WO2004050655A1 - Formes polymorphes de ziprasidone et son chlorhydrate - Google Patents

Formes polymorphes de ziprasidone et son chlorhydrate Download PDF

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Publication number
WO2004050655A1
WO2004050655A1 PCT/US2003/038489 US0338489W WO2004050655A1 WO 2004050655 A1 WO2004050655 A1 WO 2004050655A1 US 0338489 W US0338489 W US 0338489W WO 2004050655 A1 WO2004050655 A1 WO 2004050655A1
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WO
WIPO (PCT)
Prior art keywords
ziprasidone
composition
hydrochloride
solid
compound
Prior art date
Application number
PCT/US2003/038489
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English (en)
Inventor
Manne Satyanarayana Reddy
Thirumalai Rajan Srinivasan
Venka Bhaskara Rao Uppala
Mummadi Venkatesh
Akundi Surya Prabhakar
Original Assignee
Dr. Reddy's Laboratories Limited
Dr. Reddy's Laboratories Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dr. Reddy's Laboratories Limited, Dr. Reddy's Laboratories Inc. filed Critical Dr. Reddy's Laboratories Limited
Priority to AU2003300814A priority Critical patent/AU2003300814A1/en
Publication of WO2004050655A1 publication Critical patent/WO2004050655A1/fr

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    • 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

  • the present invention relates to new amorphous form of ziprasidone hydrochloride and crystalline forms of ziprasidone and its hydrochloride salt, processes for preparation thereof, and compositions containing the amorphous and crystalline forms.
  • the present invention also relates to a method of treating a psychosis, comprising administering to a patient in need of such treatment an effective amount of amorphous form of ziprasidone hydrochloride or crystalline forms of ziprasidone or its hydrochloride salt BACKGROUND OF THE INVENTION
  • Ziprasidone 5-(2-(4-(l ,2-benzisothiozole-3yl)- 1 -piperaziny ⁇ )ethyi)-6- chloro-l,3-dihydro-2H-indole-2-one is an anti psychotic agent that is used for the treatment of psychotic disorders of the schizophrenic types, and is also useful for removing or ameliorating such symptoms as anxiety, agitation, excessive aggression, tension and social or emotional withdrawal in psychotic patients.
  • the invention relates to an amo ⁇ hous form of ziprasidone hydrochloride.
  • the amorphous form of ziprasidone hydrochloride may have substantially the same X-ray diffraction pattern as shown in Figure 1.
  • Various embodiments and variants are provided.
  • the invention also relates to a composition that comprises ziprasidone hydrochloride in a solid form, wherein at least 80 % by weight of the solid ziprasidone hydrochloride is an amorphous form of ziprasidone hydrochloride.
  • the invention also relates to a process for preparation of amo ⁇ hous form of ziprasidone hydrochloride by converting ziprasidone to amo ⁇ hous ziprasidone hydrochloride.
  • the invention also relates to a pharmaceutical composition that comprises an amo ⁇ hous form of ziprasidone hydrochloride and one or more pharmaceutically acceptable carriers or diluents.
  • the pharmaceutical composition is in a solid dosage form for oral administration, such as a tablet.
  • the invention also relates to a crystalline form of ziprasidone.
  • the crystalline form of ziprasidone has an X-ray diffraction pattern, expressed in terms of
  • the invention also relates to a pharmaceutical composition having the crystalline form of ziprasidone.
  • Pharmaceutical compositions of the invention may be formulated, for example, as solid dosage forms for oral administration.
  • the invention also relates to a method of treating a psychosis, comprising administering to a patient in need of such treatment an effective amount of an amo ⁇ hous form of ziprasidone hydrochloride or crystalline forms of ziprasidone or its hydrochloride salt.
  • Figure 1 shows a sample X-ray power diffractogram of an amo ⁇ hous form of ziprasidone hydrochloride.
  • Figure 2 shows a sample X-ray power diffractogram of a crystalline form of ziprasidone.
  • compositions for pu ⁇ oses of the present invention, the following terms are defined below.
  • Pharmaceutically acceptable means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable and includes that which is acceptable for veterinary use and/or human pharmaceutical use.
  • composition includes, but is not limited to, a powder, a suspension, an emulsion and/or mixtures thereof.
