COMPLETE SPECIFICATION
(See section 10 and rule 13)

PREPARATION OF ZIPRASIDONE HYDROCHLORIDE MONOHYDRATE

Dr. Reddy’s Laboratories Limited
an Indian Company having registered office at
7-1-27, Ameerpet, Hyderabad - 500 016,
Andhra Pradesh, India
and

Dr.Reddy’s Laboratories Inc.,
having its office at
200, Somerset Corporate, Boulevard,
Seventh Floor, Bridgewater, New Jersey-08807,
United States of America.

The following specification particularly describes the nature of this invention and the manner in which it is to be performed:

INTRODUCTION
The present application relates to processes for the preparation of ziprasidone or salts thereof with defined particle size distribution parameters.
Ziprasidone hydrochloride is the adopted name for a drug having a chemical name 5-[2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one hydrochloride monohydrate, and having structural Formula I.

Formula I
Ziprasidone, ziprasidone hydrochloride and other pharmaceutically acceptable salts are useful as antipsychotic agents in the treatment of schizophrenia. ziprasidone hydrochloride monohydrate is commercially available as the active ingredient in GEODON™ Capsules, sold by the Roerig division of Pfizer Inc. in 20 mg, 40 mg, 60 mg and 80 mg dosage strengths.
U.S. Patent No. 5,312,925 discloses process to prepare ziprasidone hydrochloride monohydrate by heating a mixture of hydrochloric acid, water and anhydrous ziprasidone free base.
U.S. Patent No. 6,150,366 discloses a process for the preparation of ziprasidone hydrochloride monohydrate which involves adding dilute hydrochloric acid to a solution of ziprasidone free base, in a mixture of tetrahydrofuran and water, followed by heating the mixture.

SUMMARY
There are provided herein processes for the preparation of ziprasidone hydrochloride monohydrate having mean particle sizes greater than about 90 m.
In an embodiment, there are provided process for preparation of ziprasidone hydrochloride monohydrate from anhydrous ziprasidone hydrochloride, while retaining the mean particle size greater than about 90 m, or about 90 m to about 300 m.
In an aspect, there are provided processes for preparation of ziprasidone hydrochloride monohydrate with mean particle sizes greater than about 90 m, from anhydrous ziprasidone hydrochloride with mean particle sizes greater than about 90 m, an embodiment comprising:
(a) mixing anhydrous ziprasidone hydrochloride with a mixture of water and a water miscible solvent; and
(b) isolating particles of ziprasidone hydrochloride monohydrate.
In embodiments, the solid isolated in step (b) is dry milled to achieve the desired particle sizes.
In another aspect, there are provided processes for preparation of ziprasidone hydrochloride monohydrate having mean particle sizes greater than about 90 m, from anhydrous ziprasidone hydrochloride having mean particle sizes greater than about 90 m, an embodiment comprising:
(1) preparing a stationary bed of anhydrous ziprasidone hydrochloride,
(2) passing a mixture of water and a water miscible solvent through the bed; and
(3) isolating particles of ziprasidone hydrochloride monohydrate.
In embodiments, the solid isolated in step (3) is dry milled to achieve the desired particle sizes.
In embodiments, there are provided pharmaceutical compositions comprising ziprasidone hydrochloride monohydrate and at least one pharmaceutically acceptable carrier, wherein ziprasidone hydrochloride monohydrate has mean particle sizes greater than about 90 m, or about 90 m to about 300 m.

