WO2008012371A1

WO2008012371A1 - Process for the preparation of amorphous and crystalline forms of candesartan cilexetil using column chromatography

Info

Publication number: WO2008012371A1
Application number: PCT/EP2007/057803
Authority: WO
Inventors: 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 dd
Current assignee: KRKA dd
Priority date: 2006-07-28
Filing date: 2007-07-27
Publication date: 2008-01-31
Anticipated expiration: 2009-01-28
Also published as: EA200900068A1; EP2066649A1; WO2008012372A1; NO20090703L; EP2049510A1

Abstract

The present invention provides processes for the preparation of amorphous and crystalline candesartan cilexetil with quality that complies to Ph.Eur./ICH Guidelines by an economical way using easy accessible substances and pure starting compounds.

Description

PROCESS FOR THE PREPARATION OF AMORPHOUS AND CRYSTALLINE FORMS OF CANDESARTAN CILEXETIL USING COLUMN CHROMATOGRAPHY

Field of the invention

The present invention relates to improved processes for the manufacture of amorphous and crystalline candesartan cilexetil.

Background of the invention

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! carbonate (ester), with candesartan being the underlying carboxyϋc acid, i.e. 2-Ethoxy-1 ~(p-(o-1 H-tetrazol-5-ylphenyl)benzyl)-7-benz- imidazolecarboxylic acid.

Because of its ability to inhibit the angiotensin-converting enzyme it is widely used for the treatment of hypertension and related diseases and conditions. As an angiotensin M receptor antagonist, candesartan cϋexetil 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

0 720 982 B1 and EP 0 459 136.

As is indicated herein below, it would be of great benefit to provide more efficient and more economical technological processes for providing candesartan cilexeti! in the amorphous and in crystalline forms.

US 5,196,444 disclosed the C-type crystal (Form I) of candesartan cilexeti!, and processes for producing it under acidic conditions.

Further on, in Chem. Pharm, Bull. 47(2), 182-186 (1999) two crystalline forms (Form

1 and Sl), together with an amorphous form, are disclosed and characterized by their DSC thermograms, X-ray diffraction patterns and IR spectra.

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 cϋexetil by precipitating it with a liquid cyclic hydrocarbon from a solution of candesartan cilexetil in a chlorinated solvent.

In WO 2005/123721 processes for the preparation of amorphous candesartan cilexetil are provided, comprising spray-drying and precipitation.

Brief description of drawing

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.

Further the present invention provides improved processes for the preparation of an amorphous form of candesartan ciiexetil by lyophiϋzation, 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. In one of the embodiments, 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).

Moreover, the present invention provides a preparation of candesartan ciiexetil containing less than 0.15%, preferably less than 0.10%, of candesartan ciiexetil pyran. In a further aspect, 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. Moreover, 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. As used herein, the term "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.

The term "reduced pressure" refers to a pressure below one atmosphere, more preferably below about 100 mmHg.

As used herein, the term "precipitation" refers to the formation of a suspension of small solid particles in a mixture.

As used herein, the term "crystallization" refers to a process for forming crystals from a liquid or gas.

As used herein, the expressions "freeze-drying" and "iyophilization" are interchangeable.

Detailed description of the invention

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.

In the first embodiment, 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.

It is important to control the size of the particles of candesartan cilexetil during its preparation. The average particle size of particles used according to the present invention is 10 to 100 μm, preferably below 50 μm, more preferably below 20 μm, and even more preferably below 10 μm 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 μm 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 μm average diameter may be produced. Moreover, the milling process can convert the crystal form of candesartan cilexetil to its amorphous form. For this purpose air jet mills, ball miils or hammer mills are commonly used as milling equipment. However, it is not enough to control only the average size of particles, but the particle size distribution should be controlled as well.

It has unexpectedly been found that the contacting of candesartan cilexetil solution with a solid phase results in the reduction of a number of impurities to a level which allows the preparation of solid oral dosage forms not suffering from stability problems in terms of formation of impurities upon storage. It was also found that this process allows the purification of solutions having a high concentration of candesartan cilexetii which makes the process very attractive also from an economic standpoint.

