DESCRIPTION

The present invention provides a process for the purification of Ziprasidone or salt thereof free from its impurities  especially  oxindole impurity.

Ziprasidone of Formula I is chemically known as (5-[2-[4-(1 2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1 3-dihydro-2H-indol-2-one.

Formula I

Ziprasidone capsules contain a monohydrochloride  monohydrate salt of Ziprasidone. Chemically  Ziprasidone hydrochloride monohydrate is 5-[2-[4-(1 2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1 3-dihydro-2H-indol-2-one  monohydrochloride  monohydrate.

U.S. Patent No. 4 831 031 discloses Ziprasidone hydrochloride and related compounds and their antipsychotic therapeutic uses. The ‘031 patent discloses a process for preparing Ziprasidone by reacting 1-(1 2-benzisothiazol-3-yl)piperazine and 5-(2-chloroethyl)-6-chloro-oxindole in a polar solvent  such as a lower alcohol  dimethylformamide or methylisobutyl ketone in the presence of a base.

Many patents and applications  US 5 206 366  US 5 359 068  US 5 338 846  US Application 2009/0163513  US Application No. 2008/0214816  WO 2010/073255 and WO 2005/054235 disclose a process for preparing Ziprasidone or its salts.

Despite various processes disclosed in the prior art for the preparation of Ziprasidone and salts thereof  still there is a need for producing Ziprasidone and pharmaceutically acceptable acid addition salts of Ziprasidone free from its impurities.

In an aspect of the present invention relates to a purification of Ziprasidone of Formula I and pharmaceutically acceptable acid addition salts of ziprasidone free from its impurity Formula II  2-chloroethyl-6-chloro oxindole (herein after oxindole impurity).

Formula II
In accordance with the present invention the process for the preparation of Ziprasidone or Its pharmaceutically acceptable salt containing  Oxindole impurity of Formula II less than 10 ppm  the process includes steps of 

Formula II
contacting of Crude Ziprasidone or pharmaceutically acceptable salts in mixture of DMSO (dimethyl sulfoxide) and THF (tetrahydrofuran) and isolating pure Ziprasidone or pharmaceutically acceptable salt thereof.
The process involves combining of Ziprasidone or pharmaceutically acceptable acid addition salt thereof in a solvent mixture of DMSO and THF and recovering solid at room temperature or at above temperature.

The crystallization process involves dissolution of Ziprasidone or pharmaceutically acceptable acid addition salt thereof in a solvent mixture of DMSO and excess of THF and recovering solid at below room temperature.

The process involves the dissolution of crude Ziprasidone or its pharmaceutical acceptable salt having oxindole impurity more than 10 ppm in the mixture of DMSO and THF  wherein DMSO and THF ratio could be in the range of 1-2:15-20 and total volume vary up to 15 to 35 times of the quantity of the Ziprasidone or its pharmaceutically acceptable salt. After dissolution the solvent mixture (DMSO: THF) is distilled out to make the reduce volume unto 5-7 times from the initial volume. The residue obtain is cooled to below 10° C and filtered the product  washed with the mixture of DMSO and THF followed by water. The material is dry to get the pure Ziprasidone or pharmaceutically acceptable salt having oxindole impurity less than 10 ppm.

The pharmaceutically acceptable acid addition salt of Ziprasidone is selected from hydrochloride salt  hydrobromide salt  maleate salt  acetate salt and the like. In an embodiment of the present invention provides pure Ziprasidone hydrochloride salt. The hydrochloride salt obtained  by refluxing the Ziprasidone base in water with concentrated hydrochloric acid for 15-22 hours.

The term "pure Ziprasidone or its pharmaceutically acceptable salt" refers to Ziprasidone or its pharmaceutically acceptable salt having the HPLC purity is more than or equal to 99.8%.

The process of present invention provides the content of oxindole impurity  less than 10 ppm in Ziprasidone or its pharmaceutically acceptable acid addition salt.

The present invention is further illustrated by the following example  which does not limit the scope of the invention. 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 application.

Experiment:

Eperiment-I: Ziprasidone Base

3-(1-Piperazinyl)-Benzisothiazole.HCl (117 gm) was condensed with 6-chloro 5-(2-chloro ethyl) oxindole (105.6 gm) by heating at reflux temperature in presences of sodium carbonate (169 gm) and catalytic amount of sodium Iodide (6 gm) in water(700 ml) to get Ziprasidone base185 gm)
Yield: 185 gm
HPLC Assay: 93.2% (OAB)
Oxindole Impurity by HPLC: 0.15%

Purification of Ziprasidone Base

Ziprasidone base (160 gm) was dissolved in 10% DMSO-THF mixture at reflux temperature to obtained clear solution it was partially distilled out  residual mass was cooled to 0-5°C and filtered  and washed with was DMSO-THF mixture and water to obtained Ziprasidone base.
Yield: 90 gm
HPLC Assay: 98.8% (OAB)
Oxindole Impurity by HPLC: 1.5 ppm.

Experiment:II: Ziprasidone Hydrochloride Monohydrate

Ziprasidone base pure (80 gm) was heated in water in presence of conc. Hydrochloric acid (81 ml) at 60-650C for 14.0 hrs to gives Ziprasidone Hydrochloride Monohydrate.
Yield: 87 gm
Assay: 99.4 % (OAB)
Oxindole Impurity by HPLC: Not detected.

We Claim:

1. A process for the preparation of Ziprasidone or Its pharmaceutically acceptable salt containing  Oxindole impurity of Formula II less than 10 ppm  the process comprising 

Formula II
contacting of Crude Ziprasidone or pharmaceutically acceptable salts in mixture of dimethyl sulfoxide and tetrahydrofuran and isolating pure Ziprasidone or pharmaceutically acceptable salt thereof.

2. The process of Claim 1  wherein Crude Ziprasidone contains oxindole impurity more than 10 ppm.

3. The process of Claim 1  wherein mixture of dimethyl sulfoxide and tetrahydrofuran in ratio of 1-2:15-20.

4. The process of Claim 3  wherein mixture of dimethyl sulfoxide and tetrahydrofuran in ratio of 1:15.

5. The process of Claim 1  wherein dimethyl sulfoxide: tetrahydrofuran volume is 15 to 35 times of the Crude Ziprasidone or its pharmaceutical acceptable salt.

6. The process of Claim 5  wherein dimethyl sulfoxide: tetrahydrofuran volume is 15 times of the Crude Ziprasidone or its pharmaceutical acceptable salt.

7. The process of Claim 1  wherein said pharmaceutically acceptable acid addition salt is HCl salt of Ziprasidone.

8. The process of Claim 1  wherein crystallization involves dissolution of Ziprasidone or pharmaceutically acceptable acid addition salt thereof in a solvent mixture of dimethyl sulfoxide and excess of tetrahydrofuran and recovering solid at below room temperature.

9. The process of Claim 1  wherein said pure Ziprasidone or pharmaceutically acceptable acid addition salt contains purity of about 99.8% or above.

10. The process of Claim 1  wherein said pure Ziprasidone or pharmaceutically acceptable acid addition salt contains the content of oxindole impurity less than 10 ppm or below the level of detection.

Dated this 8th day of June  2012 For Wockhardt Limited

(Dr Mandar Kodgule)
Authorized Signatory