WO2008012371A1 - Procédé de préparation de formes amorphes et cristallines de candésartan cilexétil par chromatographie sur colonne - Google Patents

Procédé de préparation de formes amorphes et cristallines de candésartan cilexétil par chromatographie sur colonne Download PDF

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Publication number
WO2008012371A1
WO2008012371A1 PCT/EP2007/057803 EP2007057803W WO2008012371A1 WO 2008012371 A1 WO2008012371 A1 WO 2008012371A1 EP 2007057803 W EP2007057803 W EP 2007057803W WO 2008012371 A1 WO2008012371 A1 WO 2008012371A1
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WO
WIPO (PCT)
Prior art keywords
candesartan
process according
solvent
amorphous
ciiexetil
Prior art date
Application number
PCT/EP2007/057803
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English (en)
Inventor
Silvo Zupancic
Primoz Benkic
Tadej Stropnik
Anica Pecavar
Joze Pucelj
Igor Plaper
Miran Hvalec
Matej Smrkolj
Renata Osolnik
Polona Smrkolj
Suzana Senicar
Nives Sostaric-Virc
Jernej Hvala
Original Assignee
Krka, Tovarna Zdravil, D.D., Novo Mesto
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
Priority claimed from SI200600176A external-priority patent/SI22340A/sl
Priority claimed from SI200700068A external-priority patent/SI22491A/sl
Application filed by Krka, Tovarna Zdravil, D.D., Novo Mesto filed Critical Krka, Tovarna Zdravil, D.D., Novo Mesto
Priority to EP07788016A priority Critical patent/EP2066649A1/fr
Publication of WO2008012371A1 publication Critical patent/WO2008012371A1/fr
Priority to NO20090703A priority patent/NO20090703L/no