Under normal chromatographic conditions, preferably unmodified silica (5-63 μm), amino modified silica (amino phase, 5 - 40 μm), cyano modified silica (cyano phase, 5 - 40 μm), dio! modified siiica (diol phase, 10 μm), which are commercially available under the names of Nucleosil, Nucleodur, Polygosil, Polygoprep, Chromolith prep., can be used as the stationary phase. As the mobile phase, ethanol, methanol, iso- propanol, TBME {tert. butyl methyl ether), THF, acetonitrile, water, n-pentane, n- hexane, n-heptane, , methylene dichloride, ethyl acetate, acetone, toluene, dioxane, chloroform, acetic acid (0,05% - 0,2% w/w) and trifluoroacetic acid (0,05% -2% w/w), or mixtures thereof may be used. The sample elution may be achieved by isocratic or gradient eiution.

Under reverted (reverse phase) chromatographic conditions, preferably 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. As the mobile 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 may be used. The sample elution may be achieved by isocratic or gradient elution.

When using supercritical chromatography, preferably Silica 3-10 μm and diol modified silica 3-10 μm; cyano modified silica 3-10 μm may be used as the stationary phase. As the mobiie phase alcohols such as methanol, ethanol and 2-propanoi as well as acetonitrile with CO₂ 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, 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.

(il) ("I)

When preparing candesartan cϋexetil (I) by the above mentioned method the tevef of detected impurities in the final substance increases significantly. Surprisingly it was found that the starting compound 1 -chloroethyi cyclohexylcarbonate or any other halogen derivative thereof has a great influence on the impurity level in the final candesartan cilexetil (I). Namely, it was found that in case that the starting compound contains a compound of formula (IV)

wherein one of A, B, and C is an Oxygen atom and the other two are -CH2-, and wherein X means Cl, Br, or I.

as an impurity, the compound with formula (V)

wherein one of A, B, and C is an Oxygen atom and the other two are -CH2-,

can be detected in the final candesartan cilexeti! substance (I). The drawback of the impurity of formula (V) is that it can hardly be separated from the final substance by the known conventiona! methods. Only appropriate quality of starting compound 1 - haloethyi cyciohexyicarbonate, wherein haio means Cl, Br, I, concerning related substances/impurities enables obtaining the final substance candesartan cilexetii with a quality that complies with Ph.Eur./ICH Guidelines. Therefore, in view of the impurity profile of the obtained final pharmaceutical active ingredient candesartan cilexetii, it is very important to detect and identify the undesired impurity in the synthetic pathway of candesartan cilexetii as soon as it appears. Moreover, it is very important to keep the original level of the identified impurity as low as possible or even better, to avoid its formation, if possible at all. Furthermore, it is known that only isolation and characterization of impurities assure better control of a manufacturing process and enables easier setting of limits of impurities.

As used herein 'cilexetii pyran¹ refers to the compound with formula (IV). An alternative notation for the compound of formula (!V) is

wherein X means Cl₁ Br or I and wherein the O atom can be in ortho, meta or para position

As used herein 'candesartan cilexetil pyran' refers to the compound with formula (V). An alternative notation for the compound of formula (V) is

wherein the Oxygen atom can be in ortho, meta or para position.

Therefore, 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.

In another embodiment 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). Optionally, 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 (lyophilization) are those containing water miscϊble 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, acetonitrϋe. Nevertheless, the process is not limited to solvent systems containing water if the freezing point of the solvent system is relatively high.

According to another embodiment of the present invention amorphous candesartan cilexetil is prepared by the step wherein the solution of candesartan ciiexetii is evaporated to dryness at temperatures lower than 60 ⁰C, preferably lower than 40 ⁰C 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.

In another embodiment 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 50⁰C, preferably up to 30⁰C₁ more preferably between 20 and 25°C and then this solution is slowly added to water at temperature up to 50⁰C, preferably up to 30⁰C, 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. We found that candesartan ciiexetil in solution is not stable at higher temperature such as for example above 5O⁰C. Therefore, crystallization as a purification method is not ideal.

Moreover, we surprisingly found that the average particle size of candesartan ciiexetil form I below 10 μm 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.

Following the preparation of amorphous candesartan ciiexetil from the previous embodiments of the present invention 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 30⁰C to reflux, preferably of 40⁰C to 80⁰C, 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.

