PROCESS FOR THE PREPARATION OF CANDESARTAN CϊLEXETIL FORM

Description

Field of the invention

The present invention relates to an improved process for the manufacture of candesartan cilexetil form I with an average particle size below 25 μm and no aggiomeration tendency.

Background of the invention

Candesartan cilexetil of formula (I) shown beiow is chemicaily described as (+/-)-1- [[(cyclohexyloxy)carbonyl]oxy]ethyl-2-ethoxy-1 -[[2'-(1 H-tetrazol-5-yl)-1 , 1 '-biphenyl- 4-yl]methyl]-1 H-benzimidazoie-7-carboxylate. An alternative designation is (+-)-1- hydroxyethyf 2~Ethoxy-1 -{p-(o-1 H-tetrazo!-5-yIphenyi)benzyJ)-7-benzϊmidazoie~ carboxyiic acid cyclohexyl carbonate (ester), with candesartan being the underlying carboxylic acid, i.e. 2-Ethoxy-1 -(p-(o-1 H-tetrazol-5-ylphenyl)benzy!)-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 Ii receptor antagonist, candesartan ciiexetil avoids the side-effects of calcium antagonists, and shows high stability and obvious curative effects. Currently candesartan ciiexetil is soid as racemic mixture, it is produced according to published patents, e.g. EP 0 720 982 B1 and EP 0 459 136.

in Chem. Pharm. Bull. 47(2), 182-186 (1999) two crystalline forms (Form I and II), together with an amorphous form, are disclosed and characterized by their DSC thermograms, X-ray diffraction patterns and IR spectra.

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

WO 04/085426 discloses the dioxane solvate of candesartan ciiexetil, together with two additional crystalline forms.

WO 2005/077941 discloses hydrates and solvates of candesartan ciiexetil, together with processes for their preparation.

WO 2006/048237 also describes the preparation of new polymorphic forms of candesartan ciiexetil, together with processes for their preparation, including the preparation of amorphous candesartan ciiexetil by precipitating it with a liquid cyclic hydrocarbon from a solution of candesartan ciiexetil in a chlorinated solvent.

in WO 2005/123721 processes for the preparation of amorphous candesartan ciiexetil are provided, comprised of spray-drying and precipitation.

As it is indicated herein, it would be of great benefit to provide a more efficient and more economical technological process for providing candesartan ciiexetil form I which is the only known stable polymorphic form of candesartan ciiexetil that can be readily used in the pharmaceutical composition. In addition to the polymorphic form, in case of candesartan ciiexetil, their particle size and tendency of sticking together play an important rote for the preparation of an approvable pharmaceutical composition and the release of the active ingredient therefrom. Namely, it is known

from the prior art that particles of candesartan cϋexetil should be as smail as possible due to its inherent low solubility. On the other hand such small particles tend to be sticky and can easily form agglomerates, which is highly undesirable in the preparation of a pharmaceutical formulation.

Brief description of drawings

Fig. 1 and Fig. 2 are photographs of candesartan cilexetil form I, showing particle size and form.

Fig. 1 presents candesartan cilexetil form I as known from the prior art, Fig. 2 presents candesartan cϋexetil form I according to the present invention.

Summary of the invention

The first embodiment of the present invention is the process for the preparation of candesartan cilexetil form I comprising the following steps: a) Conversion of an ester of 1-((2'~cyano(1 ,1 '-biphenyl)-4-yl)methyl)-2-ethoxy-

1 H-benzimidazoie~7-carboxylate into the corresponding ester of candesartan, b) Hydrolysis of said candesartan ester to obtain candesartan, c) Trityiation of candesartan to obtain trityicandesartan, d) Esterification of trityicandesartan to obtain trityicandesartan cilexetil, e) Deprotection of trityicandesartan in the presence of a Lewis acid to obtain candesartan cilexetil, f) Crystallization of candesartan cilexetil from an alcohol to obtain candesartan cilexetil.

Preferably, the esters used and formed in step a) are alky! esters. The resulting particles of candesartan cilexetil form I have a small average particle size (below 25 /vm) and no agglomeration tendency. By "no agglomeration tendency" it is meant that a preparation of candesartan cilexetil form I does not significantly change its particle size distribution upon storage under usual ambient conditions (e.g. at 23°C and 75% relative humidity) for at least 1 day, preferably at least 1 week and more preferably at least 1 month.

