FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
PROVISIONAL SPECIFICATION / COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
A PROCESS FOR PURIFICATION OF PIOGLITAZONE
2. APPLICANT(S)
(a) NAME : CADILA PHARMACEUTICALS LIMITED
(b) NATIONALITY : An INDIAN Company
(c) ADDRESS : "Cadila Corporate Campus", Sarkhej - Dholka Road, Bhat,
Ahmedabad -382210, Gujarat, India
3. PREAMBLE TO THE DESCRITION

PROVISIONAL SPECIFICATION
The following specification describes the invention.

COMPLETE SPECIFICATION
The following specification particularly describes the invention and the manner in which it is to be performed

4. DESCRIPTION
(Description starts from next page)

FIELD OF THE INVENTION
The present invention relates to an improved process for purification of pioglitazone using a mixture of solvents involving toluene and methanol.
BACKGROUND OF THE INVENTION
United States patent no. 4687777 (herein referred as US 777 patent) discloses 5-[[4-[2-(S-ethyl-2-pyridinyl)ethoxyl]phenyl]methyl]-2,4-thiazolidinedione, a compound of formula VI, commonly known as pioglitazone, and its hydrochloride salt is useful in treatment of diabetes. The US 777 patent describe the synthesis of pioglitazone as per scheme-1. In the US 777 patent pioglitazone was recrystallised using a mixture of dimethylformamide-water. The patent discloses the process for preparation of sodium salt of pioglitazone from pioglitazone. The process for the preparation of pioglitazone hydrochloride is not exemplified.



United States patent no. 4812570 (herein referred as US '570 patent) discloses the process for crystallization of pioglitazone. In example 3(b) of US '570 patent, piogiitazone residue is dissolved in 6N hydrochloric acid and the solution is neutralized with sodium hydrogen carbonate to give crystalline pioglitazone. In example 3(e) and example 3(f) of the US '570 patent, pioglitazone was recrystallized from solvent mixture of acetic acid-water and acetic acid-ethanol respectively.
United States patent no. US5585495, filtrate containing pioglitazone is treated with a
1 solution of acetic acid in water in order to precipitate the product.
United States patent no. 7009057 discloses the process for the recrystallization of pioglitazone. In the'057 patent pioglitazone is recrystallized from a mixture of DMF-water.
WO2005049532 provides a process for purification of pharmaceutically active compounds selected from the group consisting of thiazolidinedione derivatives such as piolglitazone, rosiglitazone and troglitazone by extraction in a solvent comprising an alkanol (C^ alcohol) and ammonia.
United States patent application no. 20070078170 (herein referred as US '170
application) describes a process for the purification of pioglitazone. The purification process
comprises: obtaining a solution of pioglitazone base by treating with an acid, optionally
treating the obtained solution with a base; and recovering the purified pioglitazone by the
removal of the solvent. The US '170 application also describes another process for the
1 purification of a pioglitazone wherein the process comprises: obtaining a solution of
pioglitazone in one or more non-hydroxylic solvents such as dimethylformamide, chloroform, acetonitrile, tetrahydrofuran, cyclohexane or mixtures thereof; and recovering the purified pioglitazone by the removal of the solvent. Further pioglitazone obtained by US '170 application is having 99.5% HPLC purity.
WO2004024059 discloses the process for the recrystallization of pioglitazone from dioxane.
There is still a need in the art to get pioglitazone and its pharmaceutically acceptable salt with a higher yield and purity, as well as purification processes for obtaining the same.

SUMMARY OF THE INVENTION
The present invention provides an improved process for the purification of pioglitazone in high yield and purity.
Another object of the invention is to provide an alternative method of purification of pioglitazone.
Yet another object of invention is to provide a process for purifying Pioglitazone comprising crystallizing Pioglitazone from mixture of toluene and methanol.
Yet another aspect of present invention is to provide a process for preparing pure Pioglitazone hydrochloride involving the use of purified Pioglitazone.
Yet another aspect of present invention is to provide pioglitazone or its pharmaceutical^ acceptable salts having with purity over 99%, preferably 99.5 or above%.
DETAILED DESCRIPTION OF THE PROCESS
In accordance with the present invention for the purification of pioglitazone base using either toluene or methanol, the purity of the resultant pioglitazone base was poor. The quality of pioglitazone hydrochloride obtained from pioglitazone base purified by using either toluene or methanol was not consistent with ICH guidelines.
We have surprisingly found that a solvent comprising mixture of toluene and methanol can be used advantageously in purification of Pioglitazone. Typically in the process of the present invention crude pioglitazone is added in solvent mixture comprising toluene and methanol and by isolating pioglitazone from the same. The purified pioglitazone thus obtained can be further transformed in to a pharmaceutically acceptable salt thereof. The hydrochloride salt of Pioglitazone obtained from purified Pioglitazone prepared by exemplified process meets ICH guidelines.
The present invention provides a process for purifying Pioglitazone comprising isolating pioglitazone from mixture of toluene and methanol. The toluene to methanol volume ratio used for the purification of pioglitazone varies from about from about 1:0.3 to about 0.3:1. Preferably the ratio of solvent volume ranges from 1:0.4 to 1:0.8 from either solvent to the other.
The present invention is further illustrated by following non-limiting examples.
Example-1 Preparation of pioglitazone base:
5 (4- (2- (5-ethyl-2-pyridyl) ethoxy) benzyl)-2-imino-4-thiazolidinone (150g) and 2N HC! was heated to reflux for 6-8 hours. The reaction mixture was cooled slowly to 10-15 °C, and pH of the reaction mixture was adjusted to about 8.5-9 using potassium carbonate solution. The reaction mass was stirred for about 2 hours. The precipitated solid was filtered, washed with water and dried at 65°C-75 °C to get the title compound.
30 JUN 2009

Example-2 Purification of pioglitazone base:
The Pioglitazone base (150 gm) was mixed with methanol (900 ml) and toluene (600 ml) and heated to reflux temperature for an hour. The reaction mass was gradually cooled to 25-30°C and then cooled to 0-5 °C. The product was filtered and washed with mixture of toluene and methanol. The wet cake was again slurried into toluene and methanol. The solvent is removed to give Pioglitazone base Yield = 129.5 gm (86.33 %) HPLC Purity^ 99.17%.
Example-3 Preparation of pioglitazone hydrochloride:
To the mixture of Pioglitazone base (115 gm) in methanol (690 ml) was added methanolic HCI (80 ml) to obtain a clear solution. Activated charcoal was added to this solution and the reaction mixture was refluxed for about an hour. The reaction mass was filtered and washed with methanol. The filtrate was concentrated and then cooled at 0-5°C. The mixture was filtered and recrystallized from methanol. The product was dried at 55-60°C under vacuum to give pioglitazone HCI. Yield= 78 gms HPLC purity= 99.79 %

For, CADILA PHARMACEUTICALS LIMITED
Bakulesh Mafatlal Khamar Executive-Director Research