WO2006048237A1

WO2006048237A1 - Novel polymorph forms of candesartan cilexetil

Info

Publication number: WO2006048237A1
Application number: PCT/EP2005/011689
Authority: WO
Inventors: Ljubomir Antoncic; Anton Copar; Alenka Jeriha
Original assignee: Lek Pharmaceuticals dd
Current assignee: Lek Pharmaceuticals dd
Priority date: 2004-11-03
Filing date: 2005-11-02
Publication date: 2006-05-11
Anticipated expiration: 2007-05-03
Also published as: EP1655298A1

Abstract

New crystalline forms of candesartan cilexetil is prepared from the solution in a chlorinated solvent by addition of an alkane while new amorphous is prepared from above solution by precipitating by addition of cycloalkane. The form depends on the concentration of a solute in a chlorinated solvent.

Description

NOVEL POLYMORPH FORMS OF CANDESARTAN CILEXETIL

FIELD OF THE INVENTION

The present invention relates to the novel process allowing control over formation of novel crystalline and amorphous forms of candesartan cilexetil, especially anhydrous forms having improved solubility and to pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION

Candesartan cilexetil is an antihypertensive agent and its therapeutic uses were disclosed in US 5,196,444, which also disclosed a crystalline form of candesartan cilexetil. Melting point of candesartan cilexetil is stated in J. Med. Chem. 36(16), 2343-2349 (1993) as being 163 ⁰C. Two crystalline forms of candesartan cilexetil, form I and form II, as well as the amorphous substance obtained by milling, are described and their IR spectra, DSC thermograms and X-ray diffraction patterns listed in Chem. Pharm. Bull. 47(2), 182-186 (1999). The amorphous powders mentioned in US 5,196,444 are said to be unstable by heat and impractical in production, which is consistent with the fact that the melting point of the amorphous solid mechanically obtained could not be specified.

Dioxane solvate and additional two crystalline forms of candesartan cilexetil were described in WO 04085426. Furthermore WO 05077941 , which was published after the priority date of the present application discloses certain hydrates and solvates of candesartan cilexetil.

The problem associated with administration of candesartan cilexetil is its low solubility, it is according to Merck index (13^th Edition) practically insoluble in water.

Present invention discloses new crystalline forms of candesartan cilexetil and, processes for preparing these forms as well as novel process to prepare amorphous candesartan cilexetil and pharmaceutical compositions containing them. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is an X-ray powder diffraction pattern of candesartan cilexetil Form 5.

Figure 2 is an X-ray powder diffraction pattern of candesartan cilexetil Form 5 of another batch.

Figure 3 is an X-ray powder diffraction pattern of candesartan cilexetil Form 6.

Figure 4 is an X-ray powder diffraction pattern of amorphous candesartan cilexetil

Figure 5 is a DSC thermogram of candesartan cilexetil Form 5.

Figure 6 is a DSC thermogram of candesartan cilexetil Form 5 of another batch.

Figure 7 is a DSC thermogram of candesartan cilexetil Form 6.

Figure 8 is a DSC thermogram of amorphous candesartan cilexetil

Figure 9 is an X-ray powder diffraction pattern of candesartan cilexetil Form 7

Figure 10 is an X-ray powder diffraction pattern of candesartan cilexetil Form 8

Figure 11 is a DSC thermogram of candesartan cilexetil Form 7.

Figure 12 is a DSC thermogram of candesartan cilexetil Form 8.

Figure 13 is an IR spectra of candesartan cilexetil Form 5.

Figure 14 is an IR spectra of candesartan cilexetil Form 6.

Figure 15 is an IR spectra of candesartan cilexetil Form 7.

Figure 16 is an IR spectra of candesartan cilexetil Form 8.

Figure 17 is an IR spectra of amorphous candesartan cilexetil.

DISCLOSURE OF THE INVENTION

Our invention is a process for preparing crystalline candesartan cilexetil consisting of following steps: preparing a solution of candesartan cileksetil in chlorinated solvent and (optionally) concentrating said solution so that the concentration is in first range from 0,26 g to 0,27 g of candesartan cilexetil / g of solution or in the second range from 0,15 to 0,21 g or alternatively from 0,6 g to 1 ,5 g of candesartan cilexetil / g of solution or in the third range of 0,55 g to 0,58 g of candesartan cilexetil / g of solution or in the forth range from 0,39 g to 0,41 g of candesartan cilexetil / g of solution; subsequently adding a liquid hydrocarbon to the above solution; and subsequently isolating said solid candesartan ciiexetil. Specifically the invention is embodied in a process for preparing polymorph forms of candesartan cilexetil selected form the group of Form 5, Form 6, Form 7, Form 8 or amorphous candesartan characterized in that each of the polymorph form is obtained by a process which comprises following steps: dissolving candesartan cilexetil in chlorinated solvent;

(optionally) subsequently concentrating thus obtained solution; subsequently adding a liquid hydrocarbon to the above concentrated solution; characterized in that if the aforesaid solution is prepared in concentration or concentrated until the concentration of 0,26 g to 0,27 g of candesartan cilexetil / g of the solution a Form 5 is obtained and if the aforesaid solution is prepared in concentration or concentrated until the concentration of 0,15 g to 0,21 g or alternatively of 0,6 g to 1 ,5 g of candesartan cilexetil / g of the solution a Form 6 is obtained and if the aforesaid solution is prepared in concentration or concentrated until the concentration of 0,55 g to 0,58 g of candesartan cilexetil / g of the solution a Form 7 is obtained and iv) if the aforesaid solution is prepared in concentration or concentrated until the concentration of 0,4 g ± 0,1 g of candesartan cilexetil / g of the solution a Form 8 is obtained and further characterized in that if the aforesaid solution is concentrated until concentration of 0,3 g to 0,38 g of candesartan cilexetil / g of the solution amorphous candesartan cilexetil is obtained after quick addition of a liquid hydrocarbon selected from cycloalkanes.

The invention is embodied in new polymorph forms of candesartan cilexetil selected form the group of Form 5, Form 6, Form 7, Form 8 characterized in that any of them is obtained by a process which consists of following steps: dissolving candesartan cilexetil in chlorinated solvent;

(optionally) concentrating thus obtained solution; adding a liquid hydrocarbon to the above solution; characterized in that if the aforesaid solution has concentration of about 0,26 g to about 0,27 g of candesartan cilexetil / g of the solution a Form 5 is obtained and if the aforesaid solution is concentrated until concentration of about 0,15 g to about 0,21 g or alternatively of about 0,6 g to about 1 ,5 g of candesartan cilexetil / g of the solution a Form 6 is obtained and if the aforesaid solution is concentrated until concentration of about 0,55 g to about 0,58 g of candesartan cilexetil / g of the solution a Form 7 is obtained and if the aforesaid solution is concentrated until concentration around 0,4 g of candesartan cilexetil / g of the solution a Form 8 is obtained.