  • composition is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product, which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • a “composition” may contain a single compound or a mixture of compounds.
  • composition is intended to encompass a product comprising the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • pharmaceutical compositions of the present invention encompass any composition made by admixing the active ingredient, additional active ingredient(s), and pharmaceutically acceptable excipients.
  • excipient means a component of a pharmaceutical product that is not the active ingredient, such as filler, diluent, carrier, and so on.
  • the excipients that are useful in preparing a pharmaceutical composition are preferably generally safe, non- toxic and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use.
  • a pharmaceutically acceptable excipient as used in the specification and claims includes both one and more than one such excipient.
  • the reaction which produces the indicated and/or the desired product, may not necessarily result directly from the combination of two reagents, which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product.
  • the term "isolating" is used to indicate separation of the compound being isolated regardless of the purity of the isolated compound from any unwanted substance which presents with the compound as a mixture. Thus, degree of the purity of the isolated or separated compound does not affect the status of "isolating".
  • the term "substantially free of in reference to a composition, as used herein, means that said substance cannot be detected in the composition by methods known to those skilled in the art at the time of the filing of this application. Ziprasidone hydrochloride has the chemical structure,
  • U.S. Patent 5,312,925 discloses mono and hemi hydrated forms and anhydrous form of ziprasidone hydrochloride, which are characterized by X-ray diffractograms and Infrared spectra.
  • the ziprasidone hydrochloride monohydrate crystal form was prepared by treating ziprasidone with aqueous hydrochloric acid at an elevated temperature, followed by controlled drying.
  • the crystalline form of ziprasidone hydrochloride monohydrate disclosed in U.S. Patent 5,312,925 herein inco ⁇ orated by reference, is designated as crystalline Form I.
  • Crystalline ziprasidone hydrochloride may be preferably prepared by making a suspension of ziprasidone in a ketone solvent, such as acetone, diethyl ketone, methyl isobutyl ketone, methyl ethyl ketone or mixtures thereof.
  • aqueous hydrochloric acid solution is added to the suspension, and the resulting mixture is heated to an elevated temperature, preferably reflux temperature.
  • the reaction mixture may be heated for 1-24 hours but preferably for 1-2 hours. After the heating, the reaction mixture is cooled preferably to ambient temperature.
  • a solid is formed and may be isolated by any conventional filtering technique. The isolated solid may then be dried at an elevated temperature, preferably between about 50°C and about 100°C until a constant ⁇ veight of the solid is obtained to afford crystalline ziprasidone hydrochloride.
  • the moisture content of crystalline ziprasidone hydrochloride obtained may be between about 3.5 and about 4.5 % by weight.
  • the moisture content of the present invention may be measured on
  • reaction times set forth above may vary depending upon the amount of the reactants used in the process.
  • Ziprasidone used in the process of the invention may be crude or purified and may be crystalline or amo ⁇ hous.
  • the ziprasidone itself may be obtained via a condensation of 5-(2-chloroethyl)-6-chloro oxindole and 3-(l-piperazinyl)-l,2- benzisothiazole or via the synthesis described in U.S. Patent No. 5,338,846, which is herein inco ⁇ orated by reference or by titrating an acid addition salt of ziprasidone with a base such as, for example, sodium hydroxide or potassium hydroxide.
  • the invention relates to an amo ⁇ hous form of ziprasidone hydrochloride.
  • the amo ⁇ hous form of ziprasidone hydrochloride of the invention can have a moisture content preferably between about 0.5 and about 7.5 %, more preferably between about 0.5 and about 4.5 % by weight, even more preferably between about 3.5 and about 4.5 %, yet further preferably between about 4.0 and about 4.5 %.
  • a particular process for preparation of an amo ⁇ hous form of ziprasidone hydrochloride includes: a) providing ziprasidone hydrochloride solution in an aqueous alcoholic solvent; b) removing said solvent, thereby forming a solid mass; and d) isolating said solid mass, which is the amo ⁇ hous form of ziprasidone hydrochloride.
  • the aqueous alcoholic solvent is a mixture of water and a lower alky alcohol such as an alcoholic solvent such as ethanol, methanol, propanol, t-butanol, n- butanol, isopropanol or mixtures thereof.
  • the solution of ziprasidone hydrochloride may be prepared by directly dissolving solid ziprasidone hydrochloride in an alcoholic solvent or may be prepared by using ziprasidone which is then treated by hydrochloric acid.