Optionally 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. After combining the solution of candesartan ciiexetil and the anti-solvent, the mixture is stirred and cooled below 30⁰C₁ 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 20⁰C to 6O⁰C.

Another process for preparing candesartan ciiexetil Form I comprises dissolving amorphous candesartan cilexeti! in a solvent at temperature below 40⁰C₅ preferably below 30⁰C, 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 25⁰C, most preferably between 18°C and 22°C. As 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 20⁰C to about 30⁰C for approximately 12 hours.

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 30⁰C and reflux temperature, preferably at a temperature between 30⁰C to 50 ⁰C, 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. Alternatively, 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. As 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. toluene), esters (such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, ethyl propionate, propyl propionate), and ethers may be used. Preferably acetone is used as the solvent and a cycloalkane, most preferably cyclohexane, is used as the anti-solvent.

Optionally, 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 ⁰C.

Another process for preparing candesartan cilexeti! form Il comprises dissolving candesartan ciiexetil in a solvent, heating the solution to a temperature of 30⁰C to reflux temperature, preferably at a temperature between 50 to 70⁰C 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 40⁰C to -10 ⁰C, 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. acetone, A- methyl-2-pentanone), ethers (e.g. cyclopentyϊ methyl ether), haiogenated hydrocarbons or haiogenated aromatic hydrocarbons (e.g. 1 ,2-dichloroethane, butyl chloride, α, α, α -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 O⁰C and 80⁰C 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. Preferably, a mixture of acetone and cyclohexane is used, in a volume to volume ratio of between 1 :10 to 10:1. in the last embodiment of the present invention, 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. After the thermal conversion is completed, candesartan cilexetil form I! is filtered, optionally washed with the inert solvent or solvent system applied, and dried at a temperature of between 20⁰C - 80⁰C. 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 crystalline forms of the products obtained by the above processes crystallized are the same as described in Chem. Pharm, BuIi. 47(2) 182-186 (1999).

During the crystallization process and during the filtration solvates of candesartan cilexetil may be formed.

The present invention is illustrated by the following Examples without being limited thereto.

Melting points were taken on a Koffler melting point apparatus and IR spectra were taken on a Paragon 100 Perkin-Elmer FT-IR spectrometer. Particle sizes were determined on a Malvern 2000 Masters izer.

Examples

A.) Purification of candesartan cilexetil

Example 1 : Purification of candesartan cilexefH under reversed conditions

Equipment:

HPLC: Preparative Knauer HPLC System

Data evaluation: Eurochrome

Chromatographic conditions:

Column: Synergy MAX_RP 250 X21 ,2 mm

Mobile Phase: 0,01 M phosphate buffer pH = 2,5: acetonitrile

Gradient: 0 min: 50 vol.% NaH₂PO₄, 50 voi.% acetonitrile; 10-15 min: 20% NaH₂PO₄, 80% acetonitrile; 15.5 - 20 min 50 vol.% NaH₂PO₄, 50 vol.% acetonitriie Post run: 5 min

Column temp,: 25°C Flow rate: 25ml/min Detection: UV₁ 225 nm Injection volume: 1 mL

Example 2: Purification of candesartan ciiexeti! under normal conditions

Equipment: Preparative Knauer HPLC System Data evaluation: Eurochrome

Chromatographic conditions:

Column: Nucleosil - unmodified silica 250 X 16 mm Mobile Phase: hexane; EtOH = 40 : 60 isocratic elution

Column temp.: 25°C

Flow rate: 24 mL/min

Detection: UV, 225 nm

Injection volume: 1 ml

Example 3: Purification of candesartan cifexetif by supercritical chromatography

Equipment: Thar SFC system

Chromatographic conditions: Column: YMC silica 5 μm, 250 x 4.6 mm Mobile Phase: methanol and CO₂ Gradient: 0-9 min: 12 % methanol in CO₂; 9-15 min: 70% methanol in CO₂

Post run: 3 min Column temp.: 40⁰C Flow rate: 3.0 mL/min Detection: UV 225 nm Injection volume: 10 μl_

Example 4: Purification of candesartan cilexeti! by supercritical chromatography

Equipment: Thar SFC system Chromatographic conditions: Column: Kromasil Diol 5 μm, 250 x 4.6 mm Mobile Phase: 45 % acetonitile and 55 % CO₂ Column temp.: 40⁰C Flow rate: 3.0 mL/min Detection: LJV 225 nm Injection volume: 10 μL

B.) Preparation of amorphous candesartan cilexetil

Example 5:

0.5 g of candesartan ciiexeti! is suspended in 3 mL of THF under reflux (60⁰C). To the refluxing suspension 5 mL of water are dropwise added, together with additional 12 mL of THF. The solution is cooled to 25°C, frozen with liquid nitrogen and lyophilized on a HETO HOLTEN ModelCD 52-1 apparatus at a pressure of 0.03 mbar.

