WO2006034965A1 - Process for the purification of ziprasidone - Google Patents

Process for the purification of ziprasidone Download PDF

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Publication number
WO2006034965A1
WO2006034965A1 PCT/EP2005/054589 EP2005054589W WO2006034965A1 WO 2006034965 A1 WO2006034965 A1 WO 2006034965A1 EP 2005054589 W EP2005054589 W EP 2005054589W WO 2006034965 A1 WO2006034965 A1 WO 2006034965A1
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Prior art keywords
formula
acid
process according
ziprasidone
maleate
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PCT/EP2005/054589
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French (fr)
Inventor
Carme Burgarolas Montero
Jordi BOSCH ILLADÓ
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Medichem, S.A.
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Publication of WO2006034965A1 publication Critical patent/WO2006034965A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

  • This invention relates to the purification of ziprasidone base using the maleic acid or acetic acid addition salt thereof.
  • 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
  • solvents e.g. to filter off insoluble contaminants, to recrystallize, or to decolorize.
  • ziprasidone base is very insoluble in common solvents. This is demonstrated e.g.
  • 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 .
  • 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.
  • 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)
  • R is CH or
  • the acid addition salt according to the above formula (II) is separated from insoluble components of the composition, preferably by filtration.
  • 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.
  • 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) :
  • 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.
  • 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.
  • 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.
  • 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
  • Suitable bases comprise sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate sodium bicarbonate, potassium bicarbonate and ammonium hydroxide.
  • the test is carried out in a Kromasil C8 column of 5 ⁇ m and 250x4.6mm.
  • 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 20 ⁇ l are injected.
  • 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%.
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Process for the purification of ziprasidone. The present invention concerns a process for the purification of 5- [2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6- chloro-1,3-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 to obtain an acid addition salt of the following formula (II), wherein R is formula (IV), or formula (V).

Description

PROCESS FOR THE PURIFICATION OF ZIPRASIDONE
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)
Figure imgf000003_0001
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) :
Figure imgf000004_0001
wherein R is CH or
Figure imgf000004_0002
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) :
Figure imgf000005_0001
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 HClO4: 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 400C 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 20-250C, 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%.

Claims

1. 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)
Figure imgf000011_0001
from a composition comprising said compound, wherein said compound is reacted with maleic acid or acetic acid to obtain an acid addition salt of the following formula (ID,
Figure imgf000011_0002
wherein R is CH or
Figure imgf000011_0003
2. The process according to claim 1, wherein maleic acid is reacted with the compound according to formula (I) 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.
3. The process according to claim 1, wherein acetic acid is reacted with the compound according to formula (I) in an amount of at least 1 molar equivalent.
4. The process according to any one of claims 1 to 3, wherein the maleate or acetate according to formula (II) is separated from insoluble components of the composition.
5. The process according to claim 4, wherein the maleate or the acetate according to formula (II) is separated from insoluble components of the composition by filtration.
6. The process according to any one of claims 1 to 5, wherein the maleate or acetate according to formula (II) is further treated with a decolorizing agent.
7. The process according to claim 6, wherein said decolorizing agent is at least one selected from alumina, activated alumina, silica and charcoal.
8. The process according to any one of claims 1 to 7, wherein the maleate or acetate according to formula (II) is reacted with an acid in order to obtain an acid addition salt according to the following formula (III) :
Figure imgf000012_0001
(HI) wherein Rl is halogen or CH3SO3.
9. The process according to claim 8, wherein the acid is one selected from hydrochloric acid, hydrobromic acid and methanesulphonic acid.
10. The process according to claim 9, wherein the acid is hydrochloric acid.
11. The process according to any one of claims 8 to 10, wherein the acid addition salt according to formula (III) is further purified by using at least one organic solvent.
12. The process according to claim 11, wherein said organic solvent is at least one selected from isopropanol, tetrahydrofuran, n-butanol and butan-2-one.
13. Use of a maleate or acetate of formula (II) in a process according to any one of claims 1 to 12.
PCT/EP2005/054589 2004-09-29 2005-09-15 Process for the purification of ziprasidone WO2006034965A1 (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1700857A1 (en) * 2005-03-07 2006-09-13 Dipharma S.p.A. Ziprasidone free from colored impurities and a process for its preparation
WO2006094396A1 (en) * 2005-03-11 2006-09-14 Apotex Pharmachem Inc. Preparation of acid addition salts of ziprasidone and intermediates thereof by solid phase-gas phase reactions
WO2008062244A1 (en) * 2006-11-24 2008-05-29 Richter Gedeon Nyrt. Polymorphs of 5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-ethyl}-6-chloro-1,3-dihydro-2h-indol-2-one hydrobromide and processes for preparation thereof
WO2011080749A1 (en) * 2009-12-29 2011-07-07 Hetero Research Foundation Process for purification of ziprasidone

