WO2007105225A1 - PROCÉDÉ DE PRODUCTION D'UNE FORME PURE ET STABLE DE 2-MÉTHYL-4-(4- MÉTHYL-1-PIPÉRAZINYL)-10H-THIÉNO[2,3-b][1,5]BENZODIAZÉPINE - Google Patents

PROCÉDÉ DE PRODUCTION D'UNE FORME PURE ET STABLE DE 2-MÉTHYL-4-(4- MÉTHYL-1-PIPÉRAZINYL)-10H-THIÉNO[2,3-b][1,5]BENZODIAZÉPINE Download PDF

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Publication number
WO2007105225A1
WO2007105225A1 PCT/IN2006/000091 IN2006000091W WO2007105225A1 WO 2007105225 A1 WO2007105225 A1 WO 2007105225A1 IN 2006000091 W IN2006000091 W IN 2006000091W WO 2007105225 A1 WO2007105225 A1 WO 2007105225A1
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WO
WIPO (PCT)
Prior art keywords
methyl
benzodiazepine
piperazinyl
olanzapine
thieno
Prior art date
Application number
PCT/IN2006/000091
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English (en)
Inventor
Dinesh Panchasara
Poorvi Gupta
Geetesh Kaushik
Sushil Kumar Dubey
Original Assignee
Jubilant Organosys Limited
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 Jubilant Organosys Limited filed Critical Jubilant Organosys Limited
Priority to JP2009500003A priority Critical patent/JP2009530267A/ja
Priority to PCT/IN2006/000091 priority patent/WO2007105225A1/fr
Priority to EP06728410A priority patent/EP1994013A4/fr
Publication of WO2007105225A1 publication Critical patent/WO2007105225A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • 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
    • 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
    • A61P25/22—Anxiolytics

