FORM2THE PATENTS ACT, 1970(39 of 1970) &The Patents Rules, 2003COMPLETE SPECIFICATION(See section 10; rule 13)
Title of the invention - "A process for the preparation of an Candesartan cilexetil." amorphous form of
2. Applicant(s)(a) NAME: ALEMBIC LIMITED(b) NATIONALITY: An Indian Company(c) ADDRESS: Alembic Campus, Alembic Road, Vadodara-390 003, Gujarat, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed :


Field of invention:
The present invention relates to a process for the preparation of an amorphous form of Candesartan cilexetil.
Background of the invention:
The chemical name of Candesartan cilexetil is 1-
[ [(cyclohexyloxy)carbonyl] oxy] ethyl 2-ethoxy-1 - [ [2-(lH-tetazole-5 -yl) [ 1,1'-
biphenyl-4-yl]methyl]-lH-benzimidazole-7-carboxylate. Its molecular formula is C33H34N6O6 and mol wt is 610.66. Candesartan cilexetil is represented by structural formula (I)

Candesartan cilexteil is an ester prodrug of 2-ethoxy-l-[[2-(lH-tetrazole-5-yl)[l,l'-biphenyl-4-yl]methyl]-lH benzimidazole-7-carboxylic acid (candesartan), known as a potent Angiotensin II receptor antagonist. It is useful in the treatment of cardiovascular complaints such as hypertension and heart failure. Candesartan cilexetil is a white to off-white powder and is sparingly soluble in water and in methanol. It is marketed by AstraZeneca under tradename ATACAND®.
U.S. Pat. No. 5,196,444 describes a process of preparation of Candesartan cilexetil in which it is formed by reacting 2-ethoxy-l-[[2'-(N-triphenylmethyltetrazol-5-yl)biphenyl -4-yl]methyl]benzimidazole-7-carboxylic acid in dimethylformamide with cyclohexyl-1-iodoethyl carbonate to form cilexetil trityl candesartan and its subsequent deprotection with a methanolic hydrochloric acid gives candesartan

cilexetil in 47% yield after column chromatography. The yield obtained by this process is very low. Moreover, the purification of final product by chromatography is commercially not suitable and is cumbersome at an industrial scale. Furthermore, amorphous form as prepared from herein having drawback such as unstable by heating and impractical in production.
Chem. Pharm. Bull, 47(2), 182-186 (1999) discloses two crystalline forms of Candesartan cilexetil such as form I and form II and an amorphous form. The grinding process reported for preparing an amorphous form from crystalline form I and form II involves repeated cycles of crushing or milling to obtain amorphous powder, which is usually contaminated with crystalline forms. In addition, candesartan cilexetil is heat sensitive and therefore grinding causes unwanted degradation and loss in purity.
WO2005077941 describes a process for the preparation of an amorphous Candesartan cilexetil by dissolving candesartan cilexetil in dioxane to form a solution and pouring the solution into water to form a mixture which is precipitated to obtain amorphous Candesartan cilexetil. The drawback of this process is use of dioxane which is carcinogen and harmful by inhalation, ingestion and through skin contact. Moreover, the yield obtained by this process is very low.
WO2005123721A1 describes a process for the preparation of an amorphous form
by dissolving candesartan cilexetil in one or more organic solvents to form a
solution
then removing the solvent from the solution by spray-drying and optionally drying
the amorphous form of candesartan cilexetil.
WO2006048237 Al describes a process for the preparation of an amorphous form by dissolving candesartan cilexetil in a chlorinated solvent to form a solution

which is concentrated and precipitating the amorphous form by adding liquid cyclic hydrocarbon.
Summary of the invention:
A primary object of the present invention is to provide a process for the preparation of an amorphous form of candesartan cilexetil.
Yet another object of the present invention is to provide a process for the
preparation of an amorphous form of Candesartan cilexetil comprising steps of
i) dissolving candesartan cilexetil in an organic solvent or optionally
heating until it becomes clear solution ii) removing the solvent from the solution formed in step (i) by distillation under reduced pressure
Detailed description of the invention:
According to the present invention, it provides a process for the preparation of an amorphous form of Candesartan cilexetil comprising steps of
i) dissolving candesartan cilexetil in an organic solvent or optionally
heating until it becomes clear solution ii) removing the solvent from the solution formed in step (i) by distillation under reduced pressure
The organic solvent as mentioned hereinabove is selected from a group comprising of halogenated hydrocarbon, alcohol, ester and ketone and the like or mixture thereof.
Halogenated hydrocarbon as mentioned hereinabove is selected from a group such as dichloromethane, ethylenedichloride, chloroform and the like or mixture thereof. The preferable halogenated hydrocarbon is dichloromethane.