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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/96—Esters of carbonic or haloformic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to improved processes for the manufacture of amorphous and crystalline candesartan cilexetil.
  • Candesartan cilexetil of formula (i) is chemically described as (+/-)- 1 - [[(cyclohexyloxy)carbonyl]oxy]ethy!-2-ethoxy-1 -[[2'-(1 H-tetrazol-5-yl)-1 ,1 '-bipheny!-4- yl]methyi]-1 H-benzimidazole-7-carboxylate,
  • An alternative designation is (+-)-1 - hydroxyethyl 2-Ethoxy-1 -(p- ⁇ o-1 H-tetrazoi-5-yipheny!)benzyl)-7-benzimidazole- carboxylic acid cyclohexy!
  • candesartan being the underlying carboxy ⁇ c acid, i.e. 2-Ethoxy-1 ⁇ (p-(o-1 H-tetrazol-5-ylphenyl)benzyl)-7-benz- imidazolecarboxylic acid.
  • candesartan c ⁇ exetil avoids the side-effects of calcium antagonists, and shows high stability and obvious curative effects. At the time being it is sold as the racemic mixture. It is produced according to published patents, e.g. EP
  • WO 04/085426 discloses the dioxane solvate of candesartan cilexeti!, together with two additional crystalline forms.
  • WO 2005/077941 discloses hydrates and solvates of candesartan cilexetil, together with processes for their preparation.
  • WO 2006/048237 also describes the preparation of new polymorphic forms of candesartan cilexetil, together with processes for their preparation, including the preparation of amorphous candesartan c ⁇ exetil by precipitating it with a liquid cyclic hydrocarbon from a solution of candesartan cilexetil in a chlorinated solvent.
  • Fig. 1 is a photography of candesartan cilexetil form I. Summary of the invention
  • the present invention provides a method of purification of candesartan ciiexetil by column chromatography using normal or reverted chromatographic conditions (i.e. normal or reverse phase chromatography) or by supercritica! chromatography.
  • the present invention provides improved processes for the preparation of an amorphous form of candesartan ciiexetil by lyophi ⁇ zation, evaporation and precipitation.
  • the improved processes enable obtaining amorphous candesartan ciiexetii which is optionally further converted to forms I and/or H as characterized in Chem. Pharm. Bull. 47 ⁇ 2), 182-186 (1999), either by crystallization, precipitation or conversion in a slurry or a suspension.
  • amorphous candesartan ciiexetil is thermally converted to form Il by heating a slurry of amorphous candesartan ciiexetil in an inert solvent or solvent system.
  • the present invention further provides the newly isolated compound (+-)-1 - hydroxyethyl candesartan oxanyl carbonate (ester), which is the tetrahydropyranyi structure analogon of candesartan ciiexetil and will for the sake of brevity also be designated herein as "candesartan ciiexetii pyran”. Its chemical structure will be shown below as formula (V).
  • the present invention provides a preparation of candesartan ciiexetil containing less than 0.15%, preferably less than 0.10%, of candesartan ciiexetil pyran.
  • the present invention provides the newly isolated compound 1 -haloethy! oxanyi carbonate ("ciiexetil pyran") of the formula (IV) shown below, wherein halo means Cl, Br, I.
  • the invention provides a preparation of 1 -haloethy!
  • cyclohexylcarbonate "ciiexetil), wherein halo means Cl, Br, !, which contains less than 0.3%, preferably less than 0.2%, more preferably less than 0.1% and even more preferably less than 0.05%, of ciiexetii pyran. All percentages in this application are by weight, unless otherwise noted.
  • drying generally refers to a removal of solvent untii candesartan cilexetil contains less than about 5000 ppm residual solvents. Drying may be achieved e.g. heating, preferably carried out under ambient or reduced pressure or via contacting candesartan cilexetil with humid air in a fluidized bed drier, wherein the atmosphere in the fluidized bed drier is at least 15% humidity.
  • reduced pressure refers to a pressure below one atmosphere, more preferably below about 100 mmHg.
  • precipitation refers to the formation of a suspension of small solid particles in a mixture.
  • crystallization refers to a process for forming crystals from a liquid or gas.
  • the main goal of the present invention is to prepare amorphous and crystalline candesartan cilexetil with a quality that complies with Ph.Eur./ICH Guidelines in an economical way using easily accessible substances and pure starting compounds.
  • the present invention provides a method of purification of candesartan cilexetil by column chromatography using normal or reverted chromatographic conditions (reverse phase chromatography) or by supercritical chromatography.