Example 6:

0.5 g of candesartan cϋexetil is suspended in 10 mL of 2-propanol under reflux temperature of the mixture (70⁰C). To the refluxing solution 5 mL of water are dropwise added. The hot solution is frozen with liquid nitrogen and lyophilized on a HETO HOLTEN ModelCD 52-1 apparatus at a pressure of 0.03 mbar.

Example 7:

0.5 g of candesartan cilexetil is suspended in 10 mL of acetone under reflux temperature of the mixture (60⁰C). 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:

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.

Example 9:

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.

Example 10:

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 20-25⁰C. 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.

C.) Preparation of Form I candesartan citexeti! from amorphous candesarfan ciiexetil

Example 11 :

1 g of amorphous candesartan cilexetii is dissolved in 2 ml of amyl alcohol at an elevated temperature, hot filtered and mixed for 1 h at room temperature. The precipitate is filtered and dried for 1 h in a vacuum drier at a temperature of 45°C and 0.97 g of candesartan ciiexetil Form I is isolated. Example 12:

1 g of amorphous candesartan ciiexeti! is dissolved in 1.1 mi of methylene dichioride at an elevated temperature, and 11 ml of isopropyl acetate are slowly added. The mixture is stirred for 1 h at room temperature and for 1 h on an ice-bath. The precipitate is filtered and dried for 1 h in a vacuum drier at a temperature of 45°C and 0.57 g of candesartan ciiexetil Form I is isolated.

Example 13:

0.5 g of amorphous candesartan ciiexetil 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 0⁰C. 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.

Example 14:

0.5 g of amorphous candesartan ciiexetil 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 0⁰C. 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.

Example 15:

Amorphous candesartan ciiexetii (10 g) is suspended in 50 mL of isopropyi acetate at 25 ⁰C. 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 ⁰C. Yield: 7,7g, HPLC purity 99.6%, average particle size is 8 μm, as showed in Figure 1 D.) Preparation of Form Il candesartan cilexeti! from amorphous candesartan cilexeti!

Example 16:

0.5 g of amorphous candesartan cilexetil is dissolved in 6 ml_ of acetone at a temperature between 30 and 40⁰C. 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.

Example 17;

0.5 g of amorphous candesartan cilexetil is dissolved in 6 ml of acetone at a temperature of ca. 35 ⁰C. 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.

Example 18:

0.5 g of amorphous candesartan cilexeti! is suspended in 5 ml of mixture (cyciohexane / acetone (3 : 1 , v;v)). The mixture is slurried at 25 to 30⁰C for 0.5 h, filtered and dried. 0.42 g of candesartan cilexetii of Form Il is isolated.

E.) Synthesis of candesartan ciiexetil

Example 19: Preparation of trityl candesartan ciiexeti! (II)

20.40 g (30 mmol) of trityl candesartan (III), 30 mL of dimethylacetamide (DMA); 4.95 g (235.9 mmol) K₂CO₃ and 10.2 g (49.4 mmol) of 1 -chloroethyl cycfohexyf carbonate are heated at 60⁰C for 4 hours. The reaction mixture is cooled to room temperature, and 240 ml of isopropyl acetate and 240 mi of water are added. The organic phase is separated from the aqueous phase and the aqueous phase is extracted again with 240 m! of isopropyi acetate. The combined organic phases are washed with 2x240 ml of water, filtered and the volatile components are evaporated in vacuum. To the oily residue 150 m! of tert-butyl methyl ether are added and the mixture is stirred at room temperature for at least 15 hours. The precipitate is filtered and dried for 2 hours at 40⁰C in a vacuum dryer. 25.09 g (98%) of compound (II) are obtained (HPLC: more than 98%).

