WO2003091260A1 - Nouvelle forme vi polymorphe cristalline d'olanzapine et procede de preparation - Google Patents

Nouvelle forme vi polymorphe cristalline d'olanzapine et procede de preparation Download PDF

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Publication number
WO2003091260A1
WO2003091260A1 PCT/US2003/012414 US0312414W WO03091260A1 WO 2003091260 A1 WO2003091260 A1 WO 2003091260A1 US 0312414 W US0312414 W US 0312414W WO 03091260 A1 WO03091260 A1 WO 03091260A1
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WO
WIPO (PCT)
Prior art keywords
olanzapine
methyl
crystalline
polymoφh
thieno
Prior art date
Application number
PCT/US2003/012414
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English (en)
Other versions
WO2003091260A9 (fr
Inventor
Buchi Reddy Reguri
Ramesh Chakka
Original Assignee
Dr. Reddy's Laboratories Limited
Cord, Janet, I.
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, Cord, Janet, I. filed Critical Dr. Reddy's Laboratories Limited
Priority to AU2003243153A priority Critical patent/AU2003243153A1/en
Priority to US10/509,473 priority patent/US20050153954A1/en
Publication of WO2003091260A1 publication Critical patent/WO2003091260A1/fr
Publication of WO2003091260A9 publication Critical patent/WO2003091260A9/fr