Definitions

  • This invention in general relates to an improved process for producing an atypical neuroleptic or antipsychotic agent. More particularly, this invention provides an improved, concise and industrially feasible process for producing thermally color stable and pure Form of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5] benzodiazepine (Olanzapine) and product thereof. Further the present invention also provides new hydrate and dihydrate forms of Olanzapine.
  • Olanzapine has antagonist activity at non- adrenergic alpha-receptors, D-I and D-2 receptors and 5 HT-2 receptor sites.
  • 2-Methyl-4-(4-methyl-l-piperazinyl)-10H- thieno[2,3-b][l ,5]benzodiazepine (Olanzapine) is an atypical neuroleptic agent that has better reported efficacy like relaxant and iolytic or anti-emetic properties, and few side effects than conventional neuroleptic agents. It is useful in the treatment of psychotic patients suffering from schizophrenia and mild anxiety states.
  • Olanzapine has many polymorphic forms including hydrates and solvates as disclosed in subsequent patents and publications.
  • US Patent No. 5,736,541 claims Form-II of
  • Olanzapine and discloses that the product obtained according to process described in
  • US Patent No. 5,229,382 is Olanzapine Form I.
  • Patent No. EP 0 733 634 Bl disclose solvates of Olanzapine in methanol, ethanol and isopropanol.
  • US Patent No. 6,020,487 and European Patent No. EP 0 831 098 Bl disclose dihydrate forms of olanzapine, selected from Dihydrate B, Dihydrate D and
  • Dihydrate E that may be used for the preparation of anhydrous olanzapine.
  • PCT applications WO 02/18390 and WO 03/097650 disclose the methods for preparation of polymorphic Form I of Olanzapine.
  • PCT application WO 02/18390 relates to a method for the preparation of hydrates of Olanzapine.
  • PCT application WO 03/097650 relates to the new mixed solvates of Olanzapine.
  • polymorphic Form I of Olanzapine is prepared by the conversion of hydrates and solvates of Olanzapine respectively.
  • Polymorphism can be influenced by controlling the conditions of obtaining a compound in solid form. These polymorphic forms are mainly distinguished on the basis of IR and X-Ray diffraction data.
  • the present invention provides an improved process, which overcomes the drawbacks of processes recited in prior arts.
  • the main aim of this invention is to provide new improved forms of Olanzapine and their preparation. '
  • the present invention provides an improved environment friendly process for producing a pure form of Olanzapine, by reacting 2-(2-aminoanilino)-5-methylthiophene-3-carbonitrile with N-methyl piperazine in conjunction with N-methyl piperazine acid salt in a one step reaction without ' employing any solvent, at a temperature of 90-138 0 C, preferably 110-125 0 C, wherein the ratio of 2-(2-aminoanilino)-5-methylthiophene-3-carbonitrile and N-methyl piperazine is more than 1 :4 weight by volume.
  • the present invention provides for an improved, industrially feasible and concise process for producing pure form of Olanzapine, by reacting 2-(2-aminoanilino)-5-methylthiophene-3-carbonitrile with N- methyl piperazine in conjunction with N-methyl piperazine acid salt in presence of a solvent.
  • the solvent can be selected from toluene, dimethylsulfoxide, n-butanol, methyl ethyl ketone, dimethyl formamide, or a mixture thereof.
  • the present invention provides an improved process for producing Olanzapine by condensing 4-amino-2-methyl-10H- thieno[2,3-b][l,5]benzodiazepine or its hydrochloride salt with N-methyl piperazine at 90 to 138 0 C without employing any solvent, wherein the ratio of 4-amino-2-methyl- 10H-lhieno[2,3-b][l,5]benzodiazepine and N-methyl piperazine is more than 1:4 weight by volume. It is surprisingly found that the absence of solvents lead to reduction in reaction time to 2-3 hours, as compared to 20 hours reported in prior art.
  • N-methylpiperazine acid salt is prepared in situ in the reaction mass or prepared separately and added to the reaction mass.
  • the present invention provides an improved process for obtaining a polymorphic Form I of Olanzapine by producing the crude Olanzapine according to the above-mentioned processes and crystallizing the same in a mixture of two or more solvents, wherein the solvents are selected from a group comprising acetonitrile, dichloromethane, diisopropylether, cyclohexane, hexane, t-butyl methyl ether and propionitrile.
  • the present invention provides an improved process for obtaining a polymorphic Form I of Olanzapine by producing the crude Olanzapine according to the above-mentioned process and crystallizing the same in a mixture of dichloromethane and diisopropylether or cyclohexane.
  • the present invention provides an improved process for obtaining a polymorphic Form I of Olanzapine by producing the crude Olanzapine according to the above-mentioned process and crystallizing the same in a mixture of dichloromethane and acetonitrile.
  • the form I is produced from crude Olanzapine, which is free from other polymorphic forms, prepared according to the above- mentioned processes, crystallizing the same in a mixture of two or more solvents as described above, further characterized by having stable colour upon storage at temperature of 4O 0 C and 75% relative humidity.