DETAILED DESCRIPTION
As used herein with regard to ziprasidone and its salts, the term “particles” refers to individual particles regardless of whether the particles exist singly or are 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 μm, and can measured using a particle size analyzer, such as using laser light scattering equipment from Malvern Instruments Ltd., Malvern, Worcestershire, United Kingdom. Other types of particle size measuring equipment are also suitable, as will be appreciated by those skilled in the art.
There are provided processes for preparation of ziprasidone hydrochloride monohydrate having mean particle sizes greater than about 90 m, from anhydrous ziprasidone hydrochloride having mean particle sizes greater than about 90 m. An embodiment of a process includes:
(a) mixing anhydrous ziprasidone hydrochloride with a mixture of water and a water miscible solvent; and
(b) isolating particles of ziprasidone hydrochloride monohydrate.
In embodiments, the solid isolated in step (b) is dry milled to achieve the desired particle sizes.
Non-limiting examples of suitable water miscible solvents include: alcohols, such as methanol, ethanol, n-propanol, isopropyl alcohol, and n-butanol; ketones, such as acetone and methyl ethyl ketone; nitriles, such as acetonitrile and propionitrile; aprotic solvents, such as N,N-dimethylformamide (DMF), and dimethylsulfoxide (DMSO); and mixtures thereof.
While the relative amounts of water miscible solvent and water in the solvent mixtures are not particularly restricted, in certain embodiments the percentages of water in the mixtures are in the range of from about 10% to about 90%, or about 10% to about 70%, or about 10% to about 50%, expressed on a volume basis.
Suitable temperatures for mixing the solid with the liquid range from about 0°C to about 60°C, or about 25°C to about 35°C. The slurry of step (a) is typically mixed for about 20 minutes to about 5 hours. Examples of suitable agitators for mixing the slurry include anchor, propeller, Teflon™ blade and other types of stirrers. The rotational speed of an agitator may be about 100-500 rpm, or any other desired speed.
The isolation of solid includes separating a solid from the slurry. The separation methods may include, for example, decantation, filtration by gravity or by suction, or centrifugation. The solid so isolated may carry some occluded mother liquor. If desired, the separated solid may be washed with a solvent or mixture of solvents in various proportions to remove the occluded mother liquor.
The isolated solid may be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying may be carried out at temperatures of from about 25°C to about 55°C, with or without the application of vacuum. The drying may be carried out for sufficient time to achieve the product with desired specifications, including moisture contents. The time periods may vary from about 30 minutes to about 20 hours, or longer. The dried solid typically has mean particle sizes from about 90 m to about 300 m, or from about 100 m to about 200 m, or from about 100 m to about 150 m.
After drying, the solid may be milled to modify the particle size. Milling may be carried out using equipment having 0.1 mm to 5 mm mesh screens to provide ziprasidone hydrochloride monohydrate with defined particle size distribution parameters.
Also provided are alternate processes for preparation of ziprasidone hydrochloride monohydrate having mean particle sizes greater than about 90 m, from anhydrous ziprasidone hydrochloride having mean particle sizes greater than about 90 m. An embodiment of a process includes:
(1) preparing a stationary bed of anhydrous ziprasidone hydrochloride,
(2) passing a mixture of water and a water miscible solvent through the bed; and
(3) isolating particles of ziprasidone hydrochloride monohydrate.
In embodiments, the solid isolated in step (3) is dry milled to achieve the desired particle sizes.
In step (1), a stationary bed of anhydrous ziprasidone hydrochloride is prepared on filter media. Examples of suitable filter media on which a stationary bed may be prepared include a Büchner funnel, Nutsche filter, sintered glass filter or other similar filter. A piece of filter paper may be placed in a Büchner funnel to cover the openings and avoid creeping of the small particles of the bed material into the liquid. Typically, anhydrous ziprasidone hydrochloride is loaded onto the top of the filter to serve as a filter bed. Optionally, the filtration operation may be carried out under reduced pressure to speed up the process.
In step (2), a mixture of water and a water miscible solvent is passed through the bed. Non-limiting examples of suitable water miscible solvents include: C1-C4 alcohols, such as methanol, ethanol, n-propanol, isopropyl alcohol, and n-butanol; ketones, such as acetone and methyl ethyl ketone; nitriles, such as acetonitrile and propionitrile; aprotic solvents, such as N,N-dimethylformamide (DMF) and dimethylsulfoxide (DMSO); and mixtures thereof.
While the relative amounts of water miscible solvent and water in the solvent mixtures are not particularly restricted, in certain embodiments the percentages of water in the mixtures are in the range of from about 10% to about 90%, or about 10% to about 70%, or about 10% to about 50%, expressed on a volume basis.
Suitable temperatures for passing the solvent through the filter bed range from about 15°C to about 45°C.
The solid cake may be removed from the filter and dried.
Drying may be carried out under reduced pressure. Drying may be carried out in equipment such as a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying may be carried out at temperatures of from about 25°C to about 55°C, with or without vacuum. The drying may be carried out for a sufficient time period to achieve the desired product specifications, including moisture contents. The dried solid has mean particle sizes from about 90 m to about 300 m, or from about 100 m to about 200 m, or from about 100 m to about 150 m.
After drying, the solid may be milled to modify the particle size. Milling may be carried out using equipment having 0.1 mm to 5 mm mesh screens to provide ziprasidone hydrochloride monohydrate with defined particle sizes.
Also provided are pharmaceutical compositions comprising ziprasidone hydrochloride monohydrate and at least one pharmaceutically acceptable excipient, wherein ziprasidone hydrochloride monohydrate has mean particle sizes greater than about 90 m, or about 90 m to about 300 m, or about 100 m to about 200 m, or about 100 m to about 150 m. In embodiments, ziprasidone hydrochloride monohydrate in the formulations contains less than about 0.25% of any individual impurity.
The composition may be formulated into solid pharmaceutical dosage forms such as tablets, powders for oral suspension, unit dose packets, and capsules for oral administration, and such dosage forms can be made using conventional methodology. The compositions, in addition to ziprasidone free base or ziprasidone hydrochloride, may contain conventional pharmaceutically acceptable excipients such as, for example: fillers and diluents such as starches and sugars; binders such as carboxymethylcellulose and other cellulose derivatives, alginates, gelatine, and polyvinylpyrrolidine; disintegrating agents such as agar-agar, calcium carbonate and sodium bicarbonate, pregelatinized starch, sodium croscarmellose, sodium starch glycolate and crosslinked poly(vinylpyrrolidine); lubricants such as talc, sodium lauryl sulfate, stearic acid, calcium and magnesium stearate, and polyethylene glycols. Some excipients can also serve more than one function; for example, a disintegrant can also serve as a filler.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.