  • the obtained fractions containing candesartan cilexetil are used to isolate candesartan cilexetil in an amorphous form as described below.
  • the average particle size of particles used according to the present invention is 10 to 100 ⁇ m, preferably below 50 ⁇ m, more preferably below 20 ⁇ m, and even more preferably below 10 ⁇ m which are usually obtained by crystallization of candesartan cilexetil from organic solvents or their mixtures with water, while stirring. Crystallization from organic solvents or their mixtures with water might also yield bigger particles, e.g. with an average diameter of above 100 ⁇ m which need to be milled or processed in any other way which reduces the particle size, prior to their application in pharmaceutical formulations. When milling, particles of less then 3 ⁇ m average diameter may be produced.
  • the milling process can convert the crystal form of candesartan cilexetil to its amorphous form.
  • air jet mills ball miils or hammer mills are commonly used as milling equipment.
  • unmodified silica preferably unmodified silica (5-63 ⁇ m), amino modified silica (amino phase, 5 - 40 ⁇ m), cyano modified silica (cyano phase, 5 - 40 ⁇ m), dio! modified siiica (diol phase, 10 ⁇ m), which are commercially available under the names of Nucleosil, Nucleodur, Polygosil, Polygoprep, Chromolith prep., can be used as the stationary phase.
  • the mobile phase ethanol, methanol, iso- propanol, TBME ⁇ tert.
  • octyl phase (C8), dodecyl phase (C12) or octadecyl (C18) phase, which are commercially available under the names of Synergy, Zorbax, and Chromoiith prep. RP, are used as the stationary phase.
  • phosphate buffer (0,05 - 0,2M), acetate buffer (0,05 - 0,2M), trifiuoroacetic acid ⁇ 0,05% -2% w/w), acetic acid (0,05% -2% w/w), acetonitrile, methanol, ethanol, isopropanol, dioxane or mixtures thereof
  • the sample elution may be achieved by isocratic or gradient elution.
  • Silica 3-10 ⁇ m and diol modified silica 3-10 ⁇ m; cyano modified silica 3-10 ⁇ m may be used as the stationary phase.
  • mobiie phase alcohols such as methanol, ethanol and 2-propanoi as well as acetonitrile with CO 2 or any mixtures thereof may be used.
  • the sample elution may be achieved by isocratic and gradient elution.
  • the starting material which is preferably candesartan cilexetil
  • the starting material may be prepared as described e.g. in EP O 0 459 136 B1 , or any other procedure method known in the art, such as e.g. WO 2005/051929, WO 2005/051928, WO 2005/021535, WO 2006/015134, or WO 2006/063578. It may be used as the isolated compound which is again dissolved in a suitable solvent or solvent system or in form of the reaction mixture. In a preferred embodiment candesartan cilexeti! is used in form of the reaction mixture, i.e. where candesartan has not been isolated previously.
  • Trityl candesartan cilexetil (II) is preferably prepared from trityl candesartan (ill) and 1-chloroethyi cyclohexylcarbonate in dimethylacetamide (DMA), in the presence of a base.
  • A, B, and C is an Oxygen atom and the other two are -CH2-, and wherein X means Cl, Br, or I.
  • A, B, and C is an Oxygen atom and the other two are -CH2-
  • X means Cl 1 Br or I and wherein the O atom can be in ortho, meta or para position
  • Oxygen atom can be in ortho, meta or para position.
  • Another embodiment of the present invention is candesartan cilexetil containing less than 0.15%, preferably less than 0.10%, of a compound of formula (V).
  • the present invention provides newiy isolated impurity candesartan ciiexetil pyran that is characterized by LC-MS (Liquid Chromatography - Mass Spectrometry).
  • the impurity is controlled by HPLC (High Performance Liquid Chromatography) with RRT (Relative retention time) at about 0.569.
  • the chromatographic method is disclosed in Example 14a.
  • One embodiment of the present invention is the substance 1 -haloethyl cyciohexyicarbonate, wherein halo means Ci, Br, I, containing less than 0.3%, preferably less than 0.2%, more preferably less than 0.1% and even more preferably less than 0.05%, of cilexetil pyran.
  • the present invention provides newiy isolated impurity ciiexetil pyran that is characterized by LC-MS (Liquid Chromatography - Mass Spectrometry).
  • the impurity is controlled by Gas Chromatography as the sum of impurities with RRT at about 1.478 and RRT at about 1.486.
  • the present invention provides a process for the preparation of amorphous candesartan cilexetil wherein the fractions containing candesartan cilexetil are combined, water is added, and the mixture is iyophiiized (freeze-dried).