  • Fig. 1 is an X-ray powder diffraction pattern corresponding to Form I of Olanzapine.
  • Fig. 2 is an X-ray powder diffraction pattern corresponding to hydrate Olanzapine Form J 2 .
  • Fig. 3 is thermo gravimetric analysis thermogram of hydrate Olanzapine Form J 2 .
  • Fig. 4 is differential scanning calorimetry thermogram of hydrate Olanzapine Form J 2 .
  • Fig. 5 is an x-ray powder diffraction pattern corresponding 1 to dihydrate Form Ji of
  • Fig. 6 is differential scanning calorimetry thermogram of dihydrate Olanzapine Form ' J 1 .
  • the process disclosed in the present invention is performed without employing additional solvent, which leads to a less cumbersome workup, which is more suitable for large-scale manufacturing of pure Olanzapine. Further, the absence of solvents saves the cost in terms of raw material, since recovery of the solvent is not needed and therefore utility costs are also saved.
  • the process is environment friendly, as the vapors of solvents are not spread in the atmosphere.
  • N-Methylpiperazine acid salt can be prepared in situ or can be prepared separately and then added into the reaction mixture.
  • N-Methylpiperazine acid salt is prepared by the reaction of N-methylpiperazine with an acid in usual fashion. The acid used to prepare
  • N-methylpiperazine acid salt can be chosen from organic or inorganic acids.
  • the preferred organic acids can be formic acid, substituted or unsubstituted acetic acid e.g. acetic acid or trifluoroacetic acid, alkyl, aryl or aralkyl sulphonic acid e.g. methane sulphonic acid, p-toluene sulphonic acid, substituted or unsubstituted benzoic acid, etc.
  • the preferred inorganic acids are phosphoric acid, hydro halide acid e.g. hydrochloric acid, sulfuric acid, perchloric acid and lewis acids such as aluminium chloride.
  • the solvent does not play any role in the reaction and reaction proceeds well in absence of any solvent, but alternatively the reaction can be performed in presence of a solvent.
  • the solvent can be selected from toluene, dimethylsulfoxide, n-butanol, methyl ethyl ketone, dimethyl formamide, or a mixture thereof.
  • water miscible or water immiscible solvent is added followed by the addition of water.
  • water miscible solvents addition of water forms crude olanzapine directly
  • solvent is removed to obtain crude Olanzapine.
  • This crude Olanzapine is dried at ambient temperature and crystallized in different solvents or solvent systems to obtain different crystallized forms of Olanzapine, as desired.
  • the solvent used for the work up can be selected from chlorinated solvent, amidic solvent, ketonic solvent, ethereal solvent, ester solvent, etc. Few examples, but not limited are dimethylformamide, tetrahydrofuran, dioxane, acetone, acetonitrile, ethyl acetate or dichloromethane.
  • the stable Form I of Olanzapine is prepared by dissolving the crude Olanzapine in a mixture of two or more solvents, concentrating the reaction mixture, distilling the reaction mixture and removing the solvents up to 30- 50% by volume, cooling the resulting reaction mixture to a temperature in the range of 0-20 0 C, preferably 0-5 0 C, crystallizing the solid and, filtering the material and drying preferably at a temperature in the range of 45-5O 0 C under vacuum to obtain the crystallized Form I of Olanzapine.
  • the crystallized Form I obtained is highly pure (>99.6%) and colour stable upon storage at high temperature at 4O 0 C.
  • the solvents used in the above-mentioned process are selected from a group comprising acetonitrile, dichloromethane, diisopropylether, cyclohexane, hexane, t- butyl methyl ether and propionitrile.
  • the ratio of the two solvents in solvent mixture is preferably 1 : 1.
  • Crystalline stable Olanzapine Form I is characterized by their X-ray powder diffraction pattern. Thus the X-ray diffraction patterns of Olanzapine Forms are measured on a PANalytical X' Pert Pro diffractometer with Cu radiation and expressed in terms of 2 ⁇ , d-spacing and relative intensities.
  • Form I of Olanzapine is given in Figure 1 and is characterized by peaks at 8.9, 10.3, 10.7, 12.8, 14.2, 17.8, 18.3, 18.8, 19.2, 19.5, 20.7, 21 .0, 21.6, 23.2, 24.1, 25.4, 28.6 ⁇ 0.2 degrees 2 theta.
  • the Form I is having stable colour at all temperatures including the high temperature (4O 0 C) and high moisture condition or under stress conditions.
  • the stable Form I is also produced when Olanzapine is crystallized directly from the reaction mixture using the same conditions as described above.
  • the crude Olanzapine is prepared either by any prior art method or by condensing 2-(2 aminoanilino)-5-methylthiophene-3-carbonitrile with N-methyl acid piperazine in conjunction with N-methylpiperazine salt in absence of any solvent at a temperature of
  • Table 1 shows the stability of Olanzapine Form I at stressed conditions upto 6 months (4O 0 C) wherein the HPLC purity, total impurity and colour is given (UV absorbance at 430 nm). The data clearly shows that olanzapine is having high stability for three months under stressed conditions.
  • the colour of Olanzapine is determined by following method:
  • the Table- 1 shows that the Form I thus produced is highly stable at stress conditions. Thus it is highly suitable for use in formulation.
  • the new polymorph of Olanzapine dihydrate Form Ji is prepared by a process comprising dissolving the Olanzapine in the mixture of water and ethyl acetate and stirring the mixture at room temperature, heating the reaction mixture gradually preferably at a temperature in the range of 75-8O 0 C to obtain a clear solution, stirring the solution preferably at a temperature in the range of 75-8O 0 C for a period in the range of 0.5-2.0 hours preferably for a period in the range of 15-30 minutes, cooling the solution to a temperature in the range of 0-30 0 C, preferably 0-5 0 C for a period in the range of 0.5 to 2 hours and filtering the material and suck drying to obtain a new polymorphic Form J 1 .
  • Form J] of Olanzapine is characterized by X-ray powder diffraction pattern and Differential Scanning Calorimetry. DSC thermogram is recorded on DSCQlOO equilibrated at 25 0 C to 35O 0 C at 10°C/minute with nitrogen flow rate of 60 ml/minute.
  • the reference X-Ray powder diffraction and DSC thermogram analyses are attached herein as Figure 5 and 6.
  • the XRD has characteristic peaks at about 8.9,18.4 ⁇ 0.2 degrees two theta and at about 16.2, 20.3, 21.1, 22.2, 22.6, 23.0, 23.5, 24.1,24.3+ 0.2 degrees two theta.
  • the new polymorphic Form Ji contains the moisture content of about 10.5% according to Karl Fisher analysis and ethyl acetate approximately 0.7%.
  • the obtained new polymorphic Form Ji is used for preparing said Form I of Olanzapine, the process comprising, contacting a new polymorphic Form Ji with cyclohexane/dichloromethane at room temperature, refluxing the reaction mixture, removing the water from material by azeotropic distillation, filtering the material and separating the solid mass, dissolving this solid mass in dichloromethane, cooling and stirring the resulting mixture to a temperature in the range of 0-5 0 C for a period in the range of 0.5-2 hours, filtering the mixture and sucking dry/drying the solid mass under vacuum at a temperature in the range of 30-35 0 C to obtain stable.
  • Form I which is further characterized in that having stable colour upon storage at high temperature at 4O 0 C and 75%.
  • the disclosed new hydrate Olanzapine Form J 2 is prepared by a process comprising exposing the Olanzapine Form I in an open flask, further exposing the material to humidity conditions for more than 24 hours, controlling the humidity conditions, absorbing the water by material, which gives a new hydrate Form J 2 of Olanzapine, drying of hydrate Olanzapine Form J 2 at 45-55 0 C under vacuum Io get Olanzapine Form I which is confirmed by XRD, DSC and TGA.
  • the hydrate Form J 2 of Olanzapine is characterized by X-ray powder diffraction pattern (PXRD), Thermo Gravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC).
  • PXRD X-ray powder diffraction pattern
  • TGA Thermo Gravimetric Analysis
  • DSC Differential Scanning Calorimetry
  • the XRD has characteristic peaks at about 8.79, 8.9, 10.7, 12.8, 18.3, 18.5, 18.7, 19.1, 19.5, 20.7, 20.9, 21.6, 21.7, 23.5, 23.6, 24.0, 25.3 ⁇ 0.2 degrees two theta.
  • the other characteristic peaks are 16.1, 22.5 + 0.2 degrees two theta.
  • TGA thermogram is recorded on TGA Q 50 with a ramp of 10°C/min to 200 0 C with nitrogen flow rate at 60 ml/minute.
  • the hydration level of hydrate Olanzapine Form J 2 is indicated by a weight loss of 1 .108% at about 100 0 C by TGA.
  • DSC thermogram is recorded on DSCQlOO equilibrated at 25 0 C to 28O 0 C at ramplO°C/minute with nitrogen flow rate at 60 ml/minute.
  • a typical DSC scan of hydrate Olanzapine Form J 2 shows an endothermic peak at about 60°-80° due mainly to water, and a subsequent endotherm at about at 196.4°C with a small endotherm peak also at 182.9°C.
  • the moisture content of this hydrate form is about 1.2-3.0%, measured by Karl Fisher technique.
  • the reaction mixture was heated at 12O 0 C until the reaction was complete.
  • the reaction mass was cooled to 70-75 0 C and acetone and activated charcoal were added.
  • the reaction mixture was stirred for 30 minutes and filtered.
  • the water was added at 45-
  • the crude Olanzapine was dissolved in a mixture of dichloromethane (5 times) and diisopropylether or cyclohexane (5 times). The solution was cooled to give solid.
  • Form JT Hydrate Form JT (5 g) was dried in oven under vacuum at 45-5O 0 C to give Form I.
  • XRD, DSC and TGA matched with Form I.
  • Olanzapine (10 g) was taken in 100 ml ethyl acetate (m/c-3.8%) and stirred at room temperature. The contents of the flask were gradually heated to 75-8O 0 C to obtain a clear solution and then stirred for 15 minutes at 75-8O 0 C. The reaction mixture was cooled to 0-5 0 C. The reaction mixture was stirred for one hour at 0-4 0 C. The solid U product was filtered and suck dried to give a new polymorphic Form Ji having moisture content 10.5%. The percentage of ethyl acetate in the Form Ji is approximately 0.7%.
  • Tlic new Form Ji (10 g) was taken in dichloromethane (150 ml) in 250 ml round bottom Flask. Water from material was removed by azeotropic distillation to give a residue. Dichloromethane (50 ml.) was added. The flask was allowed to cool to 0-5 0 C and stirred the residue for one hour at same temperature. The solid was separated. The solid product was filtered and dried under vacuum at 3O 0 C to give Form I.