Specific embodiments are processes as above, limited to each specific concentration range and each specific form which may be defined as: the crystalline candesartan cilexetil Form 5, preferably characterized by an X-ray powder diffraction pattern exhibiting strongest peaks at about 6,1 ; 11 ,6; 20,0; 21 ,2; 25,6 ± 0,2° 2Theta; the crystalline candesartan cilexetil Form 6, preferably characterized by an X-ray powder diffraction pattern exhibiting strongest peaks at about 6,9; 8,9; 16,6; 17,4; 19,4± 0,2° 2Theta; the crystalline candesartan cilexetil Form 7, preferably characterized by an X-ray powder diffraction pattern exhibiting strongest peaks at about 6,0; 9,0; 12,0; double peak between 19 and 20 (19,4 and 19,8); 21 ,3; 22,4; 25,6 ± 0,2° 2Theta; and The crystalline candesartan cilexetil Form 8, preferably characterized by an X- ray powder diffraction pattern exhibiting strongest peaks at about 7,1 ; 16,3; 17,8; 19,5; 20,2; 24, O± 0,2° 2Theta. Each of the forms may be in further embodiments further characterized by reference to complete diffraction pattern and/or by reference to specific IR spectral pattern and/or DSC and/or melting point range.

Candesartan cilexetil, preferably made in accordance with our invention, characterized in that it exhibits solubility above 10 μg/ml, preferably above 30 μg/ml after 30 min in system composed of phosphate buffer at pH=6.76 and sodium tauroholat (2,5 mM) and lecithin (0,5 mM) is especially advantageous embodiment of the invention, as well as its use as a medicament.

Specifically the invention is also amorphous candesartan cilexetil having melting point in range from 106,0 to 109,4 ⁰C, characterized by an X-ray powder diffraction pattern exhibiting a continuum of diffractions substantially throughout the measured range from 2° to 37° 2Theta prepared by a process which comprises precipitating the amorphous candesartan cilexetil by adding a liquid cyclic hydrocarbon to the concentrated solution in a chlorinated solvent.

Yet another embodiment of the inventions is any crystalline candesartan cilexetil selected from the group consisting of Form 5, Form 6, Form 7, and Form 8, characterized in that it is substantially anhydrous, preferably one that it is not solvated, preferably one of later three forms characterized in that it contains less than 0,2% water as determined by Karl Fischer method.

It is further preferred that candesartan cilexetil is in a form selected from those having melting point in range from 100 to 132 ⁰C.

yet another embodiments of the invention are use of candesartan cilexetil Form 5 or candesartan cilexetil Form 6 or candesartan cilexetil Form 7 or candesartan cilexetil Form 8 or amorphous candesartan cilexetil for the preparation of a medicament for treating hypertensive diseases or hypercardia or heart failure or cardiac infarction or stroke or cerebral apoplexy or nephritis and the pharmaceutical composition comprising one or mere of said forms.

DETAILED DESCRIPTION OF THE INVENTION

Polymorph forms of candesartan cilexetil can be obtained by a process at room temperature which consists of following steps: a) dissolving candesartan cilexetil, which may be obtained by the known methods, in chlorinated solvent; b) (optionally) concentrating thus obtained solution to the desired concentration range and c) adding a hydrocarbon to the above concentrated solution, whereupon a crystalline or amorphous solid is formed; whereas the polymorph form produced depends solely on the concentration of aforesaid solution in a chlorinated solvent, which is preferably an alkane substituted with one ore more chlorine atoms, more preferably CH₃CI, CH₂CI₂, CHCI₃, CCI₄, most preferably CH₂CI₂, CHCI₃. The said solid can be isolated from the above combined solvent by conventional methods, such as filtration or centrifugation.

If the solution of candesartan cilexetil in a chlorinated solvent such as chloroform or dichloromethane is prepared or concentrated until concentration of about 0,26 g to about 0,27 g of candesartan cilexetil / g of the solution a Form 5, is obtained and if the aforesaid solution is prepared or concentrated until concentration of about 0,15 g to about 0,21 g or alternatively of about 0,6 g to about 1 ,5 g of candesartan cilexetil / g of the solution a Form 6 is obtained and if the aforesaid solution is prepared or concentrated until concentration of about 0,4 of candesartan cilexetil / g of the solution Form 8 is formed and by preparing or concentrating to about 0,55 g - 0,58 g of candesartan cilexetil / g of the solution Form 7 is formed, upon addition of a liquid hydrocarbon. In the range of 0,3 g to about 0,4 g or under certain conditions in the range of 0,3 g to 0,5 g of candesartan cilexetil / g of the solution amorphous candesartan cilexetil can be obtained by quick addition of cycloalkane.

Novel forms are formed simply on addition of a liquid hydrocarbon, preferably selected from alkanes, preferably C₅-C₈ alkane or cycloalkane, more preferably pentane, hexane, heptane, most preferably cyclopentane, cyclohexaπe, methylcyclohexane, hexane or n-heptane, without the need to heat or cool the solution. The amount of added liquid hydrocarbon is preferably from 2 to 50 ml per g of starting solution of candesartan cilexetil in a chlorinated solvent, preferably 3 to 25ml, most preferably around 10 ml.

To shorten times of dissolving it may be advantageous to prepare a diluted solution of candesartan in a chlorinated solvent and subsequently concentrate this diluted solution to a desired concentration range.

Table bellow shows dependence of polymorph formed of the concentration of candesartan cilexetil in a chlorinated solvent.

Above mentioned polymorph forms are characterized by their physical and chemical properties, for example Form 5 by an X-ray powder diffraction pattern such as in Figure 1 comprising strongest peaks at about 6,1 ; 11 ,6; 20,0; 21 ,2; 25,6 ± 0,2° 2Theta; or Form 6 by an X-ray powder diffraction pattern such as in Figure 3 comprising strongest peaks at about 6,9; 8,9; 16,6; 17,4; 19,4 ± 0,2° 2Theta; or Form 7 by an X-ray powder diffraction pattern such as in Figure 9 comprising strongest peaks at about 6,0; 9,0; 12,0; double peak between 19 and 20 (19,4 and 19,8); 21 ,3; 22,4; 25,6 ± 0,2° 2Theta; or Form 8 by an X-ray powder diffraction pattern such as in Figure 10 comprising strongest peaks at about 7,1 ; 16,3; 17,8; 19,5; 20,2; 24,0 ± 0,2° 2Theta or an amorphous form exhibiting a continuum of X-ray diffractions throughout the entire difractogram scale and a thermogram as presented on Figure 8.

Present process allows advantages over previously known processes, where different polymorphs have been obtained from variety of solvents, i.e. lower alcohols, their mixture with water and a mixture of lower alkyl ketone with water or acetone or dioxane or toluene or methyl tert butyl ether, at different temperatures, while our process allows the unification of solvents at room temperature in order to produce various polymorph by essentially varying only the concentration of the solute.