In a further aspect the present invention provides the newly isolated compound (+-)-1 -Hydroxyethyl candesartan oxanyl carbonate (ester), which is the tetrahydropyranyl structure analogon of candesartan ciiexetil and will for the sake of brevity also be designated herein as "candesartan ciiexetil pyran". Its chemical structure will be shown below as formuia (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-haloethyl oxanyl carbonate {"ciiexetil pyran") of the formula ((V) shown below, wherein halo means Ci, Br, I. Moreover, the invention provides a preparation of 1-haloethyl cyclohexyl carbonate ("ciiexetil"), wherein halo means Cl, Br, I, 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 ciiexetil pyran. All percentages given herein are by weight, unless otherwise noted.

Detailed description of the invention

One object of the present invention is to prepare candesartan ciiexetil form i with an average particle size below 25 μm and no agglomeration tendency.

According to the first embodiment of the present invention, candesartan ciiexetil is prepared by a process comprising the following steps: a) Conversion of an ester, preferably an alkyl ester of 1-((2'-cyano(1 ,1'- biphenyl)-4-yl)methyl)-2-ethoxy-1 H-benzimidazole-7~carboxylate to an ester, preferably an alkyl ester of candesartan, b) Hydrolysis of said candesartan (alkyl) ester to obtain candesartan, c) Tritylation of candesartan to obtain tritylcandesartan, d) Esterification of tritylcandesartan to obtain tritylcandesartan cilexetii, e) Deprotection of tritylcandesartan in the presence of a Lewis acid to obtain candesartan cilexetii,

f) Crystallization of candesartan cilexetil from an alcohol to obtain candesartan cilexetil form I having an average particle size less than 25 //m and no agglomeration tendency.

The starting compound ester of 1-((2'-cyano{1 ,1 '-biphenyl)-4-yl)methyI)-2-ethoxy- 1 H-benzimidazole-7-carboxylate may be prepared by any known methods, such as for example described in EP 459136 Bl

Preferably the conversion step of the starting compound into the candesartan ester (a) is performed by tributyl tin azide at elevated temperature in organic solvent such as for example toluene and xylene. As mentioned above, the ester is preferably an alkyl ester, more preferably a C^ _Q alkyl ester, most preferably a methyl or ethyl ester.

Preferably the hydrolysis step (b) is performed in the presence of and with the aid of a base such as for example NaOH or KOH. For the quality of the end product candesartan cilexetil it is very important that the hydrolysis of candesartan ester to candesartan is as complete as possible (below 0.10 % of candesartan ester in candesartan). Alkyl esters of candesartan can hardly be removed from candesartan ciiexetii by crystallization or even using chromatographic methods.

Tritylation of candesartan (c) may be performed by reaction of candesartan with trityl chloride in the presence of a base such as for example triethylamine, diisopropylethylamine and K ₂ CO ₃ .

Preferably the esterification step (d) is performed by reacting trityl candesartan with 1-haioethy! cyclohexyi carbonate in the presence of a base such as for example potassium carbonate and a solvent such as for example dimethylacetamide. The term halo as used herein refers to Cl, Br or I. The isolation of tritylcandesartan cilexetil may be performed by addition of water foliowed by extraction with ester such as for example isopropyl acetate, washing the organic phase, concentrating the organic phase, adding of an ether such as for example tert-butyl methyl ether

and isolating precipitated tritylcandesartan ciiexeti! in high yield (at least 95%) and purity (Area % HPLC at least 98% of tritylcandesartan cilexetil).

Preferably the Lewis acid used in the deprotection step(s) is selected from the group consisting of, but not limited to, zinc (II) trifluoromethanesulfonate, zinc (II) acetate, tin (ll)-salts such as for example SnX ₂ wherein X means F, Cl, Br or I or tin

(I l)-salts with organic acids such as for example acetate and trifiuoromethane sulfonate and BX ₃ wherein X means F, Cl, Br or I. The deprotection step is performed in an organic solvent such as for example methylene chloride and methanol.

Alcohol used in the crystallization step (f) is selected from the group consisting of methanol, ethanol, isopropanol, n-propano! and mixtures of alcohols with water preferably isopropyl alcohol.

The main advantage of the process for the preparation of candesartan ciiexetil according to the present invention is that small particles of the stable crystalline form I of candesartan cilexetil are produced having an average particle size of preferably less than 25 μm, more preferably between 10 and 20 μm, more preferably less than 10 μm, without agglomeration tendency and in a highly economical manner.