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    • 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
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention also relates to compositions made using the crystalline form of 2-methyl-4-(4- methyl-piperazinyl)-10H-thieno[2,3-b][l,5] benzodiazepine and the use of crystalline form and compositions made using the crystalline form for the treatment of disorders of the central nervous system, for treating psychotic patients and mild anxiety.
  • U.S. 5,229,382 discloses the preparation of Olanzapine and its acid addition salts, having pharmaceutical properties, particularly in the treatment of disorders of the central nervous system.
  • the patent does not refer to any specific polymorphic crystalline forms of Olanzapine.
  • the patent also states that the product obtained according to the process described in U.S. 5,229,382 as Olanzapine Form-I.
  • EP 0 733 635 Al discloses the d values for Form-1 and Form-2 from their X-ray Diffractograms.
  • the d values are as follows: d value d value
  • EP 831098B1 discloses Olanzapine Form-II as the most stable anhydrous form of Olanzapine, providing a stable anhydrous formulation with pharmaceutically desired characteristics.
  • the patent further discloses that substantially pure Olanzapine Form-II, which can be prepared using an Olanzapine dehydrate.
  • the patent discloses the preparation of a series of dihydrates of Olanzapine namely Dehydrate B, Dehydrate D and Dehydrate E characterized by their XRD pattern which serve as intermediates for the preparation of Olanzapine Form-II.
  • U.S. 6,348,458 Bl discloses the preparation of a series of crystalline polymorphic forms of Olanzapine namely Form-Ill, Form-IV and Form-V.
  • the d values for these forms from their X-Ray Diffractograms are also incorporated in the patent and are mentioned in the following Table- 1.
  • WO 02/18390 discloses Olanzapine monohydrate I and Olanzapine dehydrate I and process for making these compounds.
  • the novel crystalline polymorphic form of Olanzapine of the present invention is well distinguished from the crystalline polymorphic forms reported in the prior art and conveniently herein after, designated as Polymorph Form- VI of Olanzapine.
  • present invention provides a novel crystalline polymorph Form- VI of Olanzapine and the present invention also embodies the process for the preparation of crystalline polymorph Form- VI of Olanzapine, more specifically the present invention is related to conversion of Polymorph Form-I of Olanzapine to novel crystalline polymo ⁇ h Form- VI of Olanzapine.
  • the invention also relates to provide the process for the preparation of crystalline polymorph Form- VI of Olanzapine, which comprises stirring of polymorph Form-I of Olanzapine in a C,-C 6 alkanol to obtain the novel crystalline polymo ⁇ h Form- VI of Olanzapine.
  • the process of the present invention is eco friendly and well suited for industrial scale up.
  • Fig. 1 is an X-ray powder diffractogram of the Form VI obtained in the present invention.
  • Fig. 2 is a DSC thermogram of the Form VI obtained in the present invention.
  • Fig. 3 is an infrared abso ⁇ tion spectrum of the Form VI obtained in the present invention.
  • the present invention provides novel crystalline polymo ⁇ h Form- VI of Olanzapine and a process for the preparation thereof.
  • Crystalline nature of polymo ⁇ h Form- VI of Olanzapine can be characterized by its X-ray diffractogram, Infrared spectrum and Differential scanning calorimetry thermogram.
  • the X-ray powder diffraction pattern of crystalline polymo ⁇ h Form-VI of Olanzapine was measured on a Rigaku D/Max 2200 Powder Diffractometer with Cu Radiation source.
  • the Crystalline polymo ⁇ h Form- VI of Olanzapine has X-ray powder diffraction pattern essentially as shown in the Table-2.
  • the X-ray powder diffraction pattern is expressed in the terms of its d values, and percentage intensity (in %).
  • the present invention of crystalline polymo ⁇ h Form- VI of Olanzapine is characterized by its X-ray powder diffraction as depicted in Figure (1).
  • the present invention also provides Differential Scanning Calonmetry thermogram of crystalline polymo ⁇ h Form- VI of Olanzapine.
  • the Differential Scanning Calonmetry thermogram of crystalline polymo ⁇ h Form- VI of Olanzapine also provides Differential Scanning Calonmetry thermogram of crystalline polymo ⁇ h Form- VI of Olanzapine.
  • Calorimetry thermogram exhibits a significant endo peak around 196°C and as depicted in Figure (2).
  • the present invention further provides the Infrared data for crystalline polymo ⁇ h Form- VI of Olanzapine, which was measured by KBr-transmission method with identified significant peaks around 3217 cm “1 , 2933 cm “1 , 1592 cm “1 , 1561 cm “1 , 1468 cm “1 , 1369 cm “1 , 1218 cm “1 , 1143 cm “1 , 1007 cm “1 , 964 cm “1 , 751 cm “1 and 674 cm “1 .
  • the present invention provides the IR spectrum of crystalline polymo ⁇ h Form- VI of Olanzapine as depicted in Figure (3).
  • the present invention provides novel crystalline polymo ⁇ hic Form- VI of 2-methyl-4- (4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5] benzodiazepine
  • the alkanol is n-butanol or tert.butanol. More preferably the alkanol is n-butanol.
  • the solid obtained in step 2) is isolated by filtering, decanting or centrifuging.
  • the present invention therefore provides novel Olanzapine Form- VI and a simple method for its preparation.
  • the invention likewise relates to the use of novel crystalline of 2-methyl-4-(4- methyl-piperazinyl)-10H-thieno[2,3-b][l,5] benzodiazepine useful in the treatment of disorders of the central nervous system, for treating psychotic patients or mild anxiety. It can be used to prepare pharmaceutically acceptable preparations, in a method for the prophylactic and/or therapeutic treatment of an animal or human.
  • the invention likewise relates to pharmaceutical preparations made using the novel crystalline of 2-methyl-4-(4- methyl-piperazinyl)-10H-thieno[2,3-b][l,5] benzodiazepine and to processes for their preparation.