Example 20: Preparation of candesartan ciEexetϊl (1)

17.06 g (20 mmol) of trityf candesartan cilθxetil, 60 ml MeOH, 240 ml methylene chloride and 2.39 g (17.5 mmol) ZnCi₂ are heated under reflux for 4 hours. After the reaction is completed, the reaction mixture is cooled to approximately 30⁰C, 200 ml of water are added, the organic and the aqueous phase are separated and the organic phase is washed with 2 x 200 ml of water and dried with Na₂SO₄ until the water content is below 0.3%, and the volatile components are evaporated to yield 18 g of an oily residue. 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.

F) Detection of impurities in candesartan ciSexetil

Example 21 : Detection of candesartan cilexetil pyran in candesartan cϋexeti! by HPLC

HPLC (external standard method) was performed using the following specifications :

Column: Zorbax Eclipse XDB-C18, 50 mm x 4.6 mm i.d., 1.8 μm particles

Eluent A: 0.01 M NaH₂PO₄, pH 2.5

Eluent B: acetonitrile Gradient of Eluent:

Flow rate: about 1.2 ml/min Diluent: acetonitrile : water = 70 : 30 (V/V). Detection: UV, wavelength 225 nm Injection volume: 5 μl Column temperature 50 ^°⁰C

Autosampler temperature: 7 ⁰C

Example 22: Detection of cilexetil pyran in 1-chioroethyf cyciohexylcarbonate by GC

GC/FiD (area percent method) was performed using the following specifications:

Column: capillary (fused-silica) AT-WAX or adequate

Length: 30 m

ID: 0.32 mm

Film thickness: 0.25 μm

Carrier gas: helium

Carrier gas flow rate: 2.0 mi/min

Split ratio: 10 : 1

Air flow rate: 400 ml/min

Hydrogen flow rate: 40 mi/min

Make up gas flow N₂ rate: 25 ml/min Column temperature 10O⁰C (O min) → 10°C/min → 200⁰C (10 min or prolonged if necessary)

Injector temperature: 21 O⁰C

Detector temperature: 25O⁰C Injection volume : 1 μl

Diluent: Acetonitrile: chromatography grade.

Chromatographic system suitability

Signal/noise of 1 -chloroethyl cyclohexyl carbonate: not less than 10

Claims

1. A method of purification candesartan cilexetil by column chromatography using normal or reverse phase chromatographic conditions or by supercritical chromatography.

2. The method according to claim 1 characterized in that under normal chromatographic conditions the stationary phase is selected from the group consisting of unmodified silica, amino modified silica, cyano modified silica and diol modified silica.

3. The method according to claim 1 characterized in that under normal chromatographic conditions the mobile phase is selected from the group consisting of ethanol, methanol, iso-propanol, tert. butyl methyl ether, THF, acetonitriie, water, n- pentane, n-hexane, n-heptane, methylene chloride, ethyl acetate, acetone, toluene, dioxane, chloroform, acetic acid and trifluoroacetic acid (0.05% -2% w/w), or any mixtures thereof.

4. The method according to claim 1 characterized in that under reverse phase chromatographic conditions the stationary phase is selected from the group consisting of octyl phase, dodecyl phase and octadecyl phase.

5. The method according to claim 1 characterized in that under reverse phase chromatographic conditions the mobile phase is selected from the group consisting of phosphate buffer, acetate buffer, trifluoroacetic acid, acetic acid, acetonitriie, methanol, ethanol, iso-propanol and dioxane or any mixtures thereof.

6. The method according to claim 1 characterized in that under supercritical chromatography the stationary phase is selected from the group consisting of silica, diol modified silica and cyano modified silica.

7. The method according to claim 1 characterized that under supercritical chromatography the mobile phase is selected from the group consisting of methanol, ethanoϊ, iso-propanol and acetonitrile with CO₂ or any mixtures thereof.

8. Candesartan ciiexetil containing less than 0.15%, preferably less than 0.10%, of candesartan ciiexetil pyran of formula (V).

9. Use of candesartan ciiexetil according to claim 8 for the preparation of oral dosage forms.

10. A pharmaceutical composition comprising candesartan ciiexetil according to claim 8.

11. Use of candesartan ciiexetil according to claim 8 for the manufacture of a medicament for treating hypertension and related diseases.

