FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
&
COMPLETE SPECIFICATION
(See section 10]
1. Title of the invention: "Process for the preparation of isolated impurity of Ziprasidone Hydrochloride Monohydrate and its use as a Reference standard"
2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashta, India.
3. The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to the process for the preparation of impurity of Ziprasidone hydrochloride monohydrate and characterization and detection of the impurity and its use as a reference standard during the analysis of Ziprasidone or its salt of Formula I.
BACKGROUND OF THE INVENTION
Ziprasidone is an antipsychotic drug with the chemical name: 5-[2-[4-(l,2-benzisothiazol-3-yl)-1 -piperaziny]]ethyl]-6-chloro-l ,3-dihydro-2H-indol-2-one of Formula I

Ziprasidone is disclosed in US4831031 and US5312925 (both assigned to Pfizer and herein after referred to as US'031 and US'925 respectively). Ziprasidone inhibits synaptic reuptake of serotonin and nor epinephrine. No appreciable affinity was exhibited for other receptors of epinephrine. The mechanism of action of Ziprasidone, as with other drugs having efficacy in schizophrenia, is unknown. However, it has been proposed that this drug's efficacy in schizophrenia is mediated

through a combination of dopamine type 2 (5HT2) antagonism. Ziprasidone
antagonism of histamine H receptors may explain the somnolence observed with this
drug.
US'925 describes a process for the synthesis of monohydrate of 5-[2-[4-(l,2-benzisothiazol-3-yI)-l-piperazinyl]ethyl]-6-chloro-l,3-dihydro-2H-indol-2-one hydrochloride and its characterization based on IR,XRD and moisture content, and describes that the hemihydrate may be obtained in Example 16 of US '031.
US6150366 discloses a manufacturing process of Ziprasidone hydrochloride monohydrate having a mean particle size equal to or less then about 85 u,m. US5026366 and US5338846 describe improved process to prepare Ziprasidone hydrochloride monohydrate. The disclosed process prepares Ziprasidone having a purity of > 99%.
US20040048876 discloses Ziprasidone composition having deschloro impurity not greater than about 1000 ppm.
US7563794 prepares Ziprasidone free base or Ziprasidone salt free from coloured impurities.
US7608711 discloses pharmaceutical composition using Ziprasidone or its salt having 5-(2-(4-benzo[d] isothiazol-3-yl)piperazin-l-yl)acetyl)-6-chloro-l,3-dihydro-2H-indol-2-one impurity not greater than about 500 ppm and the impurity 5-(2-chloroacetyl)-6-chIorooxindole not greater than about 500 ppm.

Ziprasidone hydrochloride useful in the treatment of bipolar disorder is currently marketed under the proprietary name of Geodon® by Pfizer in U.S.A. and is described in US and EP Pharmacopeia.
Pharmacopeia lists the method of identification of impurities and also specifies the impurities. Impurities are generated during the manufacturing process or during the shelf life of the drug substance.
While analyzing the commercial and non-commercial batches of the compound synthesized, by specific instruments such as HPLC, there is a requirement of impurity reference standard.
5,5'-bis[2-[4-(l,2-benzisothiazol-3-yl) piperazin-lyl]-6,6' -dichloro-3-hydroxy -l,r,3,3'-biindole-2,2'-dione (Formula II,) is one of the impurity designated as impurity D in EP Pharmacopoeia and impurity C in US Pharmacopoeia. This impurity is formed during the synthesis of Ziprasidone. This particular impurity is not available in the market and it is also not possible to isolate this impurity in a pure form by conventional techniques such as chromatography, flash chromatography, distillation or crystallization.


Hence there is a need to prepare this impurity by a chemical reaction, which results
in the product of compound of formula II which may be used as an impurity
reference standard for Ziprasidone or salt thereof.
SUMMARY OF THE INVENTION
The present invention seeks to provide a cost effective process for the preparation of
compound of Formula II (impurity C) and its pharmaceutically acceptable salts.
The invention relates, in general, to a novel process for preparing compound of
Formula II (impurity C).
It is a further object of the present invention to provide a process for the preparation
of Ziprasidone impurity C of Formula II in high purity so that it can be used as a
reference standard for qualitative and quantitative estimation of Ziprasidone or salt
thereof.
Yet another object of the present invention is to describe the use of this impurity as
the reference standard during the analysis of Ziprasidone hydrochloride prepared by
any chemical process.

DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term "reference standard" refers to a compound that may be used
both for quantitative and qualitative analysis of an active pharmaceutical ingredient.
For example, the HPLC retention time of the reference standard compound allows a
relative retention time with respect to the active pharmaceutical ingredient to be
determined, thus making qualitative analysis possible. Furthermore, the
concentration of the compound in solution before injection into an HPLC column
allows the areas under the HPLC peaks to be compared, thus making quantitative
analysis possible.
The present invention provides isolated impurity C represented by compound of
formula II and a process for preparation thereof.
The compound of formula II prepared by the process of the present invention is
highly pure. Preferably it has about 95% purity by weight with respect to other
compounds. More preferably it is isolated in about 99% purity. Even more preferably
it is isolated in about 99.99 % purity.
The isolated impurity C of formula II of the present invention may be characterized
by data selected from:'H NMR(400MHZ, DMSO-d6) 5 (ppm):EI+m/z (MH4):
The isolated impurity C of formula II of the present invention may be characterized
by 1H NMR, as depicted in FIGURE 1.
The isolated impurity C of formula II of the present invention may be characterized
by Mass spectrum, as depicted in FIGURE 2.

The isolated impurity C of formula II of the present invention may be characterized
by IR spectrum, as depicted in FIGURE 3.
The compound of formula II (impurity C) of the present invention is prepared by a
novel process.
Generally the process comprises the steps of:
a) reacting a compound of formula IIIa or a salt thereof


to obtain compound of formula II or a salt thereof
wherein 'PG' denotes a suitable amino protecting group with a compound of formula IV or a salt thereof

b) and optionally isolating the compound of formula II More preferably the process for the preparation of compound of formula II (impurity C) comprises the steps of:
a) reacting compound of formula la

with 'PC under suitable conditions to obtain compound of formula IIIa or salt thereof


wherein 'PG denotes a suitable amino protecting group.
b) reacting a compound of formula IIIa or a salt thereof with a compound of formula IV or a salt thereof

to obtain compound of formula II or a salt thereof


c) optionally converting a salt of compound of formula II to its base form and
d) optionally isolating the compound of formula II.
As used herein, the term "PG" refers to a suitable amino protecting group and includes commonly used amino protecting groups such as di-tert-butyldicarbonate (t-BOC),Carbobenzy1oxy (Cbz), 9-FluorenyImethyloxycarbonyl (FMOC), acetyl, benzoyl, benzyl etc. Preferably the protecting group is di-tert-butyldicarbonate (t-BOC) or 9-FluorenyImethyloxycarbonyl (FMOC). Most preferably the protecting group is di-tert-butyldicarbonate (t-BOC).
The protection of amino groups can be accomplished by using appropriate reaction conditions wherein a specific protecting group or a derivative thereof is reacted with a compound bearing amino functional group or moiety. For instance di-tert-butyldicarbonate also known as Boc anhydride reacts with amines in presence of bases such as sodium bicarbonate to give N-tert-butoxycarbonyl derivatives which

can later be removed using acid such as trifluoroacetic acid or hydrochloric acid in methanol. Furthermore, many other suitable amino protecting groups, and methods for the protection of amino groups, can be found in Green et al., Protecting Groups In Organic Synthesis, Third Edition, John Wiley & Sons, Inc. New York, 1999, which is incorporated herein by reference.
The examples as mentioned below describe some of the preferred embodiments of the present invention and are not intended to limit the scope of the present invention in any manner whatsoever.
Example 1 Step a: Protection of Ziprasidone base
Under nitrogen atmosphere Ziprasidone (50.0 gm) along with DMSO is added to a flask at room temperature. Subsequently di-tert-butyldicarbonate (30.0gm) is added to the above reaction mass in a drop wise manner. The reaction mass is heated to up to the reflux temperature and then cooled to 25-30°C.The mass is quenched with 5000mL of water and stirred for 60 minutes followed by filtration and washing with acetone. The resulting material is dried at 50-60°C for 2 Hrs Step b; Preparation of Impurity B
In a round bottom flask charged Ziprasidone base (50.0 gm), selenium oxide 13 gm in 10 ml water, 10 ml water. The reaction mass refluxed for 24 hours. The reaction mass is filtered, concentrated and THF is added to the residue. The solution is

