FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
A PROCESS FOR PURIFICATION OF PIOGLITAZONE HYDROCHLORIDE
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a process for the purification of piogiitazone
hydrochloride.
The following specification particularly describes the invention and the manner
in which it is to be performed.
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4. DESCRIPTION
The present invention provides a process for purification of pioglitazone hydrochloride.
Pioglitazone hydrochloride of Formula I is chemically [(±)-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-] thiazolidinedione monohydrochloride. It is an active antidiabetic agent and is a member of 2,4-thiazolidinone classes of compounds.
Formula I
US patent Nos. US 4,687,777; US 6,100,403; US 4,812,570; US 4,895,947; US 5, 554,758; US 5,952,509 and EP 0257781 describe the process of preparation of pioglitazone hydrochloride and its intermediate.
The present inventors developed a purification process for pioglitazone and its salt. The present inventors have surprisingly found that suspension of pioglitazone free base into a mixture of alcohol and halogenated hydrocarbon results in increase purity of pioglitazone, which can be then converted to its hydrochloride salt. The purity at salt stage also increased by suspending the pioglitazone salt in alcohol.
In one of the aspect of the present invention there is provided a process of purification of pioglitazone, wherein the said process comprises of
a) suspending pioglitazone in mixture of alcohol and halogenated solvent,
b) isolating the product from the reaction mass thereof.
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The process of present invention involves suspending pioglitazone free base in organic solvent mixture, reflux of reaction mixture for more than 4 hours and filter the product at temperature below 10°C, the filtered solid washed with alcohol and dried to get purified free base pioglitazone. The organic solvent mixture includes the mixture of alcohol and halogenated solvent.
The free base obtained is converted to hydrochloride salt by treating the base with alcoholic-hydrogen chloride, having hydrogen chloride content less than 12% w/w. The pioglitazone hydrochloride further purified & improved in colour by dissolving in aqueous alcohol. The salt is precipitated on cooling the reaction mixture to below 10°C. The aqueous alcohols are where the alcohol containing water in the range of 6-10%.
Alcohol may be selected from a group comprising one or more of C1-C4 linear chain, branched chain alcohols. Further linear chain alcohols include but not limited to methanol, ethanol, propanol, butanol. Branched chain alcohols include but not limited to isopropyl alcohol, isobutanol. Halogenated solvent includes chloroform, dichloromethane, dichloroethane, carbon tetra chloride and the like.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES
Example 1
Purification of Pioglitazone Base
Pioglitazone free base (0.41 Kg) was suspended in a mixture of chloroform (0.82 Ltr) and methanol (4.10 Ltr), refluxed under stirring for 12 hours. Then it was
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cooled to 0 to 5°C, precipitated solid was filtered, washed with methanol and
dried in oven at 80°C for 5 hours to get purified free base Pioglitazone.
Yield = 0.40 Kg.,
Purity by HPLC = 99.4%.
Example 2
Preparation of Pioglitazone Hydrochloride
Pioglitazone base (0.4 Kg) was suspended in methanol (1.2 L) at room
temperature, to it under stirring was added a methanolic solution of hydrogen
chloride (hydrogen chloride content 12.5%) (0.5L) A clear solution was formed
and at once solid crystallizes out. It was then cooled to 0 to 5°C further stirred for
2 hours filtered and dried under vacuum.
Yield = 0.32 Kg.
Purity by HPLC = 99.7%.
Example 3
Purification of Pioglitazone Hydrochloride
Pioglitazone hydrochloride (0.32 Kg) was suspended in isopropyl alcohol (3.20 L)
under heating and to it water (0.22 Ltr) was added to form clear solution. The
solution was charcoalised and filtered under hot condition. The filtrate was cooled
to 0°C for 1 hour to crystalline solid, it was filtered dried to get pure pioglitazone
hydrochloride.
Yield = 0.31 Kg.
Purity by HPLC = 99.8 %
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WE CLAIM:
1. A process of purification of pioglitazone, wherein the said process comprises
of
a) suspending pioglitazone in mixture of alcohol and halogenated solvent,
b) isolating the product from the reaction mass thereof.

2. A process of claim 1, wherein the alcohol may be selected from a group comprising one or more of C1-C4 linear chain alcohols.
3. A process of claim 1, wherein the halogenated solvents are chloroform, dichloromethane, dichloroethane and carbon tetra chloride.
4. A process of claim 1, further comprising conversion of pure pioglitazone free base to pioglitazone or salt thereof.
5. A process of claim 4 wherein the salt is hydrochloride.
6. A process of claim 4, wherein pioglitazone or salt obtained having purity is 99.8% or more by HPLC.

Dated this 29th day of September, 2006

For Wockhardt Limited

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(Mandar Kodgule) Authorized Signatory