The solubility studies of the novel polymorphs show faster dissolution compared to known most stable Form I at the physiologically important conditions. Not wishing to be bound by the theory it is believed that polymorphs which may be thermodynamically less stable, which thus exhibit melting points substantially lower than those of most stable polymorph, (i.e. 30° lower than m.p. of Form I) will dissolve more readily in water or in the physiologically relevant medium than the thermodynamically most stable polymorph. On the other hand the stability of the polymorphs must be such to allow manufacturing of the pharmaceutical composition, i.e. not melting at the temperatures which may occur during the processing into a pharmaceutical formulation. The novel polymorphs are sufficiently stable for incorporation into a pharmaceutical formulation because each of the polymorphs obtained, even the amorphous form exhibits a detectable melting point, above 100 ⁰C while for example the prior art processes using mechanical grinding have produced a heat unstable substance. By our process we have been also able to produce form with substantially large surface area.

It is possible that the solubility properties of novel polymorphs are (at least partially) caused by the facts that the new polymorphs Form 5, Form 6, Form 7 and Form 8 are not hydroscopic as proven by the observation that even when exposed to atmosphere nearly saturated with water vapors ( relative humidity = 90%) the hidroscopicity was below 0,5%, and are not in forms of solvates i.e. they are not hydrates. Without committing to a definite mechanism it is believed that solvates would be less soluble in water because of solvation energy barrier. Although it is advantageous to use anhydrous solvents, the substances produced using commercially available solvents are not hydroscopic and is prepared in substantially anhydrous form. In particular the water content as determined by Karl Fischer method in Form 5 is about 0,2%, while in Form 6 about 0,1%, and even less for Form 7 about 0,05% and same for Form 8 thus term substantially anhydrous will mean having less than 0,4%, preferably less than 0,3% in particular for Form 5 less than 0,25%, for Form 6 less than 0,15% and for Forms 7 and 8 less than 0,1% of water as determined by Karl Fischer method.

All forms, here described by a term anhydrous and which are dried by methods known for the skilled persons are essentially free of residual solvents and are therefore defined not to be solvates.

In one embodiment of our invention in case candesartan cilexetil, is dissolved in chlorinated solvent, preferably in dichloromethane or chloroform and the concentration is approximately 0,26 g / g of solution or/the solution is concentrated to such concentration and thus obtained solution is precipitated with an hydrocarbon for example a liquid hydrocarbon such as alkane, preferably with hexane or its derivative, for example methylcyclohexane or n-hexane, a solid is formed which is a new crystalline form of candesartan cilexetil (Form 5).

Applying the above process, where however the obtained clear solution in chlorinated solvent is comparably substantially less (having concentration above 0,6 g / g solution) or more concentrated (having concentration bellow 0,21 g / g solution) after the workup with methylcyclohexane or n-hexane a new crystalline form of candesartan cilexetil (Form 6) is formed.

Surprisingly the intermediate concentrations do not facilitate the formation of the mixture of those two forms At the intermediate concentration ranges additional polymorph forms of candesartan cilexetil (Form 7 and Form 8) can be obtained, preferably n-heptane should be added to aforementioned solution to obtain those two polymorphs.

All four described forms do not bind solvents and are not hydroscopic. However leaving the concentration ranges described above, the solids that form are more unstable, may lose mass on drying and are harder to characterize. Contrary to the teaching of prior art where amorphous candesartan cilexetil was obtained mechanically from other crystalline forms, but no X-ray data on thus obtained substance was presented to confirm whether it is indeed amorphous, we have as yet another embodiment of the invention developed a process in which candesartan cilexetil is dissolved in chlorinated solvent, preferably in dichloromethane or chloroform and the obtained solution is optionally concentrated and thus obtained solution is precipitated with a liquid cyclic hydrocarbon, preferably with cyclohexane or cyclopentane an amorphous solid is formed that exhibits a continuum of X-ray diffractions throughout the entire difractogram scale. The amorphous form obtainable by this process exhibits a melting paint 106 - 109,4 ^CC whereas the previously mechanically obtained amorphous form was already liquid phase at 75 ⁰C.

In accordance with the present invention, there is provided a pharmaceutical composition comprising amorphous candesartan cilexetil or Form 5 or Form 6 or Form 7 or Form 8 of candesartan cilexetil alone or in combination with another active ingredient such as hydrochlorotiazide and a pharmaceutically acceptable carrier comprising inactive ingredients such as fillers, binders, disintegrants, glidants, lubricants and other excipients.

The new polymorphs of candesartan cilexetil can be produced in substantially pure form. Depending on the desired characteristic, for example desired dissolution properties, the substantially pure polymorph forms can be incorporated into a pharmaceutical composition in form or alternatively a mixture thereof.

The described forms of candesartan cilexetil have a potent antihypertensive activity and incorporated pharmaceutical composition can be in a form suitable for peroral or parental application. Pharmaceutical composition in accordance with this invention can be embodied for example in form of tablet, capsules, pellets, granules and supozitories or their combined forms. Solid pharmaceutical compositions can be shielded, for example coated with the aim of increasing peletibility or regulating the disintegration or absorption. As shown by solubility characteristics of new forms, they are advantageous over the known Form I₁ because no special ingredients are needed in a pharmaceutical composition to facilitate the dissolution. A new crystalline form of candesartan cilexetil (Form 5)

To obtain a Form 5 of candesartan cilexetil, candesartan cilexetil, which may be obtained by the known methods, is dissolved in chlorinated solvent, such as dichloromethane or chloroform in the concentration of up to 0,35 g of candesartan cilexetil / g of the solvent at room temperature and the obtained solution is preferably concentrated in vacuum to the concentration of 0,26 g - 0,27g of candesartan cilexetil / g of the solution and thus obtained solution is precipitated by quick addition (in few seconds) of a liquid hydrocarbon, preferably n-heptane or hexane or its derivative, for example methylcyclohexane or n-hexane in the amount 2 ml - 50 ml of hydrocarbon/g of the solution at room temperature a solid is formed which is a new crystalline form of candesartan cilexetil (Form 5)

The candesartan cilexetil Form 5 is for example characterized by an X-ray powder diffraction pattern having peaks at about 4,5; 6,1 ; 7,2; 8,5; 9,9; 10,7; 11 ,7; 12,1 ; 13,0; 13,8; 14,4; 16,3; 17,1 ; 17,9; 18,3; 18,8; 19,5; 19,9; 21 ,2; 21 ,5; 22,0; 22,6; 22,8; 23,3; 24,4; 25,7; 26,0; 26,7; 27,2; 28,5; 29,2; 29,4; 30,5; 31 ,3; 32,6; 33,1 ; 34,3; 35,5 ± 0,2° 2Theta. Of those the most characteristic are the peaks at about 6,1; 11 ,7; 16,3; 17,9; 18,8; 19,9; 21 ,2; 21 ,5; 22,0; 23,3; 24,4; 25,7; 26,0° Figures 1 and 2 shows typical X-ray powder diffraction pattern of candesartan cilexetil Form 5 with strongest peaks at about 6,1 (the most intense); 11 ,6; 20,0; 21 ,2; 25,6 ± 0,2°. The candesartan cilexetil Form 5 is further characterized by DSC as presented on Figure 5, IR spectra having the characteristic absorptions substantially at: 1756, 1574, 1465, 1002, 988, 911 , and 751 cm^'1 and 1725 cm^"1 and having m.p. = 118,2 to 123,3 ⁰C.

