Title of Invention

PROCESS FOR PREPARATION OF CANDESARTAN CILEXETIL CRYSTALLINE POLYMORPHS

Abstract The present invention relates to processes for preparation of candesartan cilexetil crystalline polymorphs. Thus, for example, candesartan cilexetil is added to toluene, the contents are heated to reflux, stirred for 15 minutes at reflux and the resulting crystals are collected at 0 -5aC by filtration to give candesartan cilexetil crystalline form III.
Full Text

The present invention relates to two novel crystalline forms and a novel 1,4-dioxane solvate of candesartan cilexetil, to processes for their preparation and to pharmaceutical compositions containing them.
BACKGROUND OF THE INVENTION Candesartan cilexetil of formula (1):

or 2-Ethoxy-1 -[[2'-(1 H-tetrazol-5-yl)[1,1 '-biphenyl]-4-yl]methyl]-1 H-
benzimidazole-7-carboxylic acid, 1-[[(Cyclohexyloxy)carbonyl]oxy]ethyl ester. Candesartan cilexetil is an antihypertensive agent and its therapeutic uses were disclosed in US 5,196,444. US 5,196,444 also disclosed a crystalline form of candesartan cilexetil (C-type crystalline form). Two crystalline forms of candesartan cilexetil, form I and form II, are described in Chem. Pharm. Bull. 47(2), 182-186(1999).
We have discovered a novel 1,4-dioxane solvate of candesartan cilexetil and two novel crystalline forms of candesartan cilexetil. The novel forms have been found to be stable and reproducible.
The object of the present invention is to provide a stable novel 1,4-dioxane solvate of candesartan cilexetil and two stable crystalline forms of candesartan cilexetil, processes for preparing these forms and pharmaceutical compositions containing them.
DETAILED DESCRIPTION OF THE INVENTION
One aspect of the present invention is to provide a novel 1,4-dioxane solvate of candesartan cilexetil (hereinafter referred to as candesartan cilexetil dioxane solvate). Typically the content of 1,4-dioxane in the solvate is 8.8 to 13.0 % w/w. The candesartan cilexetil dioxane solvate is characterized by an x-ray powder diffraction pattern having peaks expressed as 26 at about 6.0, 10.7,

16.2, 18.0, 19.7, 20.6, 21.3, 21.7, and 22.3 degrees. Figure 1 shows typical x-ray powder diffraction pattern of candesartan cilexetil dioxane solvate.
Candesartan cilexetil dioxane solvate is prepared by dissolving crystalline form or amorphous form of candesartan cilexetil in 1,4-dioxane and crystallizing at 5°C to15°C, preferably at 5°C to 10°C.
Another aspect of the present invention is to provide a novel crystalline form of candesartan cilexetil (hereinafter referred to as candesartan cilexetil form III, characterized by an x-ray powder diffraction pattern having peaks at about 6.3, 7.3, 8.1, 8.9, 10.1, 14.6, 15.0, 15.8, and 18.8 degree. Figure 2 shows typical x-ray powder diffraction pattern of candesartan cilexetil form III.
The candesartan cilexetil form III is prepared by dissolving candesartan cilexetil in toluene by heating, cooling the solution slowly to 0°C to 5°C, maintaining at 0°C to 5°C for about 1 hour and separating the crystals formed by filtration. The solvent may be heated to dissolve candesartan cilexetil. Candesartan cilexetil used in the process may be any of the crystalline forms except form III, amorphous form or candesartan cilexetil dioxane solvate.
Another aspect of the present invention is to provide a novel crystalline form of candesartan cilexetil (hereinafter referred to as candesartan cilexetil form IV). The candesartan cilexetil form IV is characterized by an x-ray powder diffraction pattern having peaks at about 6.1, 7.1, 11.6, 11.9, 17.9, 19.8 and 21.2 degree. Figure 3 shows typical x-ray powder diffraction pattern of candesartan cilexetil form IV.
The candesartan cilexetil form IV is prepared by mixing candesartan cilexetil, methyl tert-butyl ether and methanol at 50°C 55°C and maintaining at 20°C to 25°C for about 10 hours. Candesartan cilexetil used in the process may be any of the crystalline forms except form IV, amorphous form or candesartan cilexetil dioxane solvate.
Candesartan cilexetil used in the above processes may be obtained by the known methods.
In accordance with the present invention, there is provided a pharmaceutical composition comprising crystalline form III or form IV of candesartan cilexetil and a pharmaceutical^ acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a x-ray powder diffraction pattern of candesartan cilexetil dioxane solvate.
Figure 2 is a x-ray powder diffraction pattern of candesartan cilexetil form III. Figure 3 is a x-ray powder diffraction pattern of candesartan cilexetil form IV. x-Ray powder diffraction spectrum was measured on a Siemens D5000 x-ray powder diffractometer having a copper-Ka radiation.
The following examples further illustrate the invention.
Example 1 Candesartan cilexetil C-type crystalline form (5 gm, obtained by a process described in US 5,196,444) is dissolved in 1,4-dioxane (50 ml) at 25°C. The solution is cooled to 5°C and maintained for 4 hours at about 5°C. The separated solid is filtered to yield 3 gm candesartan cilexetil dioxane solvate.
Example 2 Candesartan cilexetil C-type crystalline form (5 gm) is added to toluene (25 ml) and heated to reflux. The contents are maintained under reflux for 15 minutes and then cooled slowly to 0°C in 1 hour and maintained at 0°C to 5°C for 1 hour. The separated crystals are collected by filtration to give 3.5 gm candesartan cilexetil form III.
Example 3 Example 1 is repeated using candesartan cilexetil form III instead of candesartan cilexetil C-type crystalline form to give Candesartan cilexetil dioxane solvate.
Example 4 The mixture of candesartan cilexetil C-type crystalline form (5 gm), methyl tert-butyl ether (50 ml) is heated to 55°C, methanol (17 ml) is added to the mixture at 55°C and maintained at about this temperature for 1 hour. The contents are cooled to 25°C and maintained at about 25°C for 13 hours. The separated solid is collected by filtration to give 3 gm candesartan cilexetil form IV.
Example 5