It is known that when the particles form agglomerates, the release of the active ingredient from the pharmaceutical composition is slower while the specific surface area is smaller in comparison to particles being in the form of small needles, it was surprisingly found that, when during crystallization of candesartan ciiexetil from alcohol the obtained solution is left to nucleate at temperature below 25 ⁰ C ₁ large agglomerates are formed, which means that a milling process is required to get a pharmaceutically acceptable particle size distribution. According to a preferred embodiment of the process of the present invention the nucleation is performed at higher temperatures such as for example around 40 ⁰ C, preferably around 35°C, resulting in an average particle size of below 25 μm without formation of agglomerates. Optionally nucleation can be provoked by seeding at temperatures

slightly above 35°C, Thus, in a further preferred embodiment the present invention provides a process for preparing candesartan cilexetil form I as claimed in the appending claims, wherein no milling step is conducted.

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

The crystalline form I of candesartan cilexetil obtained by the process according to the present invention is the same as described in Chem. Pharm. Bull. 47(2) 182- 786 (7999).

in step (d) tritylcandesartan cilexetil (II) is preferably prepared from tritylcandesartan (IiI) and 1-chioroethyi cyciohexylcarbonate in the presence of dimethylacetamide (DMA) as a solvent and potassium carbonate as a base:

(Ii) (II!)

When preparing candesartan cilexetil (I) by the above mentioned method the level of detected impurities in the final substance increases significantly. Surprisingly it was found that the purity of the starting compound 1-chloroethyl cyciohexylcarbonate or any other halogen (Br, I) derivative thereof has a great

influence on the impurity level in the final candesartan cilexet.il (I). Namely, it was found that in case that the starting compound contains a 1 -haloethyl oxanyl carbonate, i.e. a compound of formula (IV)

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

as an impurity, the compound with formula (V), i.e. (+-)-1 -hydroxyethyl candesartan oxanyl carbonate (ester),

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

can be detected in the final candesartan cilexetil substance (I). It should be noted that candesartan cilexetil only differs from the compound of formula (V) in that each of the residues A, B and C is a methylene group. The drawback of the impurity of formula (V) is that it is very hard to separate from the final substance candesartan cilexetil by the known conventional methods. Only an appropriate quality of the starting compound 1-haloethyl cyclohexylcarbonate, wherein halo means Cl, Br, I, concerning related substances/impurities enables obtaining the final substance candesartan cilexetil with a quality that complies to Ph.Eur./ICH Guidelines. Therefore, in view of the impurity profile of the obtained final active ingredient candesartan cilexetiS it is very important to detect and identify the undestred

impurity in the synthetic pathway of candesartan ciiexeti! as soon as it appears. Moreover, it is very important to keep the original ievel of the identified impurity as iow 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 manufacturing process and enables easier setting of limits of impurities.

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

wherein X means Cl ₁ Br or I and 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 formuia (V) is

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

Therefore, another embodiment of the present invention is a candesartan cilexetil containing less than 0.15%, preferably less than 0.10%, of a compound of formula (V), i.e. candesartan cilexetil pyran.

The present invention provides newly isolated impurity candesartan cilexetil 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 more detai! in Example 14a.

One further embodiment of the present invention is a preparation of the substance 1 -haloethy! cyclohexyl carbonate, wherein halo 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 cilexetil pyran (1-haloethyl oxanyl carbonate of formula (IV)).

The present invention also provides the newly isolated impurity cilexetil pyran which can be characterized by LC-MS (Liquid Chromatography - Mass Spectrometry). The impurity is controlled by Gas Chromatography as the sum of impurities with RRT at about 1.478 and RRT at about 1.486. The chromatographic method is disclosed in Example 14b.

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

Melting points were taken on a Koffler meiting point apparatus and IR spectra were taken on a Paragon 100 Perkin-Elmer FT-IR spectrometer. The particle size was determined on a Malvern Mastersizer Apparatus MS 2000.