A new crystalline form of candesartan cilexetil (Form 6)

To obtain a Form 6 of candesartan cilexetil, candesartan cilexetil, which may be obtained by the known methods, is dissolved in chlorinated solvent, such as dichloromethane or chloroform in the concentration of up to 1 ,5 g of candesartan cilexetil /g of the solvent at room temperature and the obtained solution is concentrated in vacuum to the concentration of between about 0,1 g and 0,21 g, preferably 0,15 g - 0,21 g of candesartan cilexetil / g of the solution or between about 0,6 g to about 2 g, preferably 0,6 g - 1.5 g of candesartan cilexetil / g of solution alternatively and thus obtained solution is precipitated by quick addition (in few seconds) of a liquid cyclic hydrocarbon, preferably with methylcyclohexane or straight chain hydrocarbon or its derivative, for example n-heptane or n-hexane in the amount of 2 ml - 40 ml of hydrocarbon/g of the solution at room temperature a solid is formed which is a new crystalline form of candesartan cilexetil (Form 6). The candesartan cilexetil Form 6 is for example characterized by an X-ray powder diffraction pattern having peaks at about: 3,8; 5,7; 6,9; 8,2; 8,9; 9,4; 10,0; 10,7; 11 ,3; 12,3; 13,9; 14,3: 14,6; 15,1 ; 15,8; 16,6; 17,0; 17,4; 18,0; 18,3; 18,9; 19,4; 19,7; 20,5; 20,8; 21 ,4; 22,0; 22,6; 23,6; 24,7; 25,3; 26,5; 27,4; 27,6; 28,2; 29,5; 30,7; 31 ,9; 32,5; 32,7; 33,0; 35,0; 35,8; 36,2 ± 0,2° 2Theta. Of those the most characteristic are the peaks at about: 6,9; 8,9; 15,1 ; 16,6; 17,4; 19,4; 19,7; 20,5; 20,8; 22,6; 23,6; 25,3°. Figure 3 shows typical X-ray powder diffraction pattern of candesartan cilexetil Form 6 with strongest peaks at about 6,9; 8,9; 16,6; 17,4; 19,4± 0,2°. The candesartan cilexetil Form 6 is further characterized by DSC as presented on Figure 7, IR spectra having the characteristic absorptions substantially at:1751 , 1322, 995, and 744 cm^'1 and peak at 1729 cm^'1 is substantially blended with peak at 1751 cm^"1 and having m.p. = 121 ,3 to 127,5 ⁰C and having low water content, preferably as determined by Karl Fischer method below 0,2%.

A new crystalline form of candesartan cilexetil (Form 7)

To obtain a Form 7 of candesartan cilexetil is dissolved in chlorinated solvent, such as dichloromethane or chloroform in the concentration of up to 1.5 g of candesartan cilexetil /g of the solvent at room temperature and the obtained solution is concentrated in vacuum to the concentration of 0,55 g - 0,58 g of candesartan cilexetil / g of solution. and thus obtained solution is precipitated by quick addition (in few seconds) of a liquid straight chain hydrocarbon, preferably with n-heptane in the amount of 2 ml - 50 ml of hydrocarbon / g of solution at room temperature, preferably about 5.7 ml of hydrocarbon/g of solution. A solid is formed which is a new crystalline form of candesartan cilexetil (Form 7) is for example characterized by an X-ray powder diffraction pattern having peaks at about 6,0; 9,0; 11 ,7; 12,0; 15,1; 16,3; 17,3; 19,4; 19,8; 21 ,0; 21 ,3; 22,0; 22,4; 23,3; 24,3; 25,3; 25,6; 26,0; 29,1 ± 0,2° 2Theta. The X-ray spectra can exhibit also the peaks at about 8,5; 10,2; 12,7; 14,4; 15,8; 17,9; 18,7; 26,6; 27,8; 28,4; 28,9; 29,5; 30,2; 31,3; 32,9; 33,4; 34,2; 35,7± 0,2° 2Theta. Figure 9 shows typical X-ray powder diffraction pattern of candesartan cilexetil Form 7 with strongest peaks at about 6,0; 9,0; 12,0; double peak between 19 and 20 (19,4 and 19,8); 21 ,3; 22,4; 25,6 ± 0,2° 2Theta °. The candesartan cilexetil Form 7 is further characterized by DSC as presented on Figure 11 , IR spectra having the characteristic absorptions substantially at: 1758, 1573, 1320, 1007, 990, 910, and 746 crτϊ¹ and 1717 cm^'1 and having m.p. = 116,5. to123,7°C.

A new crystalline form of candesartan cilexetil (Form B)

To obtain a Form 8 of candesartan cilexetil, it is dissolved in chlorinated solvent, such as dichloromethane or chloroform at room temperature and the obtained solution is concentrated in vacuum to the concentration of 0,40 g of candesartan cilexetil / g of solution and thus obtained solution is precipitated by quick addition (in few seconds) of a liquid straight chain hydrocarbon, preferably n-heptane or n-hexane in the amount 2 ml - 50 ml of hydrocarbon / g of the solution at room temperature, preferably about 8 ml of hydrocarbon / g of the solution a solid is formed which is a new crystalline form of candesartan cilexetil (Form 8). The candesartan cilexetil Form 8 is characterized by an X-ray powder diffraction pattern having peaks at about 6,7; 7,1 ; 8,4; 9,7; 11 ,0; 11 ,9; 14,2; 14,5; 15,4; 16,3; 16,9; 17,8; 19,5; 20,2; 20,7; 21 ,6; 22,1 ; 23,1 ; 24,0; 24,6; 25,1 ; 25,5; 26,5; 26,9; 27,8; 28,6; 28,8; 30,7; 33,0 ± 0,2° 2Theta. Figure 10 shows typical X-ray powder diffraction pattern of candesartan cilexetil Form 8 with strongest peaks at about 7,1; 16,3; 17,8; 19,5; 20,2; 24,0 ± 0,2° 2Theta °. The candesartan cilexetil Form 8 is further characterized by DSC as presented on Figure 12, IR spectra having the characteristic absorptions substantially at: 1751 , 1322, 994, 910, and 745 cm^'1 and 1729 cm^'1 and having m.p. = 127,3 to 132,4°C

Amorphous candesartan cilexetil

Candesartan cilexetil is dissolved in chlorinated solvent, preferably in dichloromethane or chloroform in the concentration of up to 0, 5 g of candesartan cilexetil/g of the solvent at room temperature and the obtained solution is concentrated in vacuum to the concentration of 0,3 g - 0,5 g of candesartan cilexetil / g of the solution and thus obtained solution is precipitated by quick addition (in few seconds) of a liquid cyclic hydrocarbon, preferably with cyclohexane or cyclopentane in the amount of 10 ml - 40 ml of hydrocarbon / g of the solution at room temperature an amorphous solid is formed that exhibits a continuum of X- ray diffractions throughout the entire difractogram scale as presented on Figure 4 . Amorphous candesartan cilexetil obtainable in accordance with our process is further characterized by DSC as presented on Figure 8, IR spectra having the characteristic absorptions substantially at: 1754, 1322, 991, and 752 cm^"1 and 1730 cm^'1 with loss of some bands characteristic for other polymorphs and having m.p. = 106,0 to 109,4 ⁰C. To produce amorphous candesartan cilexetil it is important that the addition of liquid cyclic hydrocarbon, preferably cyclopentane, cyclohexane or cycloheptane, is quick, i.e. not dropwise but pouring whole quantity at once.

The solid dosage forms comprising the candesartan cilexetil Form 5 or Form 6 or Form 7 or Form 8 or amorphous candesartan cilexetil can be prepared by conventional method. Tablet can be for example manufactured by direct compression though wet granulation is another commonly used technique. In wet granulation at least one of the ingredients can be mixed or contacted with liquid and further processed to provide aggregates, the liquid can be partially or completely removed and optionally other or more of the same ingredients may be further added and solid dosage forms manufactured.

Tableting compositions may have in addition to active pharmaceutical ingredient few or many components depending upon the tableting method used, the release rate desired and other factors. For example, compositions of the present invention may contain inactive ingredients (excipients) which function as such as different fillers, binders, disintegrants, glidants, lubricants and excipients that enhance the absorption of drugs from gastrointestinal tract.

Suitable fillers may be selected from microcrystalline cellulose, powdered cellulose, lactose, starch, pregelatinized starch, sucrose, glucose, mannitol, sorbitol, calcium phosphate, calcium hydrogen phosphate, aluminium silicate, sodium chloride, potassium chloride, calcium carbonate, calcium sulphate, dextrates, dextrin, maltodextrin, glycerol palmitostearate, hydrogenated vegetable oil, kaolin, magenesium carbonate, magnesium oxide, polymethacrylates, talc, and others. Preferred fillers are microcrystalline cellulose and lactose. Suitable binders may be starch, pregelatinized starch, gelatine, sodium carboxymethylcellulose, polyvinylpyrrolidone, alginic acid, sodium alginate, acacia, carbomer, dextrin, ehylcellulose, guar gum, hydrogenated vegetable oil, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, glucose syrup, magnesium aluminium silicate, maltodextrin, polymethacrylates, zein. Preferably hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone are used. Suitable disintegrants may be selected from starch, pregelatinized starch, sodium starch glycolate, sodium carboxymethylcellulose, cross-linked sodium carboxymrethylcellulose, calcium carboxymethylcellulose, methylcellulose, microcrystalline cellulose, powdered cellulose, polacrilin potassium, cross-linked polivinylpyrrolidone, alginic acid, sodium alginate, colloidal silicon dioxide, guar gum, magnesium aluminium silicate, and others. Preferred disintegrants are sodium starch glycolate, cross-linked carboxymethylcellulose sodium and cross-linked polyvinylpyrrolidone. Suitable glidants may be magnesium stearate, calcium stearate, aluminium stearate, stearic acid, palmitic acid, cetanol, stearol, polyethylene glycols of different molecular weights, magnesium trisilicate, calcium phosphate, colloidal silicon dioxide, talc, powdered cellulose, starch and others. Preferred glidant is colloidal silicilon dioxide. Suitable lubricants may be selected from stearic acid, calcium, magnesium, zinc or aluminium stearate, siliconized talc, glycerol monostearate, glycerol palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, light mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulphate, sodium stearyl fumarate, talc and others. Preferred lubricants are calcium or magnesium stearate and stearic acid. Suitable absorption enhancers may be selected from surface active agents, fatty acids, middle chain glycerides, steroide detergents (salts of bile salts), acyl carnitine and alcanoloil choline (esters of carnitine and choline and fatty acids with middle chain and long chain), N-acyl derivatrives of alpha-amino acids and N-acyl derivatives of non-alpha-amino acids, chitosanes and other mucoadhesive polymers. Especially suitable absorption enhancers are sodium deoxycholate, sodium taurocholate, polisorbate 80, sodium lauryl sulfate, sodium dodecylsulfate, octanoic acid, sodium docusate, sodium laurate, glyceride monolaurate, stearic acid, palmitinic acid, palmitooleinic acid, glycerilmonooleate, sodium taurocholate, ethylenediaminetetraacetic acid, sodium edentate, sodium citrate, β- cyclodextrine and sodium salicylate.

Different salts or esters and different polymorph forms sometimes require different techniques Pharmaceutical composition comprising novel forms of candesartan cilexetil, incorporated into a pharmaceutically acceptable carrier, which may comprise above excipients can be prepared by suitable procedures for example by dry granulation or peletization. All the new polymorph crystalline forms of our invention exhibit melting points in range of about 105 ⁰C to about 130° preferably crystalline forms have m.p. from about 115° to about 130 ⁰C which is above the temperatures which may normally develop during formulation into pharmaceutical composition.

In one embodiment of the invention one can prepare film coated tablets by direct compression. Amorphous candesartan cilexetil or candesartan cilexetil of Form 5 or Form 6 or Form 7 or Form 8 is mixed with lactose, microcrystalline cellulose, starch and mixture is sieved. A suitable glidant and/or lubricant is added and mixed again. Cores are tableted and coated with suitable suspension, for example comprising cellulose derivatives and titan dioxide in water or alcohol and the film coated tablets are polished with talc.

EXPERIMENTAL PART

Thermograms were obtained with Mettler Toledo DSC822^e differential scanning calorimeter. The sample (4-6 mg) was placed in an unsealed aluminium pan with one hole and heated at 5 ⁰C /min in the temperature range from 30 ⁰C to 200 ⁰C in the nitrogen (100 ml/min).

Infrared spectra were obtained with Nicolet Nexus FTIR spectrophotometer. Samples were analyzed in KBr and scanned from 400 to 4000 cm^'1 with 16 scans and 2 cm^"1 resolution. Table bellow depicts the differences in position of characteristic peaks of IR spectra of polymorph forms Form 5, Form 6, Form 7, Form 8 and amorphous form obtained according to our invention of candesartan cilexetil. Although the intensities of peaks may differ among the samples of the same polymorph, the positions of the peaks are specific for certain polymorph. It can be seen that those differ from position of a characteristic peak of known forms I₁ Il and amorphous, obtained by milling [Chem. Pharm. Bull. 47(2), 182-186 (1999)].

Powder X-ray diffraction spectra of the samples were recorded on Philips PW1710 with reflexion technique: CuKa radiation, range from 2° to 37° 2Theta, step 0.04° 2Theta, integration time 1 sec. From an X-ray diffraction pattern of a powdery substance one can establish differences among different crystal lattices, and can obtain information on level of order i.e. crystallinity where lover crystallinity causes peaks to broaden. The ultimate form of non orderness of a solid is amorphous state which does not show the repeatability of molecular directions and positions in a solid. Completely amorphous substance thus shows diffuse dispersion of a roentgen radiation, which exhibits a continuum of diffractions throughout of whole the measured range.

The diffraction values for a crystalline substance will be substantially independent of the diffractometer used, if the diffractometer is calibrated the values can differ for about 0,05° 2 Theta, taking into account the rounding the differences in values lay in the order of ± 0,1 ° 2Theta, however the different recording conditions or differences in preparing or handling samples can cause the variations from the values reported for as much as ± 0,2 2Theta. The intensities of each specific diffraction peak may vary as a function of various factors, one of those being a particle size and preferred orientation. However the skilled person will differentiate the forms, which are the embodiment of our invention from other forms by comparing the whole X-ray powder diffraction patterns and specifically the strongest peaks or any three to five or more distinct peaks selected from the above listed peaks for each specific crystalline form.

In order to prepare a pharmaceutical composition physical properties were measured. Table below gives comparable solubility of Form I and Form 5 prepared in accordance with our invention. Forms in accordance with our invention exhibit increase in solubility in physiologically relevant medium as compared to Form I₁ i.e. above 10, preferably above 25 μg/ml after 30 min.

Because of relatively low solubility in buffer having pH = 6,8, solubility was measured also in a physiologically relevant medium, mimicking in-vivo dissolution, that is a phosphate buffer at pH=6.76 + Sodiumtauroholat (2,5 mM) + Lecitin (0,5 mM). Surface area of Form 1 was 2.15 - 2,68 m²/g whereas the surface area of Form 5 was 7,66 m²/g (BET - isotherm), the hygroscopity as established by DVS - first cycle at 90 % humidity was 0,23% for Form I and 0,44% for Form 5. Other forms, in particular Form 6 show similar dissolution in physiologically relevant medium as the Form 5 and similar low hygroscopicity. Not wishing to be bound by the theory this solubility characteristics are attributed to the thermodynamic stability of the new polymorphs.

Following examples further illustrate the invention. They are provided for illustrative purposes only and are not intended to limit in any way the invention.

EXPERIMENT 1 (candesartan cilexetil Form 5)

0,5g of candesartan cilexetil was dissolved in 15 ml of dichloromethane. The solution was evaporated in vacuum to the rest of 1 ,9 g, then 20 ml of methylcyclohexane was added under stirring in one portion at room temperature. Gummy precipitate was obtained, which crystallized overnight. Product was filtered and vacuum dried at 50⁰C. Yield: 0,43g. M. p. : 118,2°C-123,3°C.

EXPERIMENT 2 (candesartan cilexetil Form 5)

1 g of candesartan cilexetil was dissolved in 30 ml of dichloromethane.The solution was evaporated in vacuum to the rest of 3,79 g, then 10 ml of n-heptane was added under stirring in one portion at room temperature. Gummy precipitate was obtained, which crystallized overnight. Product was filtered and vacuum dried at 5O⁰C. Yield: 1 ,03 g. Water by Karl Fischer: 0.21%. EXPERIMENT 3 (candesartan cilexetil Form 5)

6 g of candesartan cilexetil was dissolved in cca 13 ml of dichloromethane. Clear solution (22,8 g) was seeded with candesartan cilexetil Form 5, and 60 ml of n-heptane was added under stirring at room temperature. Gummy precipitate was obtained, which crystallized overnight. Product was filtered and dried at 5O⁰C. Yield: 6,19 g of Form 5.

EXPERIMENT 4 (candesartan cilexetil amorphous)

0,5g of candesartan cilexetil was dissolved in 15 ml of dichloromethane or in chloroform. The solution was evaporated in vacuum to the rest of 1 ,25 g, then 10 ml of cyclohexane or cyclopentane was added in one portion. Gummy precipitate was obtained, which solidified in 1-2 hours. White suspension was stirred another hour at 5-10⁰C. Product was filtered and vacuum dried at 50°C.Yield: 0,44g of amorphous product. M. p. : 106, 0⁰C-109,4⁰C

EXPERIMENT 5 (candesartan cilexetil Form 6)

1g of candesartan cilexetil was dissolved in 15 ml of dichloromethane. The solution was carefully evaporated in vacuum to the rest of 5,66 g (less than in experiments 1 to 3). 40 ml of methylcyclohexane was added under stirring at room temperature and stirring was continued overnight. Product was filtered and vacuum dried at 50⁰C. Yield: 0,93 g of Form 6, M.p.:121,3°C-127,5°C.

EXPERIMENT 6 (candersartan cilexetil Form 6)

1g of candesartan cilexetil was dissolved in 30 ml of dichloromethane. The solution was evaporated in vacuum to the rest of 1 ,67g (more than in experiments 1 to 4). Oily residue was seeded with candesartan cilexetil Form 6 and 40 ml of methylcyclohexane was added under stirring at room temperature. Stirring was continued overnight. Product was filtered and vacuum dried at 50°C. Yield: 0,87g of Form 6, Water by Karl Fischer: 0.13%. EXPERIMENT 7 (candersartan cilexetil Form 5)

A solution of 300 ml of methanol and 7,6 ml of methanesulfonic acid is cooled to approximately 3⁰C. 50 g of trityl candesartan cilexetil is added and the mixture is stirred at approximately 3⁰C for 30 minutes. 24.4 ml of triethylamine are added at a rate that temperature does not exceed 10⁰C. 1000 ml of heptane are added followed by 50 ml of H₂O. The mixture is stirred for 10 min in an ice bath. The layers are then separated, the lower phase is extracted with 250 ml of heptane under ice cooling. The layers are again separated and the lower phase is warmed up to approximately 20°C. 1 5 ml of 2 m HCI is added drop wise followed by seeds of candesartan cilexetil Form 5. The suspension is briefly stirred and 14.3 ml of 2 m HCI are added within approximately 60 min. The suspension is then stirred for additional 30 min and the product is then isolated by filtration, washed with 75 ml of a mixture methanol and H20 ( 3: 1 v/v) and dried in vacuum at ambient temperature over night.