  • the pharmaceutical preparations according to the invention which contain the compound according to the invention are those for enteral, such as oral, furthermore rectal, and parenteral administration to (a) warm-blooded animal(s), the pharmacological active ingredient being present on its own or together with a pharmaceutically acceptable carrier.
  • the daily dose of the active ingredient depends on the age and the individual condition and also on the manner of administration.
  • the novel pharmaceutical preparations contain, for example, from about
  • compositions are formulated in unit dosage form, each dosage containing from 0.1 mg to 20 mg or 0.5 to 10 mg of the 2-methyl-4-(4- methyl-piperazinyl)-10H-thieno[2,3-b][l,5] benzodiazepine.
  • compositions of this invention can contain and or comprise a therapeutically effective amount of the 2-methyl-4-(4- methyl-piperazinyl)- 10H-thieno[2,3-b][l,5] benzodiazepine made from the novel crystalline form of this invention, together with one or more inorganic or organic, solid or liquid, pharmaceutically acceptable carriers, diluents, excipients, additives, fillers, lubricants, binders, stabilizers, solvents or solvates.
  • the compositions may be in the form of a tablet, capsule, lozenge, powder, syrup, solution, suspension, ointment or dragee.
  • compositions may be sterilized and or may comprise of one or more excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating the osmotic pressure and/or buffers.
  • excipients for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating the osmotic pressure and/or buffers.
  • Pharmaceutical preparations according to the invention for enteral or parenteral administration are, for example, those in unit dose forms, such as sugar-coated tablets, tablets, capsules or suppositories, and furthermore ampoules. These are prepared in a manner known per se, for example by means of conventional mixing, granulating, sugar-coating, dissolving or lyophihzing processes.
  • compositions for oral use can be obtained by combining the active ingredient with solid carriers, if desired granulating a mixture obtained, and processing the mixture or granules, if desired or necessary, after addition of suitable excipients to give tablets or sugar-coated tablet cores.
  • Suitable carriers are, in particular, fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, furthermore binders, such as starch paste, using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and/or polyvinylpyrrolidone, if desired, disintegrants, such as the above mentioned starches, furthermore carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate; auxiliaries are primarily glidants, flow-regulators and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol.
  • fillers such as sugars, for example lactose, suc
  • Sugar-coated tablet cores are provided with suitable coatings which, if desired, are resistant to gastric juice, using, inter alia, concentrated sugar solutions which, if desired, contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, coating solutions in suitable organic solvents or solvent mixtures or, for the preparation of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.
  • Colorants or pigments may be added to the tablets or sugar-coated tablet coatings.
  • Other orally utilizable pharmaceutical preparations are hard gelatin capsules, and also soft closed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the hard gelatin capsules may contain the active ingredient in the form of granules, for example in a mixture with fillers, such as lactose, binders, such as starches, and/or lubricants, such as talc or magnesium stearate, and, if desired, stabilizers.
  • the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, it also being possible to add stabilizers.
  • Suitable rectally utilizable pharmaceutical preparations are, for example, suppositories, which consist of a combination of the active ingredient with a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
  • gelatin rectal capsules which contain a combination of the active ingredient with a base substance may also be used.
  • Suitable base substances are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.
  • Suitable preparations for parenteral administration are primarily aqueous solutions of an active ingredient in water-soluble form, for example a water-soluble salt, and furthermore suspensions of the active ingredient, such as appropriate oily injection suspensions, using suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, or aqueous injection suspensions which contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if necessary, also stabilizers.
  • suitable lipophilic solvents or vehicles such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides
  • viscosity-increasing substances for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if necessary, also stabilizers.
  • the dose of the active ingredient depends on the warm-blooded animal species, the age and the individual condition and on the manner of administration. In the normal case, an approximate daily dose of about 10 mg to about 350 mg is to be estimated in the case of oral administration for a patient weighing approximately 75 kg.
  • the preferred daily dose is between 0.1 mg to 1000 mg per kilogram, preferably between 1 mg to 100 mg daily for warm-blooded species. More, preferably, between 1 mg to 40 mg daily.
  • Fig. 1 is a characteristic X-ray powder diffraction pattern of novel crystalline-polymo ⁇ h Form- VI of Olanzapine.
  • Fig. 2 is a characteristic Differential Scanning Calorimetric thermogram of novel crystalline polymo ⁇ h of Form- VI of Olanzapine.
  • Vertical axis Temperature (in °C);
  • Horizontal axis Signal (in mV).
  • the Differential Scanning Calorimetric Thermogram exhibits a significant endo peak at 196°C.
  • Fig. 3 is a characteristic infrared abso ⁇ tion spectrum in potassium bromide of Olanzapine Form- VI. [Vertical axis, Transmission (%); Horizontal axis: Wave number (cm "1 )].
  • EXAMPLE 1 A mixture of polymo ⁇ h Form- 1 of Olanzapine (10.0 g) and n-butanol (30 ml) was stirred at a temperature of 25 - 30° C for 1-2 hours. Further the compound was filtered, washed with n-butanol (5.0 ml) and dried at a temperature of 60 - 70°C to a constant weight to render the desired crystalline polymo ⁇ h Form- VI of Olanzapine. (Yield: 7.1 grams, 71.0%).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