Examples

A) Preparation of candesartan cilexetH form I according to the present invention

Example 1 : Preparation of candesartan (step a, step b)

A mixture of 0,85 g (2 mmol) of ethyl 1-((2'-cyanobiphenyl-4-yl)methy!)-2-ethoxy- 1H-benzo[d3imidazole-7-carboxy!ate, 2.6 g (8 mmol) of tributyltin azide and 7 ml of toluene is heated under reflux temperature for 2 days. After the reaction is completed, the mixture is cooled and then 10 ml 1 M NaOH is added and the mixture is refluxed for at least 1 h. After the hydrolysis is completed, the mixture is cooled and the phases were separated. The water phase is extracted with toluene (15 ml) and then 1 M HC! is added to estimate the pH of the water phase to 3 to 4. The precipitated product is filtered and dried (0.79 g). The product is recrystallized from methanol or acetone, MP: 199-211 ⁰ C

Example 2: Preparation of tritylcandesartan (step c)

To a solution of 0.88 g (2 mmoS) of candesartan in 4 ml of methylene chloride, 0,66 g (2.4 mmol) of trity! chloride and 0.34 ml (2.4 mmo!) of triethylamine were added. The mixture is stirred at room temperature for 1h, and the mixture is washed with 5 ml of water (twice). Organic phase is evaporated and to the residue tert-butyl methyl ether is added. The product is separated and dried {1 ,2 g).

Example 3: Preparation of trifylcandesartan cifexetil (step d)

20,40 g (30 mmol) of tritylcandesartan, 30 ml_ of dimethylacetamide (DMA); 4,95 g (235,9 mmol) K ₂ CO ₃ and 10,2 g (49,4 mmoi) of 1-chioroethyl cyclohexy! carbonate are heated at 6O ⁰ C 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 ml of isopropyi acetate. The combined organic phases are washed with 2x240 ml of water, fϋtered and the volatile components are evaporated in vacuum. To the oily residue 150 mi of tert-butyi 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 40 ⁰ C in a vacuum dryer. 25.09 g (98%) of compound (M) are obtained (HPLC: more than 98%).

Example 4: Preparation of candesartan ciiexetil (step e)

Example 4a:

17,06 g (20 mmol) of tritylcandesartan ciiexetil, 60 ml MeOH, 240 ml methylene chloride and 2,39 g (17,5 mmol) ZnCi ₂ are heated under reflux for 4 hours. After the reaction is completed, the reaction mixture is cooled to approximately 30 ⁰ C, 200 ml of water are added, the organic and the aqueous phase are separated and the organic phase is washed with 2x200 ml of water and dried with Na ₂ SO ₄ 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 over night at room temperature.

Example 4b: 1.6 g (1.88 mmol) of tritylcandesartan ciiexetil, 5.6 ml MeOH, 23 ml methylene chloride and 0.23 ml (1.8 mmol) BF ₃ etherate are stirred at 0 to 10 ⁰ C for 5 hours. After the reaction is completed, 19 ml of water are added, the organic and the aqueous phase are separated and the organic phase is washed with 2 x 19 mt of water and dried with Na ₂ SO ₄ until the water content is below 0.3%, and the volatile components are evaporated to yield 1.7 g of an oily residue. The oily residue obtained is dissolved in 5.6 ml of isopropyi acetate and the mixture is stirred at room temperature (between 15 and 25 ⁰ C) for approximately 7 hours, The precipitate is filtered and dried for 2 hours at 45°C. 0.95 g of a partially wet product

is obtained which are further suspended in 10 mi of tert-butyl methyl ether for 1 hour at room temperature. The product is dried over night at room temperature.

Example 4c: 1.6 g (1.88 mmol) of tritylcandesartan cilexetil, 5.6 ml MeOH ₅ 23 ml methylene chloride and 0.31 g (1.61 mmol) SnCI ₂ are heated under reflux temperature for 3.5 hours. After the reaction is completed, 19 m! of water are added, the organic and the aqueous phase are separated and the organic phase is washed with 2 x 19 ml of water and dried with MgSO ₄ until the water content is below 0.3%, and the volatile components are evaporated to yield 1.7 g of an oily residue. The oiiy residue obtained is dissoived in 5.6 ml of isopropyl acetate and the mixture is stirred at room temperature (between 15 and 25 ⁰ C) for approximately 7 hours. The precipitate is filtered and dried for 2 hours at 45°C. 0.85 g of a partially wet product is obtained which are further suspended in 10 mi of tert-butyl methyl ether for 1 hour at room temperature. The product is dried over night at room temperature.