Example 2 is repeated using candesartan cilexetil form IV instead of candesartan cilexetil C-type crystalline form to give Candesartan cilexetil form III.
Example 6
Example 4 is repeated using candesartan cilexetil dioxane solvate instead of candesartan cilexetil C-type crystalline form to give Candesartan cilexetil form IV.




We claim:
1. A process for the preparation of candesartan cilexetil crystalline polymorphs,
1,4-dioxane solvate, characterized by an x-ray powder diffraction pattern
having peaks expressed as 29 at about 6.0, 10.7, 16.2, 18.0, 19.7, 20.6,
21.3, 21.7, and 22.3 degrees as shown in figure 1; form III, characterized by
an x-ray powder diffraction pattern having peaks expressed as 29 at about
6.3, 7.3, 8.1, 8.9, 10.1, 14.6, 15.0, 15.8, and 18.8 degrees as shown in figure
2; form IV, characterized by an x-ray powder diffraction pattern having peaks
expressed as 29 at about 6.1, 7.1, 11.6, 11.9, 17.9, 19.8 and 21.2 degrees
as shown in figure 3; as herein described comprising the steps of:
a) suspending or dissolving candesartan cilexetil in a specific organic solvent or a combination of the specific organic solvents selected from the group consisting of 1,4-dioxane, toluene, methyl tert-butyl ether, methanol; and
b) isolating i) crystalline candesartan cilexetil 1,4-dioxane solvate when 1,4-dioxane is used as the solvent, ii) crystalline polymorph form III when toluene is used as the solvent, and iii) crystalline polymorph form IV when the combination of methyl tert-butyl ether and methanol is used as the solvent.
2. The process as claimed in claim 1, wherein the process comprising the steps
of:
a) dissolving candesartan cilexetil in 1,4-dioxane; and
b) crystallizing candesartan cilexetil as 1,4-dioxane solvate from the solution at 5°C to 15°C.

3. The process as claimed in claim 2, wherein the content of 1,4-dioxane is 8.8 to 13.0% w/w.
4. The process as claimed in claim 1, wherein the process comprising the steps of:

a) mixing candesartan cilexetil with toluene;
b) heating to obtain clear solution;
c) cooling slowly to 0°C to 5°C in about 1 hour;
d) maintaining at 0°C to 5°C for about 1 hour; and
e) collecting the separated candesartan cilexetil crystalline form III by filtration.

5. The process as claimed in claim 1, wherein the process comprising the steps of:
a) heating the mixture of candesartan cilexetil, methyl tert-butyl ether and
methanol to 50°C to 55°C;
b) cooling to 20°C to 25°C;
c) maintaining at 20°C to 25°C for about 10 hours; and
d) collecting the separated candesartan cilexetil crystalline form IV by
filtration.


Documents:

778-chenp-2003-abstract.pdf

778-chenp-2003-claims duplicate.pdf

778-chenp-2003-claims original.pdf

778-chenp-2003-correspondnece-others.pdf

778-chenp-2003-correspondnece-po.pdf

778-chenp-2003-description(complete) duplicate.pdf

778-chenp-2003-description(complete) original.pdf

778-chenp-2003-drawings.pdf

778-chenp-2003-form 1.pdf

778-chenp-2003-form 3.pdf

778-chenp-2003-form 4.pdf

778-chenp-2003-form 5.pdf

778-chenp-2003-pct.pdf


Patent Number 206268
Indian Patent Application Number 778/CHENP/2003
PG Journal Number 26/2007
Publication Date 29-Jun-2007
Grant Date 23-Apr-2007
Date of Filing 21-May-2003
Name of Patentee HETERO DRUGS LIMITED
Applicant Address Hetero House, 8-3-166/7/1, Erragadda, Hyderabad 500 018.
Inventors:
# Inventor's Name Inventor's Address
1 PARTHASARADHI, Reddy, Bandi Hetero House, 8-3-166/7/1, Erragadda, Hyderabad 500 018, Andhrapradesh
2 RATHNAKAR, Reddy, Kura Hetero Drugs Limited (R & D), Plot No. B-80 & 81, A.P.I.E., Balanagar, Hyderabad 500 018, Andhrapradesh
3 RAJI, Reddy, Rapolu Hetero Drugs Limited (R & D), Plot No. B-80 & 81, A.P.I.E., Balanagar, Hyderabad 500 018, Andhrapradesh
4 MURALIDHARA, Reddy, Dasari Hetero Drugs Limited (R & D), Plot No. B-80 & 81, A.P.I.E., Balanagar, Hyderabad 500 018, Andhrapradesh
5 SUBASH CHANDER, Reddy, Kesireddy Hetero Drugs Limited (R & D), Plot No. B-80 & 81, A.P.I.E., Balanagar, Hyderabad 500 018, Andhrapradesh
PCT International Classification Number A61K9/20
PCT International Application Number PCT/IN2003/000090
PCT International Filing date 2003-03-27
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA