FIELD OF THE INVENTION

This invention relates to the purification of ziprasidone base using the maleic acid or acetic acid addition salt thereof.

BACKGROUND OF THE INVENTION

In producing ziprasidone, the ziprasidone free base (i.e. 5- [2- [4- (1, 2-benzisothiazol-3-yl) -1-piperazinyl] ethyl] - 6-chloro-l, 3-dihydro-2H-indol-2-one) has to be dissolved in solvents, e.g. to filter off insoluble contaminants, to recrystallize, or to decolorize. However, ziprasidone base is very insoluble in common solvents. This is demonstrated e.g. in example 2 of US 5,338,846 and corresponding example 3 of EP 584 903, where it is disclosed that 1 kg of ziprasidone base requires 9 to 10 gallons of tetrahydrofurane (one US gallon corresponds to 36,2 litres; one UK gallon corresponds to 43,4 litres) and reflux temperature (66°C) to obtain a solution of ziprasidone base.

It is evident, that the very large volumes of solvent needed are not satisfactory for industrial implementation. In addition, the filtration temperature near to reflux temperature is disadvantageous.

Thus, the object of the present invention is to obtain a derivative of ziprasidone base that is more soluble than

ziprasidone base, thereby reducing the need for large volumes of solvents and/or high temperatures .

BRIEF DESCRIPTION OF THE INVENTION

The inventors solved this objective by providing the maleic acid or acetic acid addition salt of ziprasidone base, ziprasidone maleate or acetate. Ziprasidone maleate or acetate is readily dissolvable, and the solution can be treated with a decolouring agent and/ or filtered at room temperature to obtain a solution of purified ziprasidone maleate or acetate of improved quality, i.e. without insoluble components / less coloured.

Thus, the invention relates to a process for the purification of 5- [2- [4- (1, 2-benzisothiazol-3-yl) -1- piperazinyl] ethyl] -6-chloro-l, 3-dihydro-2H-indol-2-one of the formula (I)

from a composition comprising said compound, wherein said compound is reacted with maleic acid or acetic acid, preferably in an amount of 0,5 to 3 molar equivalents, preferably 1 to 2 molar equivalents, and most preferably

1.1 to 1.6 molar equivalents to obtain an acid addition salt of the following formula (II) :

wherein R is CH or

Then, the acid addition salt according to the above formula (II) is separated from insoluble components of the composition, preferably by filtration.

Alternatively, or in addition, the acid addition salt according to the above formula (II) can be further treated with a decolorizing agent, preferably at least one selected from alumina, activated alumina, silica and charcoal.

The acid addition salt according to the above formula (II) can be reacted with an acid, preferably selected from hydrochloric acid, hydrobromic acid and methanesulphonic acid, most preferably hydrochloric acid in order to obtain an acid addition salt of the compound according to the following formula (III) :

wherein Rl is halogen or CH3SO3

The acid addition salt according to the above formula (III) can be further purified by using at least one organic solvent, preferably selected from isopropanol, tetrahydrofuran, n-butanol and butan-2-one.

The present invention further provides for the use of an acid addition salt of formula (II) in a process according to any one of the embodiments described above.

DETAILED DESCRIPTION OF THE INVENTION

For the purpose of this invention, the term "ziprasidone" relates to the free base of ziprasidone (i.e. 5- [2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl]ethyl] -6-chloro- 1, 3-dihydro-2H-indol-2-one) , unless stated otherwise.

The free base of ziprasidone can be used in the current invention irrespective of the process used for its production.

The maleate or acetate acid addition salt according to formula (II) can be treated with any conventional decolorizing agent. Such conventional decolorizing agents

include, but are not limited to, alumina, activated alumina, silica and charcoal.

The solution of the acid addition salt according to formula (II) can be treated with hydrochloric acid or with hydrogen chloride or with a solution of hydrogen chloride in order to precipitate ziprasidone hydrochloride.

Alternatively, the solution of addition salt according to formula II can be treated with a base in order to precipitate ziprasidone base, which is then converted to the corresponding acid addition salt according to formula

(III) . Suitable bases comprise sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate sodium bicarbonate, potassium bicarbonate and ammonium hydroxide.

EXAMPLES

The following analytical chromatographic HPLC method is used to test the purity of ziprasidone:

The test is carried out in a Kromasil C8 column of 5μm and 250x4.6mm. The mobile phase is prepared by mixing 370 ml of acetonitrile with 630 ml of buffer at a pH=3.0, which is prepared from 1.2 g of KH2PO4 and 0.7 g of 1- pentanesulfonic acid sodium salt dissolved in 630 ml of water, adjusting the pH with H3PO4. This mobile phase is mixed and filtered through a 0.22 μm nylon filter under vacuum.

The chromatograph is equipped with a UV detector set at 229 nm and the flow rate is 1.0 ml per minute at room temperature The samples are prepared by dissolving the appropriate amount of sample to obtain 0.5 mg per ml of a mixture of acetonitrile / trifluoroacetic acid 19.6:0.4 v/v and 20μl are injected.