  • the solvent system can be changed after chromatographic elution by common methods, e.g. by distiilation of fractions containing candesartan cilexetil and addition of another solvent system.
  • Suitable solutions of candesartan cilexetil for the freeze drying procedure are those containing water misc ⁇ ble co-solvents of reasonable volatility at low temperatures and a relatively high melting point, e.g. alcohols, such as isopropanol, n-propanol, butanol, iso-butanot, ketones (e.g. acetone), THF, dioxane, acetonitr ⁇ e. Nevertheless, the process is not limited to solvent systems containing water if the freezing point of the solvent system is relatively high.
  • amorphous candesartan cilexetil is prepared by the step wherein the solution of candesartan ciiexetii is evaporated to dryness at temperatures lower than 60 0 C, preferably lower than 40 0 C to collect amorphous material.
  • Appropriate solvents are low boiling point solvents as for example alcohols, ketones and halogenated hydrocarbons, most preferable dichioromethane. As drying technique thin layer evaporation can be used.
  • amorphous candesartan cilexetil can be prepared by precipitation.
  • Candesartan cilexetil is dissolved in organic solvents such as for example DMSO (dimethyisulfoxide), DMA (dimethylacetamide) and n- methylpyrolidone at temperatures up to 50 0 C, preferably up to 30 0 C 1 more preferably between 20 and 25°C and then this solution is slowly added to water at temperature up to 50 0 C, preferably up to 30 0 C, more preferably between 20 and 25°C.
  • the suspension is stirred at the same temperature for at least 4 hours, filtered and dried.
  • the isoiated product is amorphous candesartan cilexetil.
  • Amorphous material, prepared by precipitation, can be optionally resuspended in a mixture of water and DMSO, DMA and N-methylpyrrolidone and the suspension is stirred for at least 2 hours. The stability of amorphous material is increased.
  • Amorphous candesartan ciiexetif prepared by the processes according to the present invention is further purified by the method of purification of candesartan ciiexetil according to the present invention.
  • Significant reduction in the ievel of impurities is achieved by isothermal conversion of amorphous candesartan ciiexetii to form I of candesartan ciiexetil at about room temperature without applying the process of cooling crystallization wherein the critical part in increasing the ievel of impurities represents dissolving of candesartan ciiexetii in a crystallization solvent at relative high temperature.
  • candesartan ciiexetil in solution is not stable at higher temperature such as for example above 5O 0 C. Therefore, crystallization as a purification method is not ideal.
  • candesartan ciiexetil form I below 10 ⁇ m can be easily obtained by the processes disclosed below. Such particles can be directly used in the preparation of pharmaceutical composition. No milling is required prior to formulation processing.
  • amorphous candesartan ciiexetil is directly converted to form I or form Ii either by crystallization, precipitation or conversion in a slurry or in a suspension.
  • One embodiment of the invention is directed towards a process for preparing form I from amorphous candesartan ciiexetil.
  • the process comprises dissolving amorphous candesartan ciiexetii in a solvent to form a solution, heating the solution at a temperature of 30 0 C to reflux, preferably of 40 0 C to 80 0 C, and precipitating candesartan ciiexetil form I with an anti-solvent, wherein the solution of candesartan ciiexetii may be added drop-wise to the anti-solvent, or the anti-solvent is added to the solution of candesartan ciiexetii.
  • the solvents applied may be alcohols, halogenated hydrocarbons and/or nitriles, and the anti-solvent may be esters and ethers.
  • the preferred solvents are ethanol, isopropanoi and methylene chloride, and as anti-solvents preferably, isopropyl acetate and tert-butyl methyl ether are applied.
  • the solution of candesartan ciiexetil is partly evaporated in vacuo until between 1/2 and 1/5 of the starting voiume remains in the vessel, and the anti- solvent is added to the concentrate, or the other way round.
  • the mixture is stirred and cooled below 30 0 C 1 preferably to a temperature between 15°C and 25°C, most preferably between 18 to 22°C for 0.5 to 24 h.
  • the process may further comprise drying crystalline candesartan ciiexetil at a temperature of 20 0 C to 6O 0 C.