12. 1 -haloethyl cyciohexyicarbonate, wherein haio means Cl, 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 ciiexetil pyran of formula (V).

13. A compound of formula (IV)

wherein one of A, B, and C is an oxygen atom and the other two are --CH2- and wherein X means CI, Br or I.

14. A compound of formula (V)

wherein one of A, B, and C is an oxygen atom and the other two are -CH2-.

15. A process for the preparation of crystalline candesartan cilexeti! comprising the steps of: a) purification of candesartan ciiexetil by column chromatography using norma! or reverted chromatographic conditions or by supercritical chromatography, b) preparation of amorphous candesartan ciiexetil from fractions containing candesartan cilexetii, c) conversion of amorphous candesartan ciiexetil to crystalline form I and/or form

Il d) isolation of crystalline candesartan cilexetii form I or form II.

16. The process according to claim 15 wherein the purification of candesartan ciiexetil is performed by column chromatography using normal or reverted chromatographic conditions or by supercritical chromatography.

17. The process according to claims 15 to 16 characterized in that under normal chromatographic conditions the stationary phase is selected from the group consisting of unmodified silica, amino-modified silica, cyano-modified silica and diol- modified silica.

18. The process according to claims 15 to 17 characterized in that under normal chromatographic conditions the mobile phase is selected from the group consisting of ethanoi, methanol, iso-propanol, tert. butyl methyl ether, THF, acetonitrile, water, n- pentane, n-hexane, n-heptane, methylene chloride, ethyl acetate, acetone, toluene, dioxane, chloroform, acetic acid and trifluoroacetic acid (0,05% -2% w/w), or any mixtures thereof.

19. The process according to claims 15 to 18 characterized in that under reverted chromatographic conditions the stationary phase is selected from the group consisting of octyi phase, dodecyl phase and octadecyl phase.

20. The process according to claims 15 to 19 characterized in that under reverted chromatographic conditions the mobile phase is selected from the group consisting of phosphate buffer, acetate buffer, trifluoroacetic acid, acetic acid, acetonitrile, methanol, ethanol, isopropanol and dioxane or any mixtures thereof.

21. The process according to claims 15 to 20 characterized in that under supercritical chromatography the stationary phase is selected from the group consisting of silica, diol-modified silica and cyano-modified silica.

22. The process according to claims 15 to 21 characterized in that under supercritical chromatography the mobile phase is selected from the group consisting of methanol, ethanol, isopropanol and acetonitrile with CO₂ or any mixtures thereof.

23. The process according to claims 15 to 22 characterized in that amorphous candesartan ciiexeti! is prepared by lyophilization.

24. The process according to claims 15 to 23 characterized in that candesartan cilexetil is purified by chromatographic methods prior to lyophilization.

25. The process according to claim 24 wherein the solvent system after chromatographic elution is changed by distillation of fractions containing candesartan cilexetil, and addition of another solvent system.

26. The process according to claims 15 to 25 characterized in that the solution of candesartan ciiexetii is evaporated to dryness.

27, The process according to claim 26 wherein the temperature of drying is lower than 60⁰C, preferably lower than 40 ^^c0C.

28. The process according to claims 15 to 27 characterized in that amorphous candesartan cilexetil is prepared by precipitation,

29. The process according to claim 28 characterized in that it comprises dissolving of candesartan ciiexeti! in an organic solvent selected from the group consisting of dimethylsulfoxide, dtmethylacetamide and n-methylpyrrolidone, slow addition of the obtained solution to water, stirring, filtering and drying and optionally further resuspending and stirring.

30. The process according to claims 15 to 29 characterized in that candesartan cilexetil form I is prepared from amorphous candesartan cilexetil, wherein amorphous candesartan cilexetii is dissolved in a solvent to form a solution, heating the solution to a temperature of 3O⁰C to reflux, and precipitating candesartan cilexetil form I with an anti-solvent, wherein the solution of candesartan cilexetil may be added drop-wise to the anti-solvent, or the anti-solvent is added to the solution of candesartan ciiexeti!.

31. The process according to claim 30, wherein alcohols, halogenated hydrocarbons and/or nitrites are used as solvents, and esters and ethers are used as anti-solvents.

