FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. - AN IMPROVED PROCESS FOR THE PREPARATION OF
CRYSTALLINE ZIPRASIDONE BASE

2. Applicant(s)
(a) NAME
(b) NATIONALITY
(c) ADDRESS

LUPIN LIMITED
An Indian company
159, CST Road, Kalina, Santacruz (East), Mumbai - 400 098, Maharashtra, India

3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed:


FIELD OF INVENTION
The present invention is related to process for preparation of crystalline ziprasidone base, 5-2-(4-(1,2-benzisothiazol-3-yl-1-piperazinyl)-6-chloro-1,3-dihydro-2H-indole-2-one of formula (I)

(I)
BACKGROUND OF INVENTION
Ziprasidone, 5-2-(4-(1,2-benzisothiazol-3-yl-1 -piperazinyl)-6-chloro-1,3-dihydro-2H-indole-2-one (I) is a potent antipsychotic agent and useful for treatment of patients suffering from schizopherina, anxiety, migrain pain and other related psychotic disorders.
US Patent No. 4,831,031 incorporated herein by reference describes the method for preparation of ziprasidone hydrochloride hemihydrate. The process involves coupling of 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride (II) with 5-(2-chloroethyl)-6-chloro oxindole (III) using sodium carbonate as acid scavenger in presence of sodium iodide in methyl isobutyl ketone as solvent. This patent does not comment about crystalline form of ziprasidone base even though it was prepared and purified.

US patent 5,338,846 discloses ziprasidone base as a solid, characterized by NMR spectrum. Examples 1 and 2 of US'846 disclose the process of preparation of ziprasidone from 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride (II) with 5-(2-chloroethyl)-6-chloro oxindole (III) in water and sodium carbonate. The product is then recrystallized from THF where 9kg material is refluxed in 86gallons of THF and then filtered through a sparkler filter. In our experience this volume of water is insufficient to cause dissolution of 9kg ziprasidone, even refluxing for several hours. Filtration before complete dissolution may cause lower yield and hence this process has a major drawback of regular batch production.
WO 03/070246 describes a process of purification by recrystallization and/or reslurry in various solvents and solvent/mixtures to remove the deschloro impurity. This application particularly describes a method of recrystallization/reslurry in a mixture of acetonitrile and water.
US Patent application. 2004/0152711 A1 describes preparation of crystalline form of ziprasidone base. The process involves initially preparation of ziprasidone base by coupling of 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride (II) with 5-(2-chloroethyl)-6-chloro oxindole (III) using sodium carbonate as acid scavenger in presence of sodium iodide and phase transfer catalyst, for example, tetrabutyl phosphonium bromide in cyclohexane. The reaction was carried out at reflux temperature. Wet solid obtained after aqueous work up was purified by slurry wash in acetone. Pure ziprasidone base was converted to methanesulphonic acid salt with methane sulphonic acid in methanol. The methane sulphonic acid salt of ziprasidone was converted to crystalline form of ziprasidone base by dissolving methane sulphonic acid salt of ziprasidone (IV) in water and then pH adjustment with sodium hydroxide to 9.0 at room temperature followed by isolation of solid by filtration and drying. The crystalline form was characterized by Powder XRD.


In this method methanesulphonic acid salt of ziprasidone (IV) is neutralized with aqueous sodium hydroxide which complicates the method and renders it lengthy and laborious. Moreover, methanesulphonic acid is a hazardous chemical and hence to be avoided during large-scale production.
US 2005/0197347 discloses a new morph of ziprasidone base, namely, Form B2, which is distinguished from the prior art product, namely Form B, by powder XRD pattern. The method of preparation of Form B2 involves treatment of a ziprasidone salt, particularly ziprasidone hydrochloride, with a base. This also involves purification from THF-H2O mixture. This process is rather cumbersome because ziprasidone hydrochloride is considered as the active pharmaceutical ingredient. Hence regeneration of base from the salt and reconverting it to the corresponding salt induces complicacy in terms of industrial applicability.
Thus there is need to provide process which is simpler, easy to operate, can be performed at neutral condition and consistently giving rise a particular morphologyof the ziprasidone base.

OBJECT OF THE INVENTION
Thus the object of the present invention is to provide a simpler and easy to operate process for preparing crystalline form of ziprasidone base of formula I.
SUMMARY OF THE INVENTION
According to the main aspect of present invention there is provided a process for the preparation of crystalline ziprasidone base for formula I comprising the steps

(i) dissolving ziprasidone in tetrahydrofuran by heating to reflux,
(ii) treating the reaction mass with activated charcoal,
(iii) adding methanol to the reaction mass, and
(iv) isolating crystalline ziprasidone base.
DETAILED DESCRIPTION OF THE INVENTION
In its major aspect the present invention provides a method for obtaining crystalline form of ziprasidone base that involves preparing clear or slightly hazy solution of ziprasidone in nearly 70 volumes of tetrahydrofuran by heating to reflux. The reflux is continued for about 20-30mins. Charcoalisation in hot condition is carried out at 60-65°C the reaction mass is then clarified by filtration and concentration of the filtrate to nearly 10 volumes is carried out to give rise to a slurry mass. This is followed by slow addition of about 10 volumes of methanol and cooling to 0-5°C. The resulting solid was filtered, washed with methanol and dried till moisture content below 4% was achieved.
The process of purification mentioned hereinabove is repeated till the desired quality of the product is obtained.
The product thus obtained is very white in colour, having a melting point about 226-227°C.