  • Another process for preparing candesartan ciiexetil Form I comprises dissolving amorphous candesartan cilexeti! in a solvent at temperature below 40 0 C 5 preferably below 30 0 C, to form a saturated soiution of candesartan ciiexetil, and slowly cooling the solution to a temperature between -15°C to 25°C, preferably between 15°C and 25 0 C, most preferably between 18°C and 22°C.
  • solvents esters, ethers and hydrocarbons preferably iso-propanol or isopropyl acetate may be used.
  • Another process for preparing candesartan ciiexetil form I comprises conversion of amorphous candesartan ciiexetil to stabile candesartan ciiexetil form ! by suspending amorphous candesartan ciiexetil in an organic solvent, such as for example aikyl acetates, preferably isopropyl acetate, at about 20 0 C to about 30 0 C for approximately 12 hours.
  • an organic solvent such as for example aikyl acetates, preferably isopropyl acetate
  • Another embodiment of the invention is directed towards a process for preparing form Il from amorphous candesartan ciiexetil.
  • the process comprises dissolving amorphous candesartan ciiexetil in a solvent to form a solution, heating the solution to a temperature between 30 0 C and reflux temperature, preferably at a temperature between 30 0 C to 50 0 C, and precipitating candesartan ciiexetil form Ii with an anti- solvent, wherein the solution of candesartan ciiexetil may be drop-wise added to the anti-solvent.
  • the anti-solvent is added drop-wise to the solution of candesartan ciiexetil, and the solution of candesartan ciiexetil is optionally seeded with crystals of form H candesartan ciiexetil.
  • suitable solvents such as ketones (e.g. acetone), tetrahydrofurane, carbonates (e.g. dimethyl carbonate, diethyl carbonate ⁇ , butyl chloride, or esters, may be used, and as the anti-so!vent solvents such as alkanes (e.g. cyclohexane, cyclopentane, methyl cyclohexane), aromatic hydrocarbons (e.g.
  • esters such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, ethyl propionate, propyl propionate
  • ethers may be used.
  • acetone is used as the solvent and a cycloalkane, most preferably cyclohexane, is used as the anti-solvent.
  • the solvent wherein candesartan ciiexetil is dissolved, is partly evaporated in vacuo until between 1/2 and 1/5 of the starting volume remains in the vessel, and the anti-solvent is added to the concentrate. After the addition of the anti- solvent, the mixture is stirred and cooled to below 25°C for 0.5 to 24 h.
  • the process may further comprise drying candesartan ciiexetil form Il at a temperature between 25°C to 50 0 C.
  • Another process for preparing candesartan cilexeti! form Il comprises dissolving candesartan ciiexetil in a solvent, heating the solution to a temperature of 30 0 C to reflux temperature, preferably at a temperature between 50 to 70 0 C to form a saturated solution of candesartan cilexetii, which is optionally seeded with crystals of form Il candesartan cilexetii, and cooling the solution to a temperature between 40 0 C to -10 0 C, preferably to a temperature between 25°C to -15°C.
  • Suitable solvents for the crystallization of form Ii of candesartan ciiexetil are ketones (e.g.
  • ethers e.g. cyclopenty ⁇ methyl ether
  • haiogenated hydrocarbons or haiogenated aromatic hydrocarbons e.g. 1 ,2-dichloroethane, butyl chloride, ⁇ , ⁇ , ⁇ -trifluorotoluene
  • carbonates e.g. diethyl carbonate, dimethyl carbonate
  • dimethoxyethane and mixtures thereof.
  • Form Il candesartan ciiexetil may also be prepared by slurrying amorphous candesartan ciiexetil at a temperature between O 0 C and 80 0 C for 0.5 - 48h, in a suitable solvent system, comprising a solvent from the group of hydrocarbons (e.g. cyclohexane), ethers, and water, and a solvent from the group of acetone, THF, and haiogenated hydrocarbons.
  • a suitable solvent system comprising a solvent from the group of hydrocarbons (e.g. cyclohexane), ethers, and water, and a solvent from the group of acetone, THF, and haiogenated hydrocarbons.
  • a mixture of acetone and cyclohexane is used, in a volume to volume ratio of between 1 :10 to 10:1.
  • amorphous candesartan cilexetil is thermally converted to form Il candesartan cilexetil by suspending it in a suitabe inert solvent or solvent system wherein amorphous candesartan cilexetil is suspended, and slowly heating the suspension to a temperature up to 120°C.
  • candesartan cilexetil form I! is filtered, optionally washed with the inert solvent or solvent system applied, and dried at a temperature of between 20 0 C - 80 0 C.