EXPERIMENT 8 (candesartan cilexetil Form 7)

1g of candesartan cilexetil was dissolved in 30 ml of dichloromethane. The solution was evaporated in vacuum to the rest of 1 ,76g. 10 ml of n-heptane was added under stirring at room temperature. Stirring was continued overnight. Product was filtered and vacuum dried at 50°C.Yield:0,08g of Form 7, m.p.:116,5°C-123,7°C, water by Karl Fischer: 0.051%..

EXPERIMENT 9 (candesartan cilexetil Form 8)

1g of candesartan cilexetil was dissolved in 30 ml of dichloromethane. The solution was evaporated in vacuum to the rest of 2,53 g. 20 ml of n-heptane was added under stirring at room temperature. Stirring was continued overnight. Product was filtered and vacuum dried at 50°C.Yield: 0,98g. Form 8, M.p.:127,3°C-132,4⁰C, Water by Karl Fischer: 0.066%.

Claims

1. A process for preparing crystalline candesartan cilexetil consisting of following steps: a) preparing a solution of candesartan cileksetil in chlorinated solvent and (optionally) concentrating said solution so that the concentration is in first range from 0,26 g to 0,27 g of candesartan cilexetil / g of solution or in the second range from 0,15 to 0,21 g or alternatively from 0,6 g to 1 ,5 g of candesartan cilexetil / g of solution or in the third range of 0,55 g to 0,58 g of candesartan cilexetil / g of solution or in the forth range from 0,39 g to 0,41 g of candesartan cilexetil / g of solution; b) subsequently adding a liquid hydrocarbon to the above solution; and c) subsequently isolating said solid candesartan cilexetil.

2. A polymorph form of candesartan cilexetil selected form the group of Form 5, Form 6, Form 7, Form 8 characterized in that it is obtained by a process which consists of following steps: a) dissolving candesartan cilexetil in chlorinated solvent; b) (optionally) concentrating thus obtained solution; c) adding a liquid hydrocarbon to the above solution; characterized in that if the aforesaid solution has concentration of about 0,26 g to about 0,27 g of candesartan cilexetil / g of the solution a Form 5 is obtained and if the aforesaid solution is concentrated until concentration of about 0,15 g to about 0,21 g or alternatively of about 0,6 g to about 1 ,5 g of candesartan cilexetil / g of the solution a Form 6 is obtained and if the aforesaid solution is concentrated until concentration of about 0,55 g to about 0,58 g of candesartan cilexetil / g of the solution a Form 7 is obtained and if the aforesaid solution is concentrated until concentration around 0,4 g of candesartan cilexetil / g of the solution a Form 8 is obtained.

3. A process for preparing polymorph forms of candesartan cilexetil selected form the group of Form 5, Form 6, Form 7, Form 8 or amorphous candesartan characterized in that each of the polymorph form is obtained by a process which comprises following steps: a) dissolving candesartan cilexetil in chlorinated solvent; b) (optionally) subsequently concentrating thus obtained solution; c) subsequently adding a liquid hydrocarbon to the above concentrated solution; characterized in that i) if the aforesaid solution is prepared in concentration or concentrated until the concentration of 0,26 g to 0,27 g of candesartan cilexetil / g of the solution a Form

5 is obtained and ii) if the aforesaid solution is prepared in concentration or concentrated until the concentration of 0,15 g to 0,21 g or alternatively of 0,6 g to 1 ,5 g of candesartan cilexetil / g of the solution a Form 6 is obtained and iii) if the aforesaid solution is prepared in concentration or concentrated until the concentration of 0,55 g to 0,58 g of candesartan cilexetil / g of the solution a Form

7 is obtained and iv) if the aforesaid solution is prepared in concentration or concentrated until the concentration of 0,4 g ± 0,1 g of candesartan cilexetil / g of the solution a Form 8 is obtained and further characterized in that if the aforesaid solution is concentrated until concentration of 0,3 g to 0,38 g of candesartan cilexetil / g of the solution amorphous candesartan cilexetil is obtained after quick addition of a liquid hydrocarbon selected from cycloalkanes.

4. A process for the preparation of crystalline candesartan cilexetil of Form 5, which consists of following steps: a) dissolving candesartan cilexetil in chlorinated solvent; b) (if needed) concentrating thus obtained solution until concentration of 0,26 g to 0,27 g of candesartan cilexetil / g of the solution; c) adding a liquid hydrocarbon to the above concentrated solution; d) isolating formed crystals of crystalline candesartan cilexetil of Form 5.

5. A process for the preparation of crystalline candesartan cilexetil of Form 6, which consists of following steps: a) dissolving candesartan cilexetil in chlorinated solvent; b) (if needed) concentrating thus obtained solution until concentration of 0,15 g to 0,21 g or alternatively of 0,5 g to 1 ,5 g of candesartan cilexetil / g of the solution; c) adding a liquid hydrocarbon to the above concentrated solution; d) isolating formed crystals of crystalline candesartan cilexetil of Form 6.

6. A process for the preparation of crystalline candesartan cilexetil of Form 7, which consists of following steps: a) dissolving candesartan cilexetil in chlorinated solvent; b) (if needed) concentrating thus obtained solution until concentration of 0,55 g to 0,58 g of candesartan cilexetil / g of the solution; c) adding a liquid hydrocarbon to the above concentrated solution; d) isolating formed crystals of crystalline candesartan cilexetil of Form 7.

7. A process for the preparation of crystalline candesartan cilexetil of Form 8, which consists of following steps: a) dissolving candesartan cilexetil in chlorinated solvent; b) (if needed) concentrating thus obtained solution until concentration of about 0,4 g of candesartan cilexetil / g of the solution; c) adding a liquid hydrocarbon to the above concentrated solution; d) isolating formed crystals of crystalline candesartan cilexetil of Form 8.

8. A process for the preparation of amorphous candesartan cilexetil, which consists of following steps: a) dissolving candesartan cilexetil in a chlorinated solvent; b) (if needed) concentrating thus obtained solution until concentration of 0,3 g to 0,5 g of candesartan cilexetil / g of the solution; c) precipitating the amorphous candesartan cilexetil by adding a liquid cyclic hydrocarbon to the above concentrated solution.

9. The crystalline candesartan cilexetil Form 5, characterized by an X-ray powder diffraction pattern exhibiting strongest peaks at about 6,1 ; 11 ,6; 20,0; 21 ,2; 25,6 ± 0,2° 2Theta.

