, which facilitates precipitating an amo ⁇ hous form.
  • the first organic solvent or first organic solvent mixture includes any solvent or solvent mixture in which candesartan cilexetil is soluble at ambient temperature or upon slight heating.
  • suitable solvents include one or more of lower alcohols (e.g., methanol, ethanol, isopropanol or mixtures thereof); ketones (e.g., acetone, ethyl methyl ketone, methyl isobutyl ketone or mixtures thereof); nitriles (e.g., acetonitrile, benzonitrile or mixtures thereof); chlorinated hydrocarbons (e.g., methylene chloride, chloroform, carbon tetrachloride, ethylene dichloride or mixtures thereof); dipolar aprotic solvents (e.g., dimethylsulphoxide, dimethylacetamide, dimethylformamide or mixtures thereof); esters (e.g., ethyl acetate, ethyl formate, methyl formate, methyl acetate, n-propyl acetate, isopropyl acetate or mixtures thereof); cyclic ethers (e.g., dioxan
  • the second organic solvent or second organic solvent mixture includes one or more of water, cyclohexane, diethyl ether, diisopropyl ether, hexane, petroleum ether, and the like, or mixtures thereof.
  • processes to prepare polymo ⁇ hic Form A of candesartan cilexetil comprising the steps of: a) suspending candesartan cilexetil in one or more solvents to form a suspension, wherein the one or more solvents comprise mono- or di- (C 1 -C 8 )-alkyl ethers of ethylene glycol, propylene glycol, diethyl ether, methyl tert-butyl ether, diisopropyl ether or mixtures thereof, b) stirring the suspension for a sufficient time to form polymo ⁇ hic Form A of candesartan cilexetil, and c) isolating polymo ⁇ hic Form A of candesartan cilexetil
  • Candesartan cilexetil in Form I or II or in amo ⁇ hous form can be used as starting material in preparing Form A of candesartan cilexetil.
  • the suspension can be optionally warmed to form a clear solution.
  • the clear solution so obtained or the suspension as such can be stirred at temperatures of about -25 °C to about 55 °C for about 2 hours to several days to effect complete conversion to Form A of candesartan cilexetil.
  • Form A can precipitate from the suspension, which can then be collected, washed with the one or more organic solvents (as mentioned above) and dried to yield polymo ⁇ hic Form A of candesartan cilexetil.
  • Also provided are processes to prepare polymo ⁇ hic Form B of candesartan cilexetil wherein the processes comprise the steps of: a) suspending candesartan cilexetil in one or more solvents to form a suspension, wherein the one or more solvents comprise aromatic hydrocarbons, aliphatic hydrocarbons or mixtures thereof, b) stirring the suspension for sufficient time to effect conversion to polymo ⁇ hic Form A of candesartan cilexetil, and c) isolation of polymo ⁇ hic Form B of candesartan cilexetil from the suspension thereof.
  • Candesartan cilexetil in Form I or II or in amo ⁇ hous form can be used as starting material in forming Form B of candesartan cilexetil.
  • the suspension can be optionally warmed to form a clear solution.
  • the clear solution so obtained or the suspension as such can then stirred at temperatures of about -25 °C to about 55 °C for about 2 hours to several days to effect complete conversion to Form B of candesartan cilexetil.
  • Form B can precipitate from the suspension and is collected, washed with one or more organic solvent (as mentioned above) and dried to yield polymo ⁇ hic Form B of candesartan cilexetil.
  • Also provided are processes to prepare polymo ⁇ hic Form A of candesartan cilexetil wherein the processes comprise the steps of: a) heating polymo ⁇ hic Form B of candesartan cilexetil to a temperature of about 35 °C or above under vacuum for sufficient time to form polymo ⁇ hic Form A of candesartan cilexetil, and b) isolating polymo ⁇ hic Form A of candesartan cilexetil.
  • Candesartan cilexetil Form B can be heated under vacuum at temperatures of about 35 °C or above for about 10 minutes to 2 days to completely convert it to Form A of candesartan cilexetil.
  • compositions comprising a storage-stable amo ⁇ hous form of candesartan cilexetil having residual solvents as per the regulatory requirements. Also provided are pharmaceutical compositions comprising a storage-stable amo ⁇ hous form of candesartan cilexetil having no detectable crystalline Form I or II. Also provided are pharmaceutical compositions comprising polymo ⁇ hic Form A of candesartan cilexetil optionally containing one or more pharmaceutically acceptable diluents or excipients. Also provided are pharmaceutical compositions comprising polymo ⁇ hic Form B of candesartan cilexetil optionally containing one or more pharmaceutically acceptable diluents or excipients.
  • Example 1 Preparation of Amo ⁇ hous Form of Candesartan Cilexetil Crystalline Form I of ( ⁇ )-l-[[(cyclohexyloxy)carbonyloxy)]ethyl] 2-ethoxy-l- [[[2 , -(lH-tetrazole-5-yl)]l, -biphenyl-4yl-]methyl]-lH-benzimidazole-7-carboxylate (50 g) was dissolved in dichloromethane (250 mL) at 25 to 30 °C. The clear solution thus obtained was subjected to spray drying using a mini spray dryer (Buchi Model 190). The spray drier was configured for a nitrogen gas flow rate of 600 NL/hour.
  • the inlet temperature was maintained at 30 °C and the outlet temperature was at 25 °C.
  • the solution was charged in the spray drier for 60 minutes and 35 g of white fluffy powder was collected and dried under reduced pressure at 35 °C to 40 °C to yield title compound in substantially pure form.
  • Example 2 Preparation of Amo ⁇ hous Form of Candesartan Cilexetil Crystalline Form I of ( ⁇ )-l-[[(cyclohexyloxy)carbonyloxy)]ethyl] 2-ethoxy-l- [[[2 , -(lH-tetrazole-5-yl)]l,l'-bi ⁇ henyl-4yl-]methyl]-lH-benzimidazole-7-carboxylate (25 g) was dissolved in dichloromethane (100 mL) at 25 °C to 30 °C. To the solution was added ethyl acetate (900 mL) resulting in a clear solution.
  • the solution was then subjected to spray drying using a mini spray dryer (Buchi Model 190).
  • the spray drier was configured for nitrogen gas flow rate at 600 NL/hour.
  • the inlet temperature was maintained at 30 °C and the outlet temperature was at 25 °C.
  • the solution was charged in the spray drier for 60 minutes and 18.5 g of white fluffy powder was collected and dried under reduced pressure at 35 °C to 40 °C to yield the title compound in substantially pure form.
  • Residual dichloromethane content not detectable. Residual ethyl acetate content: less than 100 ppm.
  • Powder XRD, IR and DSC were similar to those shown in Figure 2, 3 and 4.
  • Type C crystals of candesartan cilexetil (5 g) was added to ethylene glycol dimethyl ether (25 mL) and the mixture was heated to 40 °C and filtered through celite bed to obtain a clear filtrate. The clear filtrate was cooled and maintained at -10 °C to -15 °C for 16 to 24 hrs to crystallize the product, which was then filtered and dried under vacuum at 35 °C to 40 °C to yield the title compound. Yield: 3.5g
  • Example 4 Preparation Of Form B Of Candesartan Cilexetil A suspension of type C crystal of candesartan cilexetil (5 g) in toluene (250 mL) was stirred at 25 °C to 30°C for 56 hours. The solid product was filtered and dried under vacuum for 4 hours at 30 °C to 35 °C to yield the title compound.
  • Example 5 Preparation Of Form B Of Candesartan Cilexetil And Its Conversion To Form A Of Candesartan Cilexetil Type C crystals of candesartan cilexetil (50 g) were added to toluene (4 L) and the mixture heated to 40 °C and filtered through celite to obtain a clear filtrate. The clear filtrate was slowly cooled to 25 °C to 30 °C and stirred at this temperature for 16 to 24 hrs to crystallize the product, which was then filtered and dried under vacuum at 35 °C to 40 °C for 3 hours to yield Form B of candesartan cilexetil.