  • the solvent system comprises a solvent from the group of hydrocarbons (e.g. cyciohexane), ethers, and water, and a solvent from the group of acetone, THF, or halogenated hydrocarbons.
  • the present invention is illustrated by the following Examples without being limited thereto.
  • Example 1 Purification of candesartan cilexefH under reversed conditions
  • Example 3 Purification of candesartan cifexetif by supercritical chromatography
  • Example 4 Purification of candesartan cilexeti! by supercritical chromatography
  • Example 8 0.5 g of candesartan cilexetil is suspended in 10 mL of acetone under reflux temperature of the mixture (60 0 C). To the refluxing solution 5 mL of water are dropwise added. The hot solution is frozen with liquid nitrogen and iyophilized on a HETO HOLTEN ModelCD 52-1 apparatus at a pressure of 0.03 mbar.
  • Example 8
  • candesartan ciiexetil 3.0 g of candesartan ciiexetil is dissolved in 9 m!_ of 1 -methylpyrrolidin-2-one at 20- 25°. The solution is then slowly dropwise added into 60 mL of water and stirred at 20- 25°C. The mixture is stirred for 6-10 hours, filtered and dried under vacuum at 38°C until dryness. 2.7 g of amorphous candesartan ciiexetil is obtained.
  • candesartan ciiexetil 3.0 g of candesartan ciiexetil is dissolved in 20 mL of dimethyl sulfoxide at 20-25°C. The solution is then slowly dropwise added into 60 mL of water and stirred at 20- 25°C. The mixture is stirred for 10 hours, filtered and dried under vacuum at 38°C until dryness. 2.8 g of amorphous candesartan ciiexetil is obtained.
  • candesartan ciiexetil 3.0 g of candesartan ciiexetil is dissolved in 6 mL of /V,W-dimethylacetamide at 20- 25°C. The solution is then slowiy dropwise added into 50 mL of water and stirred at 20-25 0 C. The mixture is stirred for 4-12 hours, filtered and dried under vacuum at 38°C until dryness. 2.7 g of amorphous candesartan ciiexetil is obtained.
  • amorphous candesartan ciiexetil 0.5 g is dissolved in 2 ml of isobutanol at an elevated temperature, hot filtered and stirred for 1 h at room temperature and 2 h at 0 0 C. The precipitate is filtered and dried for 17 h in a vacuum drier at a temperature of 25°C and 0.47 g of candesartan ciiexetil Form I is isolated.
  • amorphous candesartan ciiexetil 0.5 g is dissolved in 2 ml of isoamyi alcohol at an elevated temperature, hot filtered and stirred for 1 h at room temperature and 2 h at 0 0 C. The precipitate is filtered and dried for 17 h in a vacuum drier at a temperature of 25°C and 0.46 g of candesartan ciiexeti! Form I is isolated.
  • Amorphous candesartan ciiexetii (10 g) is suspended in 50 mL of isopropyi acetate at 25 0 C. The temperature of the suspension is kept constant. Stirring is continued at constant temperature for 12 hours to convert amorphous material to candesartan ciiexeti! form I. The suspension is filtered, washed with isopropyl acetate and dried for 2 hours at 38 0 C. Yield: 7,7g, HPLC purity 99.6%, average particle size is 8 ⁇ m, as showed in Figure 1 D.) Preparation of Form Il candesartan cilexeti! from amorphous candesartan cilexeti!
  • amorphous candesartan cilexetil is dissolved in 6 ml_ of acetone at a temperature between 30 and 40 0 C.
  • 4 ml_ of cyciohexane are drop-wise added to the solution of candesartan ciiexetil at room temperature. The mixture is stirred over night and filtered after 24 hours. 0.43 g of candesartan cilexetil Form Il is isolated.
  • amorphous candesartan cilexetil is dissolved in 6 ml of acetone at a temperature of ca. 35 0 C. 4 mL of cyciohexane are dropwise added to the solution of candesartan cilexetil. The mixture is cooled to 25°C, stirred for 20 h, and filtered. 0.41 g of candesartan cilexetil Form H is isolated.
  • amorphous candesartan cilexeti! is suspended in 5 ml of mixture (cyciohexane / acetone (3 : 1 , v;v)). The mixture is slurried at 25 to 30 0 C for 0.5 h, filtered and dried. 0.42 g of candesartan cilexetii of Form Il is isolated.
  • the oily residue obtained is dissolved in 60 ml of isopropyi acetate and the mixture is stirred at room temperature (between 15 and 25°C) for approximately 7 hours.
  • the precipitate is filtered and dried for 2 hours at 45°C.
  • 10.7 g of a partially wet product are obtained which are further suspended in 107 ml of tert- butyl methyl ether for 1 hour at room temperature.
  • the product is dried overnight at room temperature.
  • Example 21 Detection of candesartan cilexetil pyran in candesartan c ⁇ exeti! by HPLC
  • HPLC (external standard method) was performed using the following specifications :
  • Example 22 Detection of cilexetil pyran in 1-chioroethyf cyciohexylcarbonate by GC
  • Carrier gas helium
  • Air flow rate 400 ml/min