  • a particular process for the preparation of ziprasidone hydrochloride solution used in this aspect of the invention may include: a) suspending ziprasidone base in acetic acid; b) adding aqueous hydrochloric acid solution at slightly above the ambient temperature, preferably at about 30-70°C, preferably 40-50°C; c) adding water and an alcoholic solvent such as ethanol, methanol, propanol, t-butanol, n-butanol, isopropanol or mixtures thereof; and d) heating the reaction mixture to an elevated temperature for 1-24 hours, preferably 1-2 hours.
  • the elevated temperature may be any temperature that allows a clear solution of the reaction mixture but preferably is reflux temperature.
  • the removal of the solvent may be done under reduced pressure and the obtained solid cake is then isolated by a conventional technique, which may or may not include washing the solid cake with a fresh cold water or an aqueous alcoholic solvent such as a mixture of water and a lower alkyl alcohol, e.g. ethanol, methanol, propanol, t- butanol, n-butanol, isopropanol or mixtures thereof.
  • the obtained amo ⁇ hous form of ziprasidone may be dried at an elevated temperature, preferably at about 50°C - about
  • amo ⁇ hous form of ziprasidone hydrochloride produced by this process may be characterized by an X-ray powder diffraction pattern, as for example shown in Figure 1.
  • the X-ray diffractograms was measured on Bruker Axe, DS advance
  • the invention also relates to a crystalline form of ziprasidone.
  • the crystalline form of ziprasidone is prepared by a process comprising a) providing a solution of a salt of ziprasidone in an aqueous solvent; b) treating said solution with aqueous basic solution or caustic lye thereby forming a precipitate; and c) isolating the precipitate, which is the crystalline form of ziprasidone.
  • the solution of a salt of ziprasidone of the above process may be prepared by a) treating crude or purified ziprasidone with methane sulfonic acid in methanol media where the ziprasidone forms a mesylate salt; and b) dissolving the ziprasidone mesylate salt in water or in a mixture of water and an alcoholic solvent.
  • the aqueous basic solution is preferably a solution of alkali metal hydroxide in water such as, for example, sodium hydroxide or potassium hydroxide solution.
  • An X-ray powder diffraction pattern of the crystalline form of ziprasidone produced via the above process of the invention was obtained as shown in Figure 2, and the characteristic 2-theta values (in degrees) of the identified peaks in the X-ray diffractogram are 16.335, 12.209, 25.156, 27.019, 24.21, 5.2555 and 18.511.
  • the X-ray diffractograms was measured on Bruker Axe, DS advance Power X-ray Diffractometer with Cu K alpha-1 Radiation source.
  • D-spacing values are calculated with observed 2 theta angles and copper K( ⁇ l) wavelength using the Bragg equation well known to those of skill in the art.
  • the assigned margin of error in the 2 theta angles for the crystalline form of ziprasidone is approximately + 0.009 for each of the peak assignments.
  • the crystalline form of ziprasidone may be characterized by an X-ray diffraction pattern, expressed in terms of 2 theta angles, that includes four or more peaks selected from the group consisting of 16.34 ⁇ 0.009, 12.21 ⁇ 0.009, 25.16 ⁇ 0.009, 27.02 ⁇ 0.009, 24.21 ⁇ 0.009, 5.26 ⁇ 0.009 and 18.51 ⁇ 0.009 degrees.
  • the preferred method of comparing X-ray powder diffraction patterns in order to identify a particular crystalline form is to overlay the X-ray powder diffraction pattern of the unknown form over the X-ray powder diffraction pattern of a known form.
  • the preferred method of comparing X-ray powder diffraction patterns in order to identify a particular crystalline form is to overlay the X-ray powder diffraction pattern of the unknown form over the X-ray powder diffraction pattern of a known form.
  • one skilled in the art can overlay an X-ray powder diffraction pattern of an unidentified crystalline form of ziprasidone obtained using the methods described herein, over FIG. 2 and readily determine whether the X-ray diffraction pattern of the unidentified form is substantially the same as the X-ray powder diffraction pattern of the crystalline form of this invention. If the X-ray powder diffraction pattern is substantially the same as FIG. 2, the previously unlcnown crystalline form of ziprasidone can be readily
  • the invention also relates to a composition containing solid ziprasidone hydrochloride or solid ziprasidone, of which at least 80%, by total weight of the solid ziprasidone or its hydrochloride salt in the composition, is the corresponding crystalline form or an amo ⁇ hous form.