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Abstract

La présente invention concerne une forme amorphe sensiblement pure de candesartan cilexetil. Elle concerne également de nouvelles formes polymorphes de candesartan cilexetil, un procédé de préparation et des compositions pharmaceutiques pour antagoniser l'angiotensine II. Les nouvelles formes polymorphes ont état désignées 'forme A' et 'forme B' de candesartan cilexetil.
PCT/IB2005/001739 2004-06-18 2005-06-20 Formes amorphes et polymorphes de candesartan cilexetil Ceased WO2005123721A2 (fr)

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IN1154DE2004 2004-06-18
IN1154/DEL/2004 2004-06-18
IN1312/DEL/2004 2004-07-16
IN1312DE2004 2004-07-16

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WO2005123721A2 true WO2005123721A2 (fr) 2005-12-29
WO2005123721A3 WO2005123721A3 (fr) 2006-06-08

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008030161A1 (fr) * 2006-09-05 2008-03-13 Astrazeneca Ab composition pharmaceutique comprenant DU CANDESARTAN CILEXETIL
EP1952806A1 (fr) 2007-02-01 2008-08-06 Helm AG Procédé de préparation des produits d'absorption de candesartan
WO2008035360A3 (fr) * 2006-06-13 2008-10-16 Alembic Ltd Nouvelles formes cristallines
EP1997479A1 (fr) * 2007-05-31 2008-12-03 Helm AG Formulations stabilisées contentant du candesartan cilexetil amorphe pour l'administration orale
JP2010510294A (ja) * 2006-11-23 2010-04-02 ケモ イベリカ， エス．ア． カンデサルタンシレキセチルの結晶形態を調製する方法
US7692023B2 (en) 2004-02-11 2010-04-06 Teva Pharmaceutical Industries Ltd. Candesartan cilexetil polymorphs

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0216700D0 (en) * 2002-07-18 2002-08-28 Astrazeneca Ab Process
US7504516B2 (en) * 2003-03-27 2009-03-17 Hetero Drugs Limited Crystalline forms of candesartan cilexetil

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7692023B2 (en) 2004-02-11 2010-04-06 Teva Pharmaceutical Industries Ltd. Candesartan cilexetil polymorphs
WO2008035360A3 (fr) * 2006-06-13 2008-10-16 Alembic Ltd Nouvelles formes cristallines
WO2008030161A1 (fr) * 2006-09-05 2008-03-13 Astrazeneca Ab composition pharmaceutique comprenant DU CANDESARTAN CILEXETIL
JP2010510294A (ja) * 2006-11-23 2010-04-02 ケモ イベリカ， エス．ア． カンデサルタンシレキセチルの結晶形態を調製する方法
EP1952806A1 (fr) 2007-02-01 2008-08-06 Helm AG Procédé de préparation des produits d'absorption de candesartan
EP1997479A1 (fr) * 2007-05-31 2008-12-03 Helm AG Formulations stabilisées contentant du candesartan cilexetil amorphe pour l'administration orale

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