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Abstract

La présente invention concerne des procédés permettant de préparer, de façon économique, du candésartan cilexétil amorphe et cristallin d'une qualité conforme aux directives Ph.Eur./ICH, à l'aide de substances facilement accessibles et de composés de départ purs.
PCT/EP2007/057803 2006-07-28 2007-07-27 Procédé de préparation de formes amorphes et cristallines de candésartan cilexétil par chromatographie sur colonne WO2008012371A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP07788016A EP2066649A1 (fr) 2006-07-28 2007-07-27 Procédé de préparation de formes amorphes et cristallines de candésartan cilexétil par chromatographie sur colonne
NO20090703A NO20090703L (no) 2006-07-28 2009-02-13 Fremgangsmate for fremstilling av amorfe eller krystallinske former av kandesartan cilexetil ved hjelp av kolonnekromatografi

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
SIP-200600176 2006-07-28
SI200600176A SI22340A (sl) 2006-07-28 2006-07-28 Postopki za pripravo amorfnih in kristalnih oblikkandesartan cileksetila
SIP-200700068 2007-03-20
SI200700068A SI22491A (sl) 2007-03-20 2007-03-20 Postopeki za pripravo amorfnih in kristalnih oblik kandesartan cileksetila
SI200700126 2007-05-30
SIP-200700126 2007-05-30

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WO2008012371A1 true WO2008012371A1 (fr) 2008-01-31

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PCT/EP2007/057804 WO2008012372A1 (fr) 2006-07-28 2007-07-27 Procédé de préparation de la forme i du candésartan cilexétil

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Cited By (2)

* 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
CN106770851A (zh) * 2016-12-21 2017-05-31 广东省农业科学院农业生物基因研究中心 一种液相色谱法测定类胡萝卜素的流动相配方及其应用

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2364011B1 (es) 2009-11-20 2013-01-24 Gp Pharm, S.A. Cápsulas de principios activos farmacéuticos y ésteres de ácidos grasos poliinsaturados para el tratamiento de enfermedades cardiovasculares.
JP5850697B2 (ja) * 2011-10-18 2016-02-03 株式会社トクヤマ カンデサルタンシレキセチルの製造方法