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Abstract

La présente invention concerne un procédé amélioré de production de la forme I cristalline pure et de coloration thermiquement stable de la 2-méthyl-4-(4-méthyl-1-pipérazinyl)-10H-thiéno[2,3-b][1,5]benzodiazépine ainsi que le produit dudit procédé. Le procédé comprend la réaction du 2-(2-aminoanilino)-5-méthylthiophène-3-carbonitrile avec la N-méthylpipérazine en conjonction avec un sel acide de N-méthylpipérazine pour obtenir la 2-méthyl-4-(4-méthyl-1-pipérazinyl)-10H-thiéno[2,3-b][1,5]benzodiazépine. La présente invention concerne également un procédé d'obtention de la forme I polymorphique de la 2-méthyl-4-(4-méthyl-1-pipérazinyl)-10H-thiéno[2,3-b][1,5]benzodiazépine par cristallisation de la 2-méthyl-4-(4-méthyl-1-pipérazinyl)-10H-thiéno[2,3-b][1,5]benzodiazépine brute dans un mélange de solvants. La présente invention concerne en outre une nouvelle forme polymorphique de l'Olanzapine, la forme J1 dihydrate, ainsi qu'un procédé de synthèse de ladite forme et la nouvelle forme J2 hydrate de l'Olanzapine, de teneur en eau comprise entre 1 et 3 %, ainsi qu'un procédé de synthèse de ladite forme.
PCT/IN2006/000091 2006-03-14 2006-03-14 PROCÉDÉ DE PRODUCTION D'UNE FORME PURE ET STABLE DE 2-MÉTHYL-4-(4- MÉTHYL-1-PIPÉRAZINYL)-10H-THIÉNO[2,3-b][1,5]BENZODIAZÉPINE WO2007105225A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2009500003A JP2009530267A (ja) 2006-03-14 2006-03-14 ２−メチル−４−（４−メチル−１−ピペラジニル）−１０Ｈ−チエノ［２，３−ｂ］［１，５］ベンゾジアゼピンの純粋かつ安定な形態の製造方法
PCT/IN2006/000091 WO2007105225A1 (fr) 2006-03-14 2006-03-14 PROCÉDÉ DE PRODUCTION D'UNE FORME PURE ET STABLE DE 2-MÉTHYL-4-(4- MÉTHYL-1-PIPÉRAZINYL)-10H-THIÉNO[2,3-b][1,5]BENZODIAZÉPINE
EP06728410A EP1994013A4 (fr) 2006-03-14 2006-03-14 PROCÉDÉ DE PRODUCTION D'UNE FORME PURE ET STABLE DE 2-MÉTHYL-4-(4- MÉTHYL-1-PIPÉRAZINYL)-10H-THIÉNO[2,3-b] [1,5]BENZODIAZÉPINE