EXAMPLE 1
To a solution of methanol (80 L) and water (20 L) in a reactor, anhydrous ziprasidone hydrochloride (20 Kg) having a mean particle size about 143 m was charged at about 30°C and the resulting slurry was stirred for 30 minutes. The solid was separated with a centrifuge, washed with a mixture of methanol (16 L) and water (4 L) and spin-dried for 3 hours. The solid was further dried at about 30°C under reduced pressure to obtain ziprasidone hydrochloride monohydrate having a mean particle size about 138 m (yield: 20 Kg).

EXAMPLE 2
A stationary bed of anhydrous ziprasidone hydrochloride (100 g) having a mean particle size about 143 m was prepared on a Büchner funnel. A mixture of methanol (450 ml) and water (50 ml) was slowly poured onto this bed for a period of 30 minutes. The traces of solvent were removed from the bed by applying vacuum/nitrogen for about 45 minutes. The solid was further dried at 50-55°C in a hot air oven for 30 minutes to obtain ziprasidone hydrochloride monohydrate having a mean particle size about 140 m (yield: 104 g).

CLAIMS:
1. A process for the preparation of ziprasidone hydrochloride monohydrate particles, comprising:
(a) forming a slurry of anhydrous ziprasidone hydrochloride having mean particle sizes greater than about 90 m with a mixture of water and a water miscible solvent; and
(b) isolating ziprasidone hydrochloride monohydrate particles having mean particle sizes greater than about 90 m.
2. A process for the preparation of ziprasidone hydrochloride monohydrate particles, comprising:
(i) preparing a stationary bed of anhydrous ziprasidone hydrochloride particles having mean particle sizes greater than about 90 m,
(ii) passing a mixture of water and a water miscible solvent through the bed; and
(iii) isolating ziprasidone hydrochloride monohydrate particles having mean particle sizes greater than about 90 m.
3. The process according to claims 1 or 2 wherein a water miscible solvent comprises an alcohol, a ketone, a nitrile, N,N-dimethylformamide, dimethylsulfoxide, or a mixture of any two or more thereof.
4. The process according to any of claims 1-7, wherein water is present in mixtures at concentrations about 10% to about 90%, by volume.
5. The process according to claim 1 wherein the slurry in (a) is maintained at temperatures from about 0°C to about 60°C.
6. The process according to any of claims 1-10, further comprising drying the isolated particles.
7. The process according to any of claims 1-11, further comprising milling the isolated particles.
8. The process according to any of claims 1-12, wherein mean particle sizes of ziprasidone hydrochloride monohydrate and anhydrous ziprasidone hydrochloride range from about 90 m to about 300 m.