10. The crystalline candesartan cilexetil Form 5, according to the previous claim characterized by an X-ray powder diffraction pattern exhibiting further peaks at about 4,5; 7,2; 8,5; 9,9; 10,7; 12,1 ; 13,0; 13,8; 14,4; 16,3; 17,1 ; 17,9; 18,3; 18,8; 19,5; 21,5; 22,0; 22,6; 22,8; 23,3; 24,4; 26,0; 26,7; 27,2; 28,5; 29,2; 29,4; 30,5; 31 ,3; 32,6; 33,1 ; 34,3; 35,5 ± 0,2° 2Theta.

11. The crystalline candesartan cilexetil Form 5, characterized by an X-ray powder diffraction pattern substantially as depicted on Figure 1.

12. The crystalline candesartan cilexetil Form 5, in accordance with any of the previous three claims, characterized in that it has melting point in range from 118,2 to 123,3 ⁰C.

13. The crystalline candesartan cilexetil Form 6, characterized by an X-ray powder diffraction pattern exhibiting strongest peaks at about 6,9; 8,9; 16,6; 17,4; 19,4± 0,2° 2Theta.

14. The crystalline candesartan cilexetil Form 6, according to the previous claim characterized by an X-ray powder diffraction pattern exhibiting further peaks at about 3,8; 5,7; 8,2; 9,4; 10,0; 10,7; 11 ,3; 12,3; 13,9; 14,3: 14,6; 15,1 ; 15,8; 17,0; 18,0; 18,3; 18,9; 19,7; 20,5; 20,8; 21 ,4; 22,0; 22,6; 23,6; 24,7; 25,3; 26,5; 27,4; 27,6; 28,2; 29,5; 30,7; 31 ,9; 32,5; 32,7; 33,0; 35,0; 35,8; 36,2 ± 0,2° 2Theta.

15. The crystalline candesartan cilexetil Form 6, characterized by an X-ray powder diffraction pattern substantially as depicted on Figure 3.

16. The crystalline candesartan cilexetil Form 6 in accordance with any of the previous three claims, characterized in that it contains less than 0,2% water as determined by Karl Fischer method.

17. The crystalline candesartan cilexetil Form 6, in accordance with any of the previous four claims, characterized in that it has melting point in range from 121 ,3 to 127,5 ⁰C.

18. The crystalline candesartan cilexetil Form 7, characterized by an X-ray powder diffraction pattern exhibiting strongest peaks at about 6,0; 9,0; 12,0; double peak between 19 and 20 (19,4 and 19,8); 21,3; 22,4; 25,6 ± 0,2° 2Theta.

19. The crystalline candesartan cilexetil Form 7, according to the previous claim characterized by an X-ray powder diffraction pattern exhibiting further peaks at about 11 ,7; 12,0; 15,1 ; 16,3; 17,3; 21 ,0; 22,0; 23,3; 24,3; 25,3; 26,0; 29,1 ± 0,2° 2Theta.

20. The crystalline candesartan cilexetil Form 7, characterized by an X-ray powder diffraction pattern substantially as depicted on Figure 9.

21. The crystalline candesartan cilexetil Form 7 in accordance with any of the previous three claims, characterized in that it has melting point in range from 116,5 to 123,7 ⁰C.

22. The crystalline candesartan cilexetil Form 8, characterized by an X-ray powder diffraction pattern exhibiting strongest peaks at about 7,1 ; 16,3; 17,8; 19,5; 20,2; 24,0± 0,2° 2Theta.

23. The crystalline candesartan cilexetil Form 8, according to the previous claim characterized by an X-ray powder diffraction pattern exhibiting further peaks at about 6,7; 8,4; 9,7; 11,0; 11 ,9; 14,2; 14,5; 15,4; 16,9; 20,7; 21,6; 22,1; 23,1; 24,6; 25,1; 25,5; 26,5; 26,9; 27,8; 28,6; 28,8; 30,7; 33,0 ± 0,2° 2Theta.

24. The crystalline candesartan cilexetil Form 8, characterized by an X-ray powder diffraction pattern substantially as depicted on Figure 10.

25. The crystalline candesartan cilexetil Form 8, in accordance with any of the previous three claims, characterized in that it has melting point in range from 127,3 to 132,4°C.

26. The crystalline candesartan cilexetil selected from the group consisting of Form 5, Form 6, Form 7, and Form 8, characterized in that it is substantially anhydrous.

27. The crystalline candesartan cilexetil selected from the group consisting of Form 6, Form 7, and Form 8 characterized in that it contains less than 0,2% water as determined by Karl Fischer method.

28. Amorphous candesartan cilexetil, characterized by an X-ray powder diffraction pattern exhibiting a continuum of diffractions substantially throughout the measured range from 2° to 37° 2Theta prepared by a process which comprises precipitating the amorphous candesartan cilexetil by adding a liquid cyclic hydrocarbon to the concentrated solution in a chlorinated solvent and having melting point in range from 106,0 to 109,4 ⁰C.

29. Candesartan cilexetil in a polymorph form selected from those having melting point in range from 100 to 132 ⁰C.

30. Candesartan cilexetil according to previous claim in a polymorph form, selected from those that are prepared by the process consisting of following steps a) preparing a solution of candesartan cileksetil in chlorinated solvent and (optionally) concentrating said solution so that the concentration is in first range from 0,26 g to 0,27 g of candesartan cilexetil / g of solution or in the second range from 0,15 to 0,21 g or alternatively from 0,6 g to 1 ,5 g of candesartan cilexetil / g of solution or in the third range of 0,55 g to 0,58 g of candesartan cilexetil / g of solution or in the forth range from 0,39 g to 0,41 g of candesartan cilexetil / g of solution; b) subsequently adding a liquid hydrocarbon to the above solution; and c) subsequently isolating said solid candesartan cilexetil.

31. Candesartan cilexetil according to previous claim, characterized in that it is not solvated.

32. Candesartan cilexetil according to any of previous two claims, characterized in that it exhibits solubility above 10 μg/ml after 30 min in system composed of phosphate buffer at pH=6.76 and sodium tauroholat (2,5 mM) and lecithin (0,5 mM).

33. Use of candesartan cilexetil Form 5 or candesartan cilexetil Form 6 or candesartan cilexetil Form 7 or candesartan cilexetil Form 8 or amorphous candesartan cilexetil as a medicament.

34. Use of candesartan cilexetil Form 5 or candesartan cilexetil Form 6 or candesartan cilexetil Form 7 or candesartan cilexetil Form 8 or amorphous candesartan cilexetil for the preparation of a medicament for treating hypertensive diseases or hypercardia or heart failure or cardiac infarction or stroke or cerebral apoplexy or nephritis.

35. A pharmaceutical composition comprising candesartan cilexetil Form 5 or candesartan cilexetil Form 6 or candesartan cilexetil Form 7 or candesartan cilexetil Form 8 or amorphous candesartan cilexetil and a pharmaceutically acceptable carrier.