REFERENCE EXAMPLE: Preparation of ziprasidone base

88.7 g (0.837 mols, 3.21 molar equivalents) of sodium carbonate, 600 mL of acetonitrile and 66.7 g (0.261 mols, 1.0 molar equivalent) of 3- (1-piperazinyl) -1, 2- benzisothiazole hydrochloride are added into a beaker equipped with a magnetic stirrer. The resulting white suspension is stirred for 10 minutes. At this point 60.0 g (0.261 mols, 1.0 molar equivalent) of 5- (2- chloroethyl) -6-chloro-l, 3-dihydro-indole-2- (2H) -one and 0.3 g (0.002 mols, 0.008 molar equivalents) of NaI are added. The resulting brown suspension is charged into a 1 L reactor vessel, which is purged with nitrogen and heated to 120-125° C (internal pressure increases to 400- 500 kPa) for 25 hours. The reaction is cooled to room temperature, stirred for 30 minutes, filtered and the solid washed with acetonitrile. A wet mixture of zipradisone and inorganic salts is obtained, that is further washed with acetonitrile. The resulting wet mixture of ziprasidone and inorganic salts is stirred with 675 ml of water at reflux temperature for 1 h to remove inorganic salts. The suspension is cooled to room temperature, stirred for 30 minutes and filtered. The solid is washed with water, and 140 g of wet solid (corresponding to 87 g of dry material) are obtained.

The wet solid is stirred again with water at reflux temperature for 1 h to remove residual inorganic salts. The suspension is cooled to room temperature, stirred for 30 minutes and filtered. The solid is washed with water, and 170 g of wet solid (corresponding to 81 g of dry- material) are obtained. HPLC analysis reveals a purity of 97.8%.

To remove starting materials present in the wet solid obtained in the previous step, it is stirred twice with

400 ml of tetrahydrofuran at reflux temperature. The solution is cooled to room temperature, stirred for 30 minutes and filtered. The solid is washed twice with 40 ml of tetrahydrofuran, and 60 g of wet solid, corresponding to 54.8 g of dry material, are obtained.

The solid obtained is ziprasidone base having a purity of 99.4% by HPLC and the global yield from the starting compounds is 51% (molar yield) . Potentiometric titration with HClO ₄ : 100.03%

The ziprasidone base obtained can be converted to its hydrochloride, or alternatively can be purified to improve its quality attributes like colour and absence of insoluble matter according to the following process.

EXAMPLE 1 : Ziprasidone Maleate

In a 1 L spherical reaction vessel, equipped with a thermometer and a magnetic stirrer, and purged with nitrogen, 400.45 ml of a tetrahydrofuran / N,N- dimethylacetamide 1:4 mixture and the wet solid of ziprasidone base obtained in the Reference Example are

added. To the resulting suspension 24.76 g of maleic acid

(1.6 molar equivalents) are added, and it is stirred for

5 minutes. At this point, 8.0 g of active charcoal are added to the deep red suspension. After stirring for 30 minutes, the suspension is filtered over celite and the solid is washed twice with 40 mL of the same solvent mixture. A clear red solution of Ziprasidone maleate is obtained, which can subsequently be converted to its hydrochloride salt by conventional means .

EXAMPLE 2 : Ziprasidone Acetate

In a 100 ml spherical reaction vessel, equipped with a thermometer and a magnetic stirrer, and purged with nitrogen, 5.96 g of wet ziprasidone (corresponding to 4 g of dry ziprazidone) and 16 ml of acetic acid are added. After fifteen minutes of stirring a solution is obtained. At this point, 0.04 g of active charcoal is added. After stirring for 30 minutes, the suspension is filtered over celite and the solid is washed twice with 2 mL of acetic acid. A clear brown solution of Ziprasidone acetate is obtained, which can subsequently be converted to its hydrochloride salt by conventional means .

EXAMPLE 3: Preparation of Anhydrous Ziprasidone Hydrochloride

In a 100 ml spherical reaction vessel, equipped with a thermometer and a magnetic stirrer, and purged with nitrogen, the solution of Ziprasidone acetate obtained in example 2 is charged. After adding 0.99 ml of 36,18% aqueous hydrochloric acid (1,2 molar equivalents) to the solution, a pink suspension is obtained. It is stirred

for two hours, filtered and the solid is washed twice with 2 ml of acetic acid. The solid is dried in vacuum at 40 ⁰ C until constant weight to obtain 3.49 g of anhydrous Ziprasidone hydrochloride. Global yield from ziprasidone base: 80.2%.

EXAMPLE 4 : Preparation of anhydrous ziprasidone hydrochloride (large scale)

In a reactor vessel equipped with a mechanical stirrer 0.604 kg of tetrahydrofurane wet ziprasidone base (0.5 kg dry), 1.2 kg (1.3 1) of tetrahydrofuran and 4.88 kg (5.2 1) of N, N- dimethylacetamide are added. The resulting beige suspension is stirred for ten minutes and then 0.17 kg of maleic acid is added. The suspension becomes almost instantaneously an almost clear red solution. It is filtered to remove insoluble particles and the clear solution is transferred to a clean vessel, to which 323 ml of a 4.5 M solution of hydrogen chloride in isopropanol are added at a rate of 1 ml/min. The mixture is stirred for 3 hours at 20-25 ⁰ C, filtered and washed twice with 1 litre of tetrahydrofuran, to obtain 0.537 kg of wet anhydrous Ziprasidone hydrochloride that corresponds to 0.521 kg of dry anhydrous Ziprasidone hydrochloride. Molar yield : 96%. Purity by HPLC: 99.9%.