32. The process according to claims 15 to 31 characterized in that candesartan cilexetil form I is prepared from amorphous candesartan cilexetil, wherein amorphous candesartan cilexetil is dissolved in a solvent at temperature below 40⁰C, preferably below 30⁰C, to form a saturated solution of candesartan cilexetil, and slowly cooling the solution to a temperature between -15 to 25°C, preferably between 15 and 25⁰C, most preferably between 18 and 22°C.

33. The process according to claim 32, characterized in that the solvent is selected from the group consisting of alcohols, esters, ethers and hydrocarbons.

34. The process according to claim 33 characterized in that the solvent is isopropanoi or isopropy! acetate.

35. The process according to claims 15 to 34 characterized in that candesartan cilexetii form I is prepared from amorphous candesartan cilexetil, wherein amorphous candesartan ctlexetil is suspended in an organic solvent at a constant temperature between about 20 to about 30⁰C.

36. The process according to claim 35 wherein the organic solvent is alkyi acetate, preferably isopropyl acetate.

37. The process according to claims 15 to 36 characterized in that candesartan cilexetil form I! is prepared from amorphous candesartan cilexetii, wherein amorphous candesartan cilexetil is dissolved in a solvent to form a solution, heating the solution at a temperature between 30⁰C and reflux, and precipitating candesartan cilexetil form Il with an anti-solvent, wherein the solution of candesartan cilexetil may be drop-wise added to the anti-soivent, or the anti-solvent is drop-wise added to the solution of candesartan cilexetii, and the solution of candesartan cϋexetii is optionally seeded with crystals of form Il candesartan cilexetil.

38. The process according to claim 37, characterized in that ketones such as acetone, tetrahydrofurane, carbonates such as dimethyl carbonate and diethyl carbonate, butyl chloride, or esters, are used as solvents, and alkanes such as cyclohexane, cyclopentane and methyl cyclohexanes, aromatic hydrocarbons such as toluene, esters such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, ethyl propionate and propyl propionate, and ethers are used as anti-solvents.

39. The process according to claims 37 and 38, characterized in that acetone is used as the solvent and a cycloalkane, most preferably cyclohexane, is used as the anti-solvent.

40. The process according to claims 15 to 39 characterized in that candesartan cilexetil form Il is prepared from amorphous candesartan cϋexetil, wherein amorphous candesartan cϋexetil is dissolved in a solvent, heating the solution to a temperature of 30⁰C to reflux, 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 to -10 ⁰C.

41. The process according to claim 40, characterized in that ketones such as acetone and 4-methyl-2-pentanone, ethers such as cyciopentyl methyl ether, halogenated hydrocarbons or halogenated aromatic hydrocarbons such as 1 ,2- dichloroethane, butyl chloride and α,α,α-trifluorotoluene, carbonates such as diethyl carbonate and dimethyl carbonate, dimethoxyethane, and mixtures thereof are used as solvents.

42. The process according to claims 15 to 41 characterized in that candesartan cilexetii form Il is prepared from amorphous candesartan cilexetii, wherein amorphous candesartan cilexetii is slurried at a temperature between 0⁰C and 80⁰C for 0.5 - 48h, in a suitable solvent system.

43. The process according to claim 42, characterized in that the solvent system is selected from the group consisting of hydrocarbons such as cyclohexane, ethers, and water, and a solvent from the group consisting of acetone, THF and halogenated hydrocarbons.

44. The process according to claims 42 and 43, characterized in that the solvent system is a mixture of acetone and cyciohexane in a volume to volume ratio of between 1 :10 to 10:1.

45. The process according to claims 15 to 44 characterized in that candesartan cilexetii form H is prepared from amorphous candesartan cilexeti! by thermal conversion, wherein amorphous candesartan cilexetii is suspended in a suitable inert solvent or solvent system and slowly heating the suspension to a temperature up to 120 ⁰C.

46. The process according to claim 45, wherein the solvent system is comprised of a solvent from the group consisting of hydrocarbons such as cyclohexane, ethers, and water, and a solvent from the group consisting of acetone, THF or haiogenated hydrocarbons.

47. The process for the preparation of crystalline candesartan ctlexetil according to claims 15 to 46 characterized in that average particle size of candesartan cilexetif form i is below 10μm.

48. Use of form Il candesartan ciiexetil for the preparation of solid oral dosage forms.