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0459136A1 (fr) * 1990-04-27 1991-12-04 Takeda Chemical Industries, Ltd. Dérivés de benzimidazole, leur préparation et utilisation
EP0617036A2 (fr) * 1993-03-16 1994-09-28 American Cyanamid Company Composés de carbapénème substitués sur la position 2
EP0668272A2 (fr) * 1994-01-28 1995-08-23 Takeda Chemical Industries, Ltd. Un procédé de production de composés de tétrazole
WO2004039352A2 (fr) * 2002-10-31 2004-05-13 Ranbaxy Laboratories Limited Forme amorphe de losartan potassium
EP1437352A1 (fr) * 2001-09-25 2004-07-14 Takeda Chemical Industries, Ltd. Compose de benzymidazole, procede de production et d'utilisation de celui-ci
EP1445249A1 (fr) * 2001-11-16 2004-08-11 Toyama Chemical Co., Ltd. Nouveaux derives de benzophenone ou sels de ceux-ci
WO2004071486A1 (fr) * 2003-02-10 2004-08-26 Chemagis Ltd. Melanges amorphes de solides, procedes d'elaboration correspondants, et compositions pharmaceutiques en contenant
US20050250828A1 (en) * 2004-02-11 2005-11-10 Entire Interest Candesartan cilexetil polymorphs
WO2005111021A1 (fr) * 2004-05-05 2005-11-24 Teva Pharmaceutical Industries Ltd. Elaboration de of candesartan cilexetil de purete elevee
WO2005123720A1 (fr) * 2004-06-18 2005-12-29 Ranbaxy Laboratories Limited Fines particules d'un antagoniste de l'angiotensine ii a base de candesartan cilexetil et leur procede de production

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005037821A2 (fr) * 2003-10-16 2005-04-28 Teva Pharmaceutical Industries Ltd. Preparation de candesartan cilexetil
CA2611293A1 (fr) * 2005-06-06 2007-07-05 Medichem, S.A. Procede de preparation de composes tetrazolyle

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0459136A1 (fr) * 1990-04-27 1991-12-04 Takeda Chemical Industries, Ltd. Dérivés de benzimidazole, leur préparation et utilisation
EP0617036A2 (fr) * 1993-03-16 1994-09-28 American Cyanamid Company Composés de carbapénème substitués sur la position 2
EP0668272A2 (fr) * 1994-01-28 1995-08-23 Takeda Chemical Industries, Ltd. Un procédé de production de composés de tétrazole
EP1437352A1 (fr) * 2001-09-25 2004-07-14 Takeda Chemical Industries, Ltd. Compose de benzymidazole, procede de production et d'utilisation de celui-ci
EP1445249A1 (fr) * 2001-11-16 2004-08-11 Toyama Chemical Co., Ltd. Nouveaux derives de benzophenone ou sels de ceux-ci
WO2004039352A2 (fr) * 2002-10-31 2004-05-13 Ranbaxy Laboratories Limited Forme amorphe de losartan potassium
WO2004071486A1 (fr) * 2003-02-10 2004-08-26 Chemagis Ltd. Melanges amorphes de solides, procedes d'elaboration correspondants, et compositions pharmaceutiques en contenant
US20050250828A1 (en) * 2004-02-11 2005-11-10 Entire Interest Candesartan cilexetil polymorphs
WO2005111021A1 (fr) * 2004-05-05 2005-11-24 Teva Pharmaceutical Industries Ltd. Elaboration de of candesartan cilexetil de purete elevee
WO2005123720A1 (fr) * 2004-06-18 2005-12-29 Ranbaxy Laboratories Limited Fines particules d'un antagoniste de l'angiotensine ii a base de candesartan cilexetil et leur procede de production

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KUBO K ET AL: "NONPEPTIDE ANGIOTENSIN II RECEPTOR ANTAGONISTS. SYNTHESIS AND BIOLOGICAL ACTIVITY OF POTENTIAL PRODRUGS OF BENZIMIDAZOLE-7-CARBOXYLIC ACIDS", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 36, no. 16, 1993, pages 2343 - 2349, XP001008066, ISSN: 0022-2623 *

Cited By (2)

* 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
CN106770851A (zh) * 2016-12-21 2017-05-31 广东省农业科学院农业生物基因研究中心 一种液相色谱法测定类胡萝卜素的流动相配方及其应用

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EP2066649A1 (fr) 2009-06-10

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