  • the invention also relates to the composition of solid ziprasidone hydrochloride comprising at least 80%, by total weight, the amo ⁇ hous form of ziprasidone hydrochloride.
  • the solid ziprasidone hydrochloride is suitable for use as active ingredient in formulating pharmaceutical products.
  • the remainder of the solid ziprasidone hydrochloride in the composition may be crystalline Form I of ziprasidone hydrochloride.
  • the composition may comprise at least 90% of the amo ⁇ hous form of ziprasidone • hydrochloride with respect to total weight of the solid ziprasidone hydrochloride in the composition.
  • the composition may comprise at least 95% of the amo ⁇ hous form of ziprasidone hydrochloride with respect to total weight of the solid ziprasidone hydrochloride in the composition.
  • the composition is substantially free of any forms of ziprasidone hydrochloride other than its amo ⁇ hous form.
  • the invention also relates to a composition of solid ziprasidone comprising at least 80%, by total weight of the crystalline of ziprasidone, which is set forth in this specification.
  • the solid ziprasidone is suitable for use as active ingredient in formulating pharmaceutical products.
  • the composition may comprise at least 90% of the crystalline form of ziprasidone with respect to total weight of the solid ziprasidone in the composition.
  • the composition may comprise at least 95% of the crystalline form of ziprasidone with respect to total weight of the solid ziprasidone in the composition.
  • the composition is substantially free of any forms of ziprasidone other than its crystalline form.
  • X-ray diffraction provides a convenient and practical means for quantitative determination of the relative amounts of crystalline and/or amo ⁇ hous forms in a solid mixture.
  • X-ray diffraction is adaptable to quantitative applications because the intensities of the diffraction peaks of a given compound in a mixture are proportional to the fraction of the corresponding powder in the mixture.
  • the percent composition of crystalline ziprasidone or its hydrochloride salt in an unknown composition can be determined.
  • the measurements are made on solid powder ziprasidone or it hydrochloride salt.
  • the X-ray powder diffraction patterns of an unlcnown composition can be compared to known quantitative standards containing pure crystalline forms of ziprasidone or its hydrochloride salt to identify the percent ratio of a particular crystalline form. This is done by comparing the relative intensities of the peaks from the diffraction pattern of the unlcnown solid powder composition with a calibration curve derived from the X-ray diffraction patterns of pure known samples. The curve can be calibrated based on the X-ray powder diffraction pattern for the strongest peak from a pure sample of crystalline forms of ziprasidone or its hydrochloride salt. The calibration curve may be created in a manner Icnown to those of skill in the art.
  • five or more artificial mixtures of crystalline forms of ziprasidone or its hydrochloride salt may be prepared.
  • such mixtures may contain, 2%, 5%, 7%, 8%, and 10%> of ziprasidone or its hydrochloride salt for each crystalline form.
  • X- ray diffraction patterns are obtained for each artificial mixture using standard X-ray diffraction techniques. Slight variations in peak positions, if any, may be accounted for by adjusting the location of the peak to be measured. The intensities of the selected characteristic peak(s) for each of the artificial mixtures are then plotted against the known weight percentages of the crystalline form.
  • the resulting plot is a calibration curve that allows determination of the amount of the crystalline forms of ziprasidone or its hydrochloride salt in an unlcnown sample.
  • the intensities of the selected characteristic peak(s) in the mixture may be used to determine the percentage of the given crystalline form in the composition, with the remainder determined to be the amo ⁇ hous material.
  • compositions comprising amo ⁇ hous form of ziprasidone hydrochloride or the crystalline fo ⁇ n of ziprasidone can be formulated with a one or more pharmaceutically acceptable carriers, also known as excipients, which ordinarily lack pharmaceutical activity, but have various useful properties which may, for example, enhance the stability, sterility, bioavailability, and ease of formulation of a pharmaceutical composition.
  • These carriers are pharmaceutically acceptable, meaning that they are not harmful to humans or animals when taken appropriately and are compatible with the other ingredients in a given formulation.
  • the carriers may be solid, semi-solid, or liquid, and may be formulated with the compound in bulk.
  • the resulting mixture may be manufactured in the form of a unit-dose formulation (i.e., a physically discrete unit containing a specific amount of active ingredient) such as a tablet or capsule.
  • a unit-dose formulation i.e., a physically discrete unit containing a specific amount of active ingredient
  • the pharmaceutical compositions may include, in addition to a compound of this invention, one or more active pharmaceutical compounds.
  • the pha ⁇ naceutical compositions of the invention may be prepared by unifo ⁇ iily admixing the active ingredient with liquid or solid carriers and then shaping the product into the desired fo ⁇ n.
  • the pha ⁇ naceutical compositions may be in the fo ⁇ n of suspensions, solutions, elixirs, aerosols, or solid dosage forms. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed.
  • a preferred oral solid preparation is a tablet.
  • a tablet may be prepared by direct compression, wet granulation, or molding, of the active ingredient(s) with a carrier and other excipients in a manner Icnown to those skilled in the art.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free- flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active agent or dispersing agent. Molded tablets may be made on a suitable machine.
  • a mixture of the powdered compound moistened with an inert liquid diluent is suitable in the case of oral solid dosage forms (e.g., powders, capsules, and tablets).
  • tablets may be coated by standard techniques.
  • the compounds of this invention may be formulated into typical disintegrating tablets, or into controlled or extended release dosage forms. Examples of suitable controlled release fomiulation vehicles are disclosed in U.S. Patents Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, inco ⁇ orated herein by reference in their entireties.
  • the pha ⁇ naceutical compositions of the invention are contemplated in various formulations suitable for various modes of administration, including but not limited to inhalation, oral, rectal, parenteral (including subcutaneous, intradermal, intramuscular, intravenous), implantable, intravaginal and transdermal administration. The most suitable route of administration in any given case depends on the duration of the subject's condition, the length of treatment desired, the nature and severity of the condition being treated, and the particular formulation that is being used.
  • the formulations may be in bulk or in unit dosage form.
  • a pha ⁇ naceutical composition of the invention will generally comprise about 0.1 % by weight to about 99% by weight of active ingredient, preferably about 1% by weight to 50% by weight for oral administration and about 0.2% by weight to about 20% by weight for parenteral administration.
  • Formulations suitable for oral administration include capsules (hard and soft), cachets, lozenges, syrups, suppositories, and tablets, each containing a pre- determined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in- water or water-in-oil emulsion.
  • Such formulations may be prepared by any suitable method of pharmacy that includes the step of bringing into association the active compound and a suitable carrier or can ⁇ ers.
  • the amount of active ingredient per unit dosage of solid fo ⁇ nulations may be as described in prior art for preparations of ziprasidone and its hydrochloride salt.
  • a preferable amount is from about 2% by weight to about 20% by weight.
  • Suitable carriers include but are not limited to fillers, binders, lubricants, inert diluents, surface active/dispersing agents, flavorants, antioxidants, bulking and granulating agents, adsorbants, preservatives, emulsifiers, suspending and wetting agents, glidants, disintegrants, buffers and pH-adjusting agents, and colorants.
  • carriers include celluloses, modified celluloses, cyclodextrins, starches, oils, polyols, sugar alcohols and sugars, and others.
  • sugar, sugar alcohols, ethanol, water, glycerol, and poyalkylene glycols are particularly suitable, and may also be used in solid fo ⁇ nulations.
  • Cyclodextrins may be particularly useful for increasing bioavailability.
  • Formulations for oral administration may optionally include enteric coatings known in the art to prevent degradation of the formulation in the stomach and provide release of the drug in the small intestine.
  • Fo ⁇ nulations suitable for buccal or sub-lingual administration include lozenges comprising the active compound in a flavored base, usually sucrose and acacia or tragacanth, although other agents are also suitable, and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.
  • Formulations suitable for rectal administration are preferably presented as unit dose suppositories. These may be prepared by admixing the active compound with one or more conventional solid carriers, e.g., cocoa butter, and then shaping the resulting mixture.
  • conventional solid carriers e.g., cocoa butter
  • the invention also provides methods of treating a psychosis, comprising adminitering to a patient in need of such treatement an effective amount of a composition comprising the amo ⁇ hous form of ziprasidone hydrochloride or the crystalline form of ziprasidone and a pharmaceutically acceptable carrier.