refluxed and filtered. Filtrate obtained is distilled out completely to get the 6 gm of impurity B.
Step c: Preparation of impurity C (compound of formula II)
The product of step a (2.0gm) prepared above is mixed with THF (20.0 mL) and
stirred at room temperature followed by stirring at -5 to -10°C for 10 min. About
1.72 ml of n-Buli is added to this mixture and is stirred for 30 minutes at -5 to -10°C.
A clear solution of 5-[2-[4-(l,2-benzisothiazol-3-yl)-l-piperazinyl] ethyl]- 6-chloro-
i,3-dihydro-2tf-indol-2,3-dione (2.0gm) (impurity B) in 10 ml of THF prepared
separately is mixed with the reaction mass. The reaction mixture is stirred for 10
minutes. 10.0 mL of water is added to the reaction mass and the pH of the mixture is
adjusted to 1.5 - 2.0 by using cone. HC1. The reaction mass is stirred for 60 minutes
at room temperature followed by filtration and drying for about 30 minutes at 40-
45°C to obtain the product.
(Dry wt 2.0gm.)
Reference example Preparation of Ziprasidone hydrochloride monohydrate
Stage-1: 6-Chloro-5-(2-chloroethyl)-l, 3-dihydro-2H-indol-2-one is reacted with 3-piperazin-l-yl-1, 2-benzisothiazole hydrochloride in presence of sodium carbonate and sodium iodide using water as a solvent at 95-100 °C. The reaction is monitored by HPLC.After completion of reaction, cool and filter the material. The crude

material purified by using IPA, acetone, acid base purification using acetic acid methanol for dissolution, Charcoalisation and adjusted pH with ammonia 5.5 to 6.5
Stage-2: To a stage-1, methanol and water mixture, hydrochloric acid + methanol mixture is added at 65-70°C. The reaction mass is cooled to 20-25°C, filtered the material and wash with methanol and followed by water. Wet material dried to get Ziprasidone hydrochloride monohydrate stage-2.
Stage-3: Stage-2 materials are dissolved in formic acid and acetic acid mixture, and add water in the reaction mass. Filter and dried. Again dissolved in Formic acid and acetic acid and add Acetone to get required partical size dried the material and make water slurry with water filter and dried .
Impurity C and other impurities detected in the final sample.

We claim:
1. A compound of formula II or a salt thereof obtained by the reaction of compound of formula III a or a salt thereof with a compound of formula IV or a salt thereof

2. A compound of formula II according to claim I wherein the purity is 98.00%
3. A compound of formula II according to claim 1 wherein the purity is 99.99%
4. A process for preparing compound of formula II or a salt thereof comprising the steps of:
a) reacting a compound of formula III a or a salt thereof


wherein 'PG' denotes a suitable amino protecting group with a compound of formula IV or a salt thereof

to obtain compound of formula II or a salt thereof


b) optionally isolating the compound of formula II or salt thereof
5. A process for preparing compound of formula II or a salt thereof comprising the
steps of:
a) reacting compound of formula la

with 'PG' or a derivative thereof under suitable conditions to obtain compound of formula IMa or salt thereof


wherein 'PG' denotes any suitable amino protecting group b) reacting a compound of formula III a or a salt thereof with a compound of formula IV or a salt thereof

to obtain compound of formula II or a salt thereof


c) optionally converting a salt of compound of formula II to its base form and
d) optionally isolating the compound of formula II or salt thereof.
with Selenium oxide to obtain compound of formula IV
6. A process according to claim 4 or 5 wherein 'PG' is di-tert-butyldicarbonate (t~ Boc)
7. A process for preparing compound of formula II comprising the steps of: a) contacting a compound of form la



b) contacting a compound of form Ia with di-tert-butyidicarbonate (t-BOC) to obtain compound of formula III

c) contacting compound of formula III with compound of formula IV to obtain compound of formula II or a salt thereof.


and
d) optionally isolating the compound of formula II or a salt thereof
8. A compound of formula II

as obtained according to any of the process of claims 4, 5, 6 and 7
9. A compound of formula II as prepared according to examples herein described.