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0584903A1 (en) * 1992-08-26 1994-03-02 Pfizer Inc. Process for preparing aryl piperazinyl-heterocyclic compounds
WO2001091756A2 (en) * 2000-06-02 2001-12-06 Pfizer Products Inc. S-methyl-dihydro-ziprasidone for treatment of psychiatric and ocular disorders
WO2003070246A1 (en) * 2002-02-20 2003-08-28 Pfizer Products Inc. Controlled synthesis of ziprasidone and compositions thereof
WO2004050655A1 (en) * 2002-12-04 2004-06-17 Dr. Reddy's Laboratories Limited Polymorphic forms of ziprasidone and its hydrochloride
US20050059680A1 (en) * 2003-06-03 2005-03-17 Anna Balanov Crystalline ziprasidone HCI and processes for preparation thereof

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IL126590A (en) * 1996-05-07 2001-11-25 Pfizer Mesylate trihydrates salt of 5-(2-(4-(1, 2-benzisothiazol-3-yl)-1-piperazinyl) ethyl)-6-chloro-1, 3-dihydro-2(1h)-indol-2-one (=ziprasidone) and pharmaceutical compositions comprising it
DE10043659A1 (en) * 2000-09-05 2002-03-14 Merck Patent Gmbh Arylpiperazinderivate
WO2003099198A2 (en) * 2002-05-24 2003-12-04 Sun Pharmaceutical Industries Limited A process for the preparation of oxindole derivatives

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Publication number Priority date Publication date Assignee Title
EP0584903A1 (en) * 1992-08-26 1994-03-02 Pfizer Inc. Process for preparing aryl piperazinyl-heterocyclic compounds
WO2001091756A2 (en) * 2000-06-02 2001-12-06 Pfizer Products Inc. S-methyl-dihydro-ziprasidone for treatment of psychiatric and ocular disorders
WO2003070246A1 (en) * 2002-02-20 2003-08-28 Pfizer Products Inc. Controlled synthesis of ziprasidone and compositions thereof
WO2004050655A1 (en) * 2002-12-04 2004-06-17 Dr. Reddy's Laboratories Limited Polymorphic forms of ziprasidone and its hydrochloride
US20050059680A1 (en) * 2003-06-03 2005-03-17 Anna Balanov Crystalline ziprasidone HCI and processes for preparation thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1700857A1 (en) * 2005-03-07 2006-09-13 Dipharma S.p.A. Ziprasidone free from colored impurities and a process for its preparation
WO2006094396A1 (en) * 2005-03-11 2006-09-14 Apotex Pharmachem Inc. Preparation of acid addition salts of ziprasidone and intermediates thereof by solid phase-gas phase reactions
WO2008062244A1 (en) * 2006-11-24 2008-05-29 Richter Gedeon Nyrt. Polymorphs of 5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-ethyl}-6-chloro-1,3-dihydro-2h-indol-2-one hydrobromide and processes for preparation thereof
WO2011080749A1 (en) * 2009-12-29 2011-07-07 Hetero Research Foundation Process for purification of ziprasidone

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