DESCRIPTION

The present invention provides a process for the preparation of pure Ziprasidone or salt thereof free from its impurities  especially  Oxindole impurity  which is Genotoxic in nature.

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 of process which can produce Ziprasidone and pharmaceutically acceptable acid addition salts free from 2-chloroethyl-6-chloro Oxindole impurity of Formula-II. The 2-chloroethyl-6-chloro Oxindole impurity is of genotoxic in nature.

Formula II 

The inventors while developing the process of making Ziprasidone and it pharmaceutically acceptable salt come across the problem of formation of 2-chloroehtyl-6-chloro Oxindole impurity during the preparation of Ziprasidone and its pharmaceutically acceptable salt.

The inventors have developed a process which is cable of making the Ziprasidone and its pharmaceutically acceptable salt free from Oxindole impurity. The inventors have also developed a process of purification of Ziprasidone and or its pharmaceutically acceptable salt and bring down the level of Oxindole impurity less than 2 ppm from 40 ppm.

In accordance with the present invention the process for the preparation of Pure Ziprasidone or Its pharmaceutically acceptable salt containing Oxindole impurity of Formula II less than 2 ppm includes of 

Formula II
contacting of Crude Ziprasidone or pharmaceutically acceptable salts in mixture of water and suitable solvent and isolating pure Ziprasidone or pharmaceutically acceptable salt thereof. The suitable solvent may includes of tetrahydrofuran and alcohols. Alcohols may be selected from one or more of C1 to C4 alcohols such as methanol  ethanol  propanol and isopropyl alcohol and the like. The reaction mixture may be stirred at below 800 C and Ziprasidone pharmaceutically acceptable salt may be isolated  filtered and dried.

The pharmaceutically acceptable acid addition salt of Ziprasidone is selected from hydrochloride salt  hydro bromide 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 6-20 hours.

The process involves the suspension of Crude Ziprasidone in a mixture of water  isopropyl alcohol and hydrochloric acid. The reaction mixture may be stirred at 400 C to 700 C till the completion of the reaction. The ratio of water and isopropyl alcohol may be in the ratio of 1:1 to 1:5. The reaction mass may be cooled  filtered and washed. The isolated Pure Ziprasidone hydrochloric acid monohydrate dried at temperature 500 C -700 C and contains Oxindole impurity less than 2 ppm.

The process of purification of crude Ziprasidone hydrochloric acid contains Oxindole impurity of more than 2 ppm involves suspension of crude Ziprasidone hydrochloride in isopropyl alcohol and stirring the contents at temperature 100 C to 700 C. The reaction mass after filtration may be washed with isopropyl alcohol followed by water. The wet cake may be dried temperature 500 C to 700 C to obtain the Pure Ziprasidone hydrochloride salts contains Oxindole purity less than 2 ppm. The moisture contain in Ziprasidone hydrochloride may vary from 0.5 % to 6%.

The term "crude Ziprasidone or its pharmaceutically acceptable salt" or Ziprasidone hydrochloric acid refers to purity of the Ziprasidone or its pharmaceutically acceptable salt is more than or equal to 99.5% when measured by HPLC and Oxindole impurity level may vary from more than 2 ppm to 40 ppm.

The process of present invention provides the content of Oxindole impurity  less than 2 ppm in Ziprasidone or its pharmaceutically acceptable acid addition salt. The invention does not limited by the moisture contains of the Ziprasidone or its pharmaceutically acceptable salt. The term Pure Ziprasidone or its pharmaceutically acceptable salt" or Ziprasidone hydrochloric acid refers to the level of Oxindole impurity less than 2 ppm and purity more than or equal to 99.8% when measured by HPLC.

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.

Example -1

Process of Preparation of Pure Ziprasidone Hydrochloride Monohydrate

Crude Ziprasidone base (100 gm  Oxindole impurity 21 ppm) is added in a mixture of water (500 ml)  isopropyl alcohol (500 ml) and hydrochloric acid (102 ml). The reaction mixture was stirred at 40-70 °C. After hydrochloride salt formation  reaction mass filtered and washed with isopropyl alcohol (100 ml) followed by water (500 ml). Wet cake is dried at 50-70 °C to get the Pure Ziprasidone HCl. Monohydrate (105 gm) of Oxindole impurity less than 2 ppm.

Water content: 3.7 %
Oxindole impurity: 1.3 ppm.

Example -2

Purification of Ziprasidone Hydrochloride Monohydrate

Crude Ziprasidone Hydrochloride (100 gm  Oxindole Impurity 28 ppm) and isopropyl alcohol (500 ml) may be heated at 40-70 °C. The reaction mass may be filtered & washed with isopropyl alcohol (100 ml) followed by water (500 ml). Wet cake may be dried at 50-70 °C to get the Pure Ziprasidone HCl. Monohydrate (95 gm) of Oxindole impurity less than 2 ppm.

Water content 3.93%
Oxindole impurity: 0.8 ppm.

We Claim:

1. A process for the preparation of pure Ziprasidone or Its pharmaceutically acceptable salt containing  Oxindole impurity of Formula II less than 2 ppm  the process comprising 

Formula II
contacting of crude Ziprasidone or pharmaceutically acceptable salts in a mixture of water and suitable solvent and isolating pure Ziprasidone or pharmaceutically acceptable salt thereof.

2. The process of Claim 1  wherein crude Ziprasidone or pharmaceutically acceptable salts contains Oxindole impurity more than 2 ppm.

3. The process of claim 1  where in the suitable solvent are THF or alcohol.

4. The process of Claim 3  wherein alcohol is selected from one or more of methanol  ethanol  propyl alcohol and isopropyl alcohol.

5. The process of Claim 4  wherein alcohol is isopropyl alcohol.

6. The process of Claim 1 and 5  wherein the ratio of water to isopropyl alcohol is 1:1 to 1:5.

7. The process of Claim 6  wherein said pharmaceutically acceptable acid addition salt is Hydrochloride salt of Ziprasidone.

8. The process of Claim 1 wherein said pure Ziprasidone or pharmaceutically acceptable acid addition salt contains the content of Oxindole impurity less than 2 ppm or below the level of detection.

9. A process for purification of Ziprasidone hydrochloride containing Oxindole impurity of Formula II more than 2 ppm  the process comprising 

Formula II

a) Contracting Ziprasidone hydrochloride monohydrate with isopropyl alcohol at 40 ° to 70 °C
b) isolating Ziprasidone hydrochloride mono hydrate wherein Oxindole impurity is in less than 2 ppm.

10. The process of claim 1 and 9  wherein Ziprasidone or its hydrochloride salt having moisture content 0.5 to 6%.

Dated this 7th day of September  2012 For Wockhardt Limited

(Dr Mandar Kodgule)
Authorized Signatory