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PCT/IN2006/000091 WO2007105225A1 (fr) 2006-03-14 2006-03-14 PROCÉDÉ DE PRODUCTION D'UNE FORME PURE ET STABLE DE 2-MÉTHYL-4-(4- MÉTHYL-1-PIPÉRAZINYL)-10H-THIÉNO[2,3-b][1,5]BENZODIAZÉPINE

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8106188B2 (en) 2006-06-01 2012-01-31 Aurobindo Pharma Ltd Process for preparing olanzapine form I
CN103145731A (zh) * 2013-02-26 2013-06-12 江苏豪森药业股份有限公司 奥氮平晶型及其制备方法和用途

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014073989A1 (fr) * 2012-11-12 2014-05-15 Callaghan Innovation Research Limited Formes de sel et formes polymorphes de (3r,4s)-1-((4-amino-5h-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-4-(methylthiomethyl)pyrrolidin-3-ol (mtdia)
JP6008734B2 (ja) * 2012-12-20 2016-10-19 株式会社トクヤマ オランザピンｉｉ型結晶の製造方法

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US20040198721A1 (en) * 2002-12-24 2004-10-07 Dolitzky Ben Zion Novel crystal forms, methods for their preparation and method for preparation of olanzapine
US6906062B2 (en) * 2001-12-24 2005-06-14 Sun Pharmaceutical Industries Limited Crystalline form I of 2-methyl-4-(4-menthyl-1-piperazinyl) 10H thieno [2,3-b][1,5]benzodiazepine

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US8044196B2 (en) * 2004-07-14 2011-10-25 Jubilant Organosys Limited Process for producing pure form of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine

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US6906062B2 (en) * 2001-12-24 2005-06-14 Sun Pharmaceutical Industries Limited Crystalline form I of 2-methyl-4-(4-menthyl-1-piperazinyl) 10H thieno [2,3-b][1,5]benzodiazepine
US20040198721A1 (en) * 2002-12-24 2004-10-07 Dolitzky Ben Zion Novel crystal forms, methods for their preparation and method for preparation of olanzapine

Non-Patent Citations (2)

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Title
REUTZEL-EDENS S.M. ET AL.: "Anhydrates and Hydrates of Olanzapine: Crystallization, Solid-State Characterization, and Structural Relationships", CRYSTAL GROWTH & DESIGN, vol. 3, no. 6, November 2003 (2003-11-01), pages 897 - 907, XP002277177 *
See also references of EP1994013A4 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8106188B2 (en) 2006-06-01 2012-01-31 Aurobindo Pharma Ltd Process for preparing olanzapine form I
CN103145731A (zh) * 2013-02-26 2013-06-12 江苏豪森药业股份有限公司 奥氮平晶型及其制备方法和用途
CN103145731B (zh) * 2013-02-26 2014-02-19 江苏豪森药业股份有限公司 奥氮平晶型及其制备方法和用途

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