Example 4d:

1.6 g (1.88 mmol) of tritylcandesartan cilexetil, 5.6 mi MeOH, 23 ml methylene chioride and 0.35 g (1.61 mmol) Zn(CH ₃ COO^ are heated under reflux temperature for 24 hours. After the reaction is completed, 19 mi of water are added, the organic and the aqueous phase are separated and the organic phase is washed with 2 x 19 ml of water and dried with MgSO ₄ until the water content is below 0.3%, and the volatile components are evaporated to yield 1 ,7 g of an oϋy residue. The oily residue obtained is dissolved in 5.6 ml of isopropyl acetate and the mixture is stirred at room temperature (between 15 and 25 ⁰ C) for approximately 7 hours. The precipitate is filtered and dried for 2 hours at 45 ⁰ C. 0.90 g of a partially wet product is obtained which are further suspended in 10 mi of tert-butyl methyl ether for 1 hour at room temperature, The product is dried over night at room temperature.

Example 4e:

1.6 g (1.88 mmol) of tritylcandesartan cilexetil, 5.6 ml MeOH, 23 ml methylene chloride and 0.58 g (1.61 mmol) zinc trifiuoromethanesulfonate are heated under

reflux temperature for 4.5 hours. After the reaction is completed, 19 ml of water are added, the organic and the aqueous phase are separated and the organic phase is washed with 2 x 19 mi of water and dried with MgSO ₄ until the water content is below 0.3%, and the volatile components are evaporated to yield 1.7 g of an oily residue. The oϋy residue obtained is dissolved in 5.6 ml of isopropyl acetate and the mixture is stirred at room temperature (between 15 and 25 ⁰ C) for approximately 7 hours. The precipitate is filtered and dried for 2 hours at 45°C. 0.92 g of a partially wet product is obtained which are further suspended in 10 ml of tert-butyi methyl ether for 1 hour at room temperature. The product is dried over night at room temperature.

Example 5: Crystallization of candesartaπ cilexetil (step f)

Example 5a: 10.4 g of candesartan cilexetil and 52 ml of isopropanol are mixed together and heated until all candesartan cilexetil dissolves. The solution is filtered, cooled to room temperature and stirred at a temperature between 15 and 25 ⁰ C for 12 hours.

The precipitate is filtered, washed and dried for 2 hours in an air drier at 35 ⁰ C. 9.3 g of pure candesartan cilexetil form I are obtained. Area % HPLC: candesartan cilexetil: 99.66%, alkyl ester of candesartan cilexetil

0.05%, candesartan cilexetil pyran 0.05%, tritylcandesartan cilexetif 0.08%.

Example 5b:

Candesartan cilexetil (60 g) is dissolved in isopropanol (900 m!_) at 60-65 ⁰ C. Solution is hot filtered into reactor and quickly cooled to 35 ⁰ C. At this temperature nucleation is provoked with 300 mg of candesartan cilexetil form I and stirring is enforced. Suspension is cooled to 3O ⁰ C in 1 hour and rigorous stirring is continued at this temperature for additional 5 hours. Then stirring power is reduced and the suspension is cooled to 2O ⁰ C in 8 hours. The product is filtered, washed with isopropanoi and dried for 2 hours at 38°C. Yield: 48.7 g of candesartan cilexetil form I.

Area % HPLC: candesartan cilexetil: 99.73%, alky ester of candesartan cilexetil 0.08%, candesartan cilexetii pyran below 0.05%, tritylcandesartan cϋexetil 0.09%

Average particle size: 19 /vm, no agglomerates present (see Figure 2)

B) Detection of impurities in candesartan cilexetil

Example 6 Detection of candesartan cϊlexetil pyran in candesartan cilexetii 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. _τ 1.8 μm particles

Eluent A: 0.01 M NaH ₂ PO ₄ , pH 2.5

Eluent B: acetonitriie Gradient of Eluent:

Flow rate: about 1.2 ml/min

Diluent: acetonitriie : water = 70 : 30 (V/V).

Detection: UV, wavelength 225 nm injection volume: 5 μl

Column temperature : 50 ⁰ C

Autosampler temperature: 7°C

Example 7

Detection of cilexetil pyran in 1 -chloroethyl cyclohexylcarbonate 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 ml/mi n

Split ratio: 10 : 1

Air flow rate: 400 ml/min

Hydrogen flow rate: 40 ml/min Make up gas flow ISb rate: 25 ml/min

Column temperature 100°C (0 min) → 10°C/min → 200 ⁰ C (10 min or prolonged if necessary)

Injector temperature: 21 O ⁰ C Detector temperature: 250OC Injection volume : 1 μl Diluent: Acetonithle: chromatography grade.

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