The examples of alcohol includes but not limited to methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol and the like or mixture thereof. The preferable alcohol is methanol.
The examples of ester includes but not limited to ethyl acetate, methyl acetate, butyl acetate and the like or mixture thereof. The preferable ester is ethyl acetate.
The examples of ketone includes but not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like or mixture thereof. The preferable ketone is acetone.
The removal of solvent form the solution is carried by distillation under reduced pressure which is achieved by vacuum distillation.
The amorphous form of Candesartan cilexetil is characterized by having X-ray diffraction pattern as in figure-1 which essentially depicts the amorphous nature of candesartan cilexetil as prepared according to present invention.
The process of the present invention is described by the following examples, which are illustrative only and should not be construed so as to limit the scope of the invention in any manner.
Examples-1
Preparation of amorphous form of Candesartan Cilexetil
5.0 g form C type solid (form-I) of candesartan cilexetil was dissolved in dichloromethane (25 ml) to get clear solution and dichloromethane was distilled out under vacuum at 40° C to get amorphous form.

X-ray powder diffraction pattern demonstrates the amorphous nature of the product (figure-1).
Examples-2
Preparation of amorphous form of Candesartan Cilexetil
3.0 g form C type solid (form-I) of candesartan cilexetil was dissolved in acetone (30 ml) and heated it to get clear solution and acetone was distilled out under vacuum at 50° C to get amorphous form.
X-ray powder diffraction pattern demonstrates the amorphous nature of the product (figure-1).
ExampIes-3
Preparation of amorphous form of Candesartan Cilexetil
3.0 g form C type solid (form-I) of candesartan cilexetil was dissolved in ethyl acetate (60 ml) and heated it to get clear solution and ethyl acetate was distilled under vacuum at 70° C to get amorphous form.
X-ray powder diffraction pattern demonstrates the amorphous nature of the product (figure-1).
Examples-4
Preparation of amorphous form of Candesartan Cilexetil
3.0 g form C type solid (form-I) of candesartan cilexetil was dissolved in methanol (60 ml) and heated it to get clear solution and methanol was distilled out under vacuum at 60° C to get amorphous form.

X-ray powder diffraction pattern demonstrates the amorphous nature of the product (figure-1).

We Claim:
1. A process for the preparation of an amorphous form of Candesartan
cilexetil comprising steps of;
i) dissolving candesartan cilexetil in an organic solvent or optionally
heating until it becomes clear solution ii) removing the solvent from the solution formed in step (i) by
distillation under reduced pressure.
2. A process according to claim 1, wherein the said organic solvent in step (i) is selected from a group comprising of halogenated hydrocarbon, alcohol, ester and ketone or mixture thereof.
3. A process according to any proceeding claim, wherein the said organic solvent in step (i) is selected from halogenated hydrocarbon such as dichloromethane, ethylenedichloride, chloroform or mixture thereof.
4. A process according to any proceeding claim, wherein the said organic solvent is selected from alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol or mixture thereof.
5. A process according to any proceeding claim, wherein the said organic solvent is selected from ester such as ethyl acetate, methyl acetate, butyl acetate or mixture thereof.
6. A process according to any proceeding claim, wherein the said organic solvent is selected from ketone such as acetone, methyl isobutyl ketone, methyl ethyl ketone or mixture thereof.
Dated this 7th day of June 2006.
Sonali Bhokarikar Of S. MAJUMDAR & CO. Applicant's Agent

Abstract:
The present invention relates to a process for the preparation of an amorphous form of Candesartan cilexetil comprising steps of
i) dissolving candesartan cilexetil in an organic solvent or optionally
heating until it becomes clear solution
ii) removing the solvent from the solution formed in step (i) by distillation under reduced pressure