FIELD OF INVENTION
The present invention relates to a process for preparing the Ziprasidone
hydrochloride monohydrate having mean particle size greater than 90 urn.
BACKGROUND OF THE INVENTION
Ziprasidone is currently marketed by Pfizer Inc under the trade name Geodon ®.
Geodon ® is indicated as a psychotropic agent (useful for the treatment of
schizophrenia).
Ziprasidone has the chemical name 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-
piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one, and has the following
chemical structure:

Ziprasidone was first disclosed and claimed in the US Patent 4,831,031
(assigned to: Pfizer Inc.; Filed on Jan 22, 1988).
US 5,312,925 claims the Ziprasidone hydrochloride monohydrate. It discloses the
process for preparing the Ziprasidone hydrochloride monohydrate by heating
mixture of hydrochloric acid, water and anhydrous Ziprasidone free base. US
6,150,366 discloses a process for the preparation of Ziprasidone hydrochloride
monohydrate, having a mean particle size equal to or less than 85 urn, which
involves adding dilute hydrochloric acid to a solution of Ziprasidone free base in a
mixture of tetrahydrofuran and water. WO 2009032558 discloses a process for
preparation of Ziprasidone hydrochloride monohydrate having mean particle size
greater than 90 urn which involves stationary bed of anhydrous Ziprasidone

hydrochloride and passing mixture of water and a water miscible solvent through
the bed. The above processes are not feasible at commercial level and
Ziprasidone hydrochloride monohydrate, thus obtained, is not stable at room
temperature. There are various polymorphs, crystalline as well as amorphous,
reported for Ziprasidone and Ziprasidone hydrochloride for e.g. US
20050059680, US 20050256139, US20070078143, US 20070225295 and WO
2004050655.
SUMMARY OF THE INVENTION
In one aspect, the present invention relates to a process for preparing the
Ziprasidone hydrochloride monohydrate.
Another aspect of the invention is to provide a process for preparing Ziprasidone
hydrochloride monohydrate having mean particle size greater than 90 urn.
A further aspect, the present invention relates to a process for preparing the
Ziprasidone hydrochloride monohydrate, which is cost effective and industrially
applicable.
Ziprasidone hydrochloride monohydrate having mean particle size greater than
90 urn shows improved bioavailability and allows its advantageous use in
therapy.
Another aspect of the invention provides a pharmaceutical composition
comprising Ziprasidone hydrochloride monohydrate having mean particle size
greater than 90 urn along with pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: Powder X Ray Diffractogram of Form I of Ziprasidone hydrochloride
monohydrate as obtained by the process of the invention.
Figure 2: TGA thermogram of Form I of Ziprasidone hydrochloride monohydrate
as obtained by the process of the invention.
DETAILED DESCRIPTION OF THE INVENTION
As used herein Ziprasidone hydrochloride monohydrate having mean particle
size greater than 90 urn, the term "particle" refer to individual particles regardless
of whether the particles exist singly or agglomerated with each other. The mean
particle size is defined as the average of the maximum dimensions of all particles
present in a given sample. The sizes of all particles present in any sample can be
characterized by a particle size distribution. The mean particle size is frequently
expressed in urn, and can measured using a particle size analyzer, such as using
laser light scattering equipment from Malvern instruments, other types of particle
size measuring .equipment are also suitable, as will be appreciated by those
skilled in the art.
The present invention relates to a process for preparing the Ziprasidone
hydrochloride monohydrate having mean particle size greater than 90 urn.
The process for preparation of Ziprasidone hydrochloride monohydrate includes
a) dissolving the Ziprasidone in a polar organic solvent or mixture of
solvents;
b) treating the reaction mixture with aqueous hydrochloric acid; and
c) isolating the Ziprasidone hydrochloride monohydrate.

The examples of polar organic solvents include: amides, such as N, N- dimethyl -
formamide, N, N-dimethylacetamide; esters such as ethyl acetate and dimethyl
sulfoxide; and mixtures thereof.
The suitable temperature for the reaction takes place ranges from about ambient
temperature to about 55°C.
Depending on the reaction temperature and other conditions, the reaction time
generally ranges from 3 hrs to 24 hrs. The concentration of the hydrochloric acid
in the reaction solution ranges from about 0.1 to about 0.2 M, and preferably
about 0.135 M.
The theoretical water content of the Ziprasidone hydrochloride monohydrate is
3.9 % by weight. According to following this invention, the water content of the
Ziprasidone hydrochloride monohydrate ranges from 3.9 to 4.4% by weight.
The Ziprasidone hydrochloride monohydrate is characterized by its water content
its powder x-ray diffraction in Fig. 1 and its Thermo gravimetric analysis
chromatogram in Fig. 2.
X-Ray powder diffraction data were obtained using by method known in the art
using a PANalytical powder X-Ray diffractometer model PW3040/60 X'Pert PRO.
Copper radiation of 1.54 A was used.
The mean particle size of Ziprasidone hydrochloride monohydrate was measured
by Mastersizer 2000 with range 0.020 to 2000 urn.
TGA analysis was done using a Pyris 1 (PerkinElmer) thermogravimetric
analyzer. The samples were scanned at a rate of 10.degree. C./min from
20.degree. C. to 250.degree. C. at 10 degree. C/min.
The moisture content of Ziprasidone hydrochloride monohydrate was measured
by halogen moisture analyzer as per 105°C for one hour.

The following example explains specific embodiment of the patent application,
which is provided by way of illustration only and should not be construed as
limiting the scope of invention in any manner.
EXAMPLE 1
Ziprasidone free base (10 g) was charged in 200mL of dimethyl sulfoxide at room
temperature. The reaction mixture was diluted by adding 150ml_ ethyl acetate.
The reaction mixture was heated at 50-52°C till the complete dissolution of solid.
The reaction mass was filtered through filter paper. The collected filtrate was
cooled for 10 min and 300mL aqueous hydrochloric acid solution was added in
drop wise fashion in 300-330 min. After the addition, the solid was filtered. The
filtered solid was washed with 100mL ethyl acetate and 100mL water thrice. The
solid was dried under vacuum at 25-30°C. (% water content 3.91%).
Yield: 8.5 g, Purity: 99-99.8%.

We claim:
1) A process for preparation of Ziprasidone hydrochloride monohydrate
having mean particle size greater than 90 urn, which comprises of
a) dissolving the Ziprasidone in a polar organic solvent or mixture
of solvents; and
b) treating the reaction mixture with hydrochloric acid; and
c) isolating the Ziprasidone hydrochloride monohydrate.
2) The process according to claim 1, wherein a polar organic solvent
comprises an amide, ester, dimethyl sulfoxide and mixtures thereof.
3) The process according to claim 1, wherein polar organic solvent
comprises dimethyl sulfoxide.
4) The process according to claim 1, wherein polar organic solvent
comprises ethyl acetate.
5) A pharmaceutical composition comprising Ziprasidone hydrochloride
monohydrate having particle size greater than 90 urn as prepared in claim
1, along with pharmaceutically acceptable excipients.

The present invention relates to a process for preparing the Ziprasidone hydrochloride monohydrate having mean particle size greater than 90 µm.