DESCRIPTION OF THE ACCOMPANYING FIGURES
FIG. 1: Powder XRD pattern of the crystalline ziprasidone base of the present
invention
FIG. 2: IR spectrum of the crystalline ziprasidone base of the present invention
The present process consistently produces a crystal form of ziprasidone base The characterized by the X-ray dtffractogram shown to figure1
The characteristic 2 theta values (in degrees) of the identified peaks in X-ray diffractogram of the crystalline form of ziprasidone base obtained by above process of the invention is given in Table-1
Table 1.

Angle 2-Theta degree Intensity %
5.23 9.4
10.512 9.2
11.272 29.5
12.166 100
13.152 11.1
15.216 22.2
16.292 29.9
17.629 11.5
18.51 22.4
18.846 8.1
22.125 21.7
24.123 7.1
25.158 25.1
25.441 15.3
26.615 7.7
26.92 8.4
27.217 10.5

This XRD is in well accordance with that of the prior art disclosed in US200/0197347, page 1, paragraph. [0011].
This demonstrates that the ziprasidone base obtained by the present process of present invention is equivalent to those of the prior art indicating that the present process without elaborate reaction steps and employing neutral conditions is capable of achieving the ziprasidone base of the known art
The infrared spectrum of the crystalline form of ziprasidone base obtained by above process of the invention is shown in figure 2.
The invention is now described by way of illustrative non limiting examples
Example 1
Preparation of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one (Ziprasidone base)
Mixture of sulfolane (150 ml), 3-(1-piperazinyl)-1,2-benzoisothaizole (50 gm, 0.228 moles), potassium carbonate (47.5 gm, 0.344 moles), 5-(2-chloroethyl)-6-chloro oxindole (68.25 gm, 0.298 moles) and potassium iodide (2.5 gm) was heated to 80-85°C and maintained at 80-85°C for 2 hours. Temperature was raised to 95-100°C and maintained for 7.5 hours. Reaction mixture was cooled to 25-30°C. Demineralized water (500 ml) was added and stirred for 1 hour. Solid was filtered, washed with water (2x250 ml). The wet cake was taken in acetone (500 ml) and mixture stirred at 25-30°C. Solid was filtered, washed with acetone (250 ml), unloaded and dried under vacuum at 40°C till LOD less than 2% obtained. Yield of crude ziprasidone base was 85 gm (90%). Purity was 98.4% and moisture content 0.1%.
Purification of crude ziprasidone base:
Crude ziprasidone base (85 gm) was dissolved in tetrahydrofuran (5950 ml) by heating to reflux at 64-66°C for 30 minutes. Activated carbon (12,75 gm) was

added and reflux continued for 1 hour. Reaction mixture was filtered while hot through celite bed and filtrate was concentrated under vacuum at 35-40°C to nearly 850 ml of slurry. To the concentrated slurry methanol (850 ml) was added at 35-40°C. Resulting mass was cooled to 0-5 and stirred for 30 minutes. Solid was filtered under nitrogen atmosphere, washed with methanol (425 ml), unloaded and dried at 40-45°C till LOD became less than 2%. Yield of pure ziprasidone base was 69.2 gm (55%). Purity was 98.83% and moisture content 0.13%.
Example 2
Preparation of crystalline form of ziprasidone base
Ziprasidone base (150 gm) in tetrahydrofuran (10.5 liters) was heated to reflux temperature 64-65°C for 20 minutes to get clear or slightly hazy solution. Solution cooled to 60°C and activated carbon (22.5 gm) added. Mixture was again heated to reflux temperature 64-65°C for 1 hour. Hot reaction mass was filtered through celite bed washed with hot tetrahydrofuran (300 ml). The combined filtrate was then concentrated under vacuum at 35-40°C to nearly 1500 ml of slurry. To the concentrated solution methanol (1500 ml) was added slowly in 30 minutes at 35-40°C. The slurry was stirred at 35-40°C for 15-30 minutes and cooled to 0-5°C for 30 minutes. Solid was filtered, washed with methanol (750 ml) and dried under vacuum at 40-50°C. After drying 84 gm (56%) of crystalline ziprasidone base was obtained. The melting point was 226-227°C

We claim,
1. A process for the preparation of crystalline ziprasidone base of formula (I)

(I)
comprising the steps
(i) dissolving ziprasidone in tetrahydrofuran by heating to reflux, (ii) treating the reaction mass with activated charcoal, (iii) adding methanol to the reaction mass, and
(iv) isolating crystalline ziprasidone base.
2. A process as claimed in claim 1 wherein charcoalisation is carried out at 60-65°C
3. A process as claimed in claim 2 wherein charcoalisation is followed by clarification of the reaction mass by filtration and concentration of the filtrate to nearly 10 volumes to give rise to a slurry mass.
4. A process as claimed in any preceding claim wherein in the step (i) tetrahydrofuran is used in 60-80 parts against 1 part of ziprasidone.

8. A process as claimed in any preceding claim wherein methanol is added
followed by cooling to temperature 0-5°C
9. A process as claimed in any preceding claim wherein isolation of crystalline
ziprasidone base is carried out by filtration, washing with methanol and
drying till moisture content is below 4%
Dated this 6th day of October 2005

Dr. Sanchita Ganguli Of S. Majumdar & Co. Applicant's Agent