  • the effective amount (i.e., dosage) of active compound for treatment will vary depending on the route of administration, the condition being treated, its severity, and duration, and the state and age of the subject. A skilled physician will monitor the progress of the subject and will adjust the dosage accordingly, depending on whether the goal is to eliminate, alleviate, or prevent a given condition. Generally, the dosage should be considered in proportion to the subject's weight.
  • the daily dose of particular fo ⁇ nulations of active compound may be divided among one or several unit dose administrations. For example therapeutic administration about fifteen to thirty minutes before main meals is preferable (i.e. three times daily), although administration of the active compounds may be carried out prophylactically, and may be maintained for prolonged periods of time. One skilled in the art will take such factors into account when determining dosage.
  • Unit dosage of active ingredient may range from about 0.1 to about 2g or from about 0.1 to about 2g.
  • Triethylsilane (57.2 gm) was added slowly to the reaction mixture of 5-(2-aminoethylsilane).
  • 1,2-benzisothiazole (47.5 gm) and cyclohexane (500 mL) into an autoclave.
  • sodium carbonate (46 gm) sodium iodide (3.2 gm)
  • terra butyl phosphonium bromide (14.8 gm) was added and the reaction was maintained at a temperature of 95-102°C and the pressure was kept at 2.5 kg/cm till the reaction was completed.
  • the reaction mass was cooled to 30°C and water (250 mL) was added.
  • the resulting compound was filtered and washed with water (100 mL).
  • the wet compound was further slurred in water (500 mL), filtered and washed with water (100 mL).
  • the reaction completion was monitored by TLC.
  • the reaction mass was cooled to room temperature.
  • the resulting compound was filtered and washed with 50 mL of water.
  • the wet compound and 250 mL of acetone were placed into a flask and the reaction mixture was sthred at room temperature for 2 hours.
  • the reaction mixture was filtered to give a solid cake, which was washed with 50 mL of acetone.

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Abstract

L'invention se rapporte à des formes cristallines de ziprasidone et à son sel de chlorhydrate et à une forme amorphe de chlorhydrate de ziprasidone et au procédé de préparation de celui-ci. Lesdites formes cristallines et ladite forme amorphe sont appropriées pour des buts pharmaceutiques dans le traitement de psychose. Les procédés de l'invention sont simples, non dangereux et commercialement appropriés.
PCT/US2003/038489 2002-12-04 2003-12-04 Formes polymorphes de ziprasidone et son chlorhydrate WO2004050655A1 (fr)

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AU2003300814A AU2003300814A1 (en) 2002-12-04 2003-12-04 Polymorphic forms of ziprasidone and its hydrochloride

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IN907/MAS/2002 2002-12-04
IN907CH2002 2002-12-04

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005061493A3 (fr) * 2003-12-18 2005-09-09 Teva Pharma Forme polymorphe b2 de base de ziprasidone
WO2005085240A2 (fr) * 2004-02-27 2005-09-15 Ranbaxy Laboratories Limited Procede de preparation de ziprasidone
WO2005100348A1 (fr) * 2004-04-15 2005-10-27 Lupin Limited Hydrochlorure de ziprasidone amorphe
WO2005111032A1 (fr) * 2004-05-14 2005-11-24 Apotex Pharmachem Inc. Nouvel hydrochlorure de ziprasidone (5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2h-indl-2-one hydrochlorure) et procede de production associe
ES2250000A1 (es) * 2004-09-29 2006-04-01 Medichem, S.A. Procedimiento para la preparacion de ziprasidona.
WO2006034965A1 (fr) * 2004-09-29 2006-04-06 Medichem, S.A. Procede de purification de la ziprasidone
WO2006047893A1 (fr) * 2004-11-05 2006-05-11 Apotex Pharmachem Inc. Procede de preparation de ziprasidone (5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2h-indol-2-one)
US7087611B2 (en) 2004-06-14 2006-08-08 Apotex Pharmachem Inc. Preparation of an anhydrate form of 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one hydrochloride (ziprasidone hydrochloride)
WO2006086779A1 (fr) * 2005-02-11 2006-08-17 Teva Pharmaceutical Industries Ltd. Ziprasidone mesylate amorphe
WO2006098834A2 (fr) * 2005-03-14 2006-09-21 Teva Pharmaceutical Industries Ltd. Formes cristallines de mesylate de ziprasidone
US7667037B2 (en) 2003-10-24 2010-02-23 Teva Pharmaceutical Industries Ltd. Processes for preparation of ziprasidone
US7678799B2 (en) 2003-06-03 2010-03-16 Teva Pharmaceutical Industries Ltd. Crystalline ziprasidone HCl and processes for preparation thereof
US7745624B2 (en) 2005-03-11 2010-06-29 Apotex Pharma Chem Inc. Preparation of acid addition salts of ziprasidone and intermediates thereof by solid phase-gas phase reactions
WO2012096632A1 (fr) 2011-01-13 2012-07-19 Silverstone Pharma Ag Nouveaux sels d'addition de ziprasidone, leur procédé de préparation et leur utilisation en thérapie

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4831031A (en) * 1988-01-22 1989-05-16 Pfizer Inc. Aryl piperazinyl-(C2 or C4) alkylene heterocyclic compounds having neuroleptic activity
EP0584903A1 (fr) * 1992-08-26 1994-03-02 Pfizer Inc. Procédé de préparation de dérivés aryl pipérazinyl-hétérocycliques
EP0586191A1 (fr) * 1992-09-01 1994-03-09 Pfizer Inc. Monohydrate du chlorhydrate de 5-(2-(4-(1,2 benzisothiazole-3 YL)-1-pipérazinyl)-éthyl)-6-chloro-1,3-dihydro-2H-indol-2-one
WO1995000510A1 (fr) * 1993-06-28 1995-01-05 Pfizer Inc. Procedes et intermediaires pour la preparation de 5-[2-(4-(benzoisothiazol-3-yl)-piperazin-1-yl)ethyl]-6-chloro-1,3-dihydro-indol-2-one
WO1997042190A1 (fr) * 1996-05-07 1997-11-13 Pfizer Inc. Trihydrate du sel mesylate de 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-ethyl)-6-chloro-1,3-dihydro-2(1h)-indol-2-one (=ziprasidone), sa preparation et son utilisation en tant qu'antagoniste du recepteur dopaminergique d2
EP0965343A2 (fr) * 1998-06-15 1999-12-22 Pfizer Products Inc. Formulations de ziprasidone
WO2000059489A2 (fr) * 1999-04-06 2000-10-12 Sepracor Inc. Methodes et compositions pour le traitement des troubles neuroleptiques et associes au moyen de metabolites de ziprasidone
EP1157726A1 (fr) * 2000-05-26 2001-11-28 Pfizer Products Inc. Procédé de cristallisation réactive pour l'amélioration de la taille des particules
WO2003063833A1 (fr) * 2002-02-01 2003-08-07 Pfizer Products Inc. Compositions pharmaceutiques de dispersions amorphes de medicaments et materiaux formant des microphases lipophiles
WO2003070246A1 (fr) * 2002-02-20 2003-08-28 Pfizer Products Inc. Synthese controlee de ziprasidone et ses compositions

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4831031A (en) * 1988-01-22 1989-05-16 Pfizer Inc. Aryl piperazinyl-(C2 or C4) alkylene heterocyclic compounds having neuroleptic activity
EP0584903A1 (fr) * 1992-08-26 1994-03-02 Pfizer Inc. Procédé de préparation de dérivés aryl pipérazinyl-hétérocycliques
EP0586191A1 (fr) * 1992-09-01 1994-03-09 Pfizer Inc. Monohydrate du chlorhydrate de 5-(2-(4-(1,2 benzisothiazole-3 YL)-1-pipérazinyl)-éthyl)-6-chloro-1,3-dihydro-2H-indol-2-one
WO1995000510A1 (fr) * 1993-06-28 1995-01-05 Pfizer Inc. Procedes et intermediaires pour la preparation de 5-[2-(4-(benzoisothiazol-3-yl)-piperazin-1-yl)ethyl]-6-chloro-1,3-dihydro-indol-2-one
WO1997042190A1 (fr) * 1996-05-07 1997-11-13 Pfizer Inc. Trihydrate du sel mesylate de 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-ethyl)-6-chloro-1,3-dihydro-2(1h)-indol-2-one (=ziprasidone), sa preparation et son utilisation en tant qu'antagoniste du recepteur dopaminergique d2
EP0965343A2 (fr) * 1998-06-15 1999-12-22 Pfizer Products Inc. Formulations de ziprasidone
WO2000059489A2 (fr) * 1999-04-06 2000-10-12 Sepracor Inc. Methodes et compositions pour le traitement des troubles neuroleptiques et associes au moyen de metabolites de ziprasidone
EP1157726A1 (fr) * 2000-05-26 2001-11-28 Pfizer Products Inc. Procédé de cristallisation réactive pour l'amélioration de la taille des particules
WO2003063833A1 (fr) * 2002-02-01 2003-08-07 Pfizer Products Inc. Compositions pharmaceutiques de dispersions amorphes de medicaments et materiaux formant des microphases lipophiles
WO2003070246A1 (fr) * 2002-02-20 2003-08-28 Pfizer Products Inc. Synthese controlee de ziprasidone et ses compositions

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HOWARD H R ET AL: "3-Benzisothiazolylpiperazine derivatives as potential atypical antipsychotic agents", JOURNAL OF MEDICINAL CHEMISTRY, vol. 39, no. 1, 5 January 1996 (1996-01-05), pages 143 - 148, XP000652318 *

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7678799B2 (en) 2003-06-03 2010-03-16 Teva Pharmaceutical Industries Ltd. Crystalline ziprasidone HCl and processes for preparation thereof
US7667037B2 (en) 2003-10-24 2010-02-23 Teva Pharmaceutical Industries Ltd. Processes for preparation of ziprasidone
WO2005061493A3 (fr) * 2003-12-18 2005-09-09 Teva Pharma Forme polymorphe b2 de base de ziprasidone
WO2005085240A3 (fr) * 2004-02-27 2005-12-01 Ranbaxy Lab Ltd Procede de preparation de ziprasidone
US8178674B2 (en) 2004-02-27 2012-05-15 Ranbaxy Laboratories Limited Process for the preparation of ziprasidone
WO2005085240A2 (fr) * 2004-02-27 2005-09-15 Ranbaxy Laboratories Limited Procede de preparation de ziprasidone
WO2005100348A1 (fr) * 2004-04-15 2005-10-27 Lupin Limited Hydrochlorure de ziprasidone amorphe
WO2005111032A1 (fr) * 2004-05-14 2005-11-24 Apotex Pharmachem Inc. Nouvel hydrochlorure de ziprasidone (5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2h-indl-2-one hydrochlorure) et procede de production associe
US7939662B2 (en) 2004-05-14 2011-05-10 Apotex Pharmachem Inc. Amorphous ziprasidone hydrochloride (5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one hydrochloride) and processes to produce the same
US7087611B2 (en) 2004-06-14 2006-08-08 Apotex Pharmachem Inc. Preparation of an anhydrate form of 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one hydrochloride (ziprasidone hydrochloride)
ES2250000A1 (es) * 2004-09-29 2006-04-01 Medichem, S.A. Procedimiento para la preparacion de ziprasidona.
WO2006034965A1 (fr) * 2004-09-29 2006-04-06 Medichem, S.A. Procede de purification de la ziprasidone
WO2006047893A1 (fr) * 2004-11-05 2006-05-11 Apotex Pharmachem Inc. Procede de preparation de ziprasidone (5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2h-indol-2-one)
WO2006086779A1 (fr) * 2005-02-11 2006-08-17 Teva Pharmaceutical Industries Ltd. Ziprasidone mesylate amorphe
US7745624B2 (en) 2005-03-11 2010-06-29 Apotex Pharma Chem Inc. Preparation of acid addition salts of ziprasidone and intermediates thereof by solid phase-gas phase reactions
WO2006098834A3 (fr) * 2005-03-14 2007-02-22 Teva Pharma Formes cristallines de mesylate de ziprasidone
WO2006098834A2 (fr) * 2005-03-14 2006-09-21 Teva Pharmaceutical Industries Ltd. Formes cristallines de mesylate de ziprasidone
WO2012096632A1 (fr) 2011-01-13 2012-07-19 Silverstone Pharma Ag Nouveaux sels d'addition de ziprasidone, leur procédé de préparation et leur utilisation en thérapie

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