L'invention concerne une nouvelle forme cristalline de 2-méthyl-4-(4-méthyl-pipérazinyl)-10H-thieno[2,3-b][1,5] benzodiazépine, et un procédé de préparation de ladite forme cristalline. La méthyl-4-(4-méthyl-1-pipérazinyl)-10H-thieno[2,3-b][1,5] benzodiazépine (Olanzapine) selon l'invention est représentée par la structure (I).
PCT/US2003/012414 2002-04-23 2003-04-22 Nouvelle forme vi polymorphe cristalline d'olanzapine et procede de preparation WO2003091260A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2003243153A AU2003243153A1 (en) 2002-04-23 2003-04-22 Novel crystalline polymorph form-vi of olanzapine and a process for preparation thereof
US10/509,473 US20050153954A1 (en) 2002-04-23 2003-04-22 Novel crystalline polymorph form-vi of olanzapine and a process for preparation thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN311/MAS/2002 2002-04-23
IN311CH2002 2002-04-23

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WO2003091260A1 true WO2003091260A1 (fr) 2003-11-06
WO2003091260A9 WO2003091260A9 (fr) 2004-06-03

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004058773A1 (fr) * 2002-12-24 2004-07-15 Teva Pharmaceutical Industries Ltd. Nouvelles formes cristallines d'olanzapine, procedes pour les preparer et procede pour preparer des formes cristallines d'olanzapine connues
US7329747B2 (en) 2004-01-27 2008-02-12 Synthon Ip Inc. Synthesis of olanzapine and intermediates thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0831098A2 (fr) * 1996-09-23 1998-03-25 Eli Lilly And Company Produits intermédiaires et procédé pour la préparation d'olanzapine
US6348458B1 (en) * 1999-12-28 2002-02-19 U & I Pharmaceuticals Ltd. Polymorphic forms of olanzapine
WO2002018390A1 (fr) * 2000-08-31 2002-03-07 Dr. Reddy's Laboratories Ltd. Procede de preparation d'hydrates d'olanzapine et de conversion de ceux-ci en formes cristallines d'olanzapine
WO2002060906A2 (fr) * 2001-01-04 2002-08-08 Geneva Pharmaceuticals, Inc. Modification de cristaux

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0831098A2 (fr) * 1996-09-23 1998-03-25 Eli Lilly And Company Produits intermédiaires et procédé pour la préparation d'olanzapine
US6348458B1 (en) * 1999-12-28 2002-02-19 U & I Pharmaceuticals Ltd. Polymorphic forms of olanzapine
WO2002018390A1 (fr) * 2000-08-31 2002-03-07 Dr. Reddy's Laboratories Ltd. Procede de preparation d'hydrates d'olanzapine et de conversion de ceux-ci en formes cristallines d'olanzapine
WO2002060906A2 (fr) * 2001-01-04 2002-08-08 Geneva Pharmaceuticals, Inc. Modification de cristaux

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004058773A1 (fr) * 2002-12-24 2004-07-15 Teva Pharmaceutical Industries Ltd. Nouvelles formes cristallines d'olanzapine, procedes pour les preparer et procede pour preparer des formes cristallines d'olanzapine connues
US7323459B2 (en) 2002-12-24 2008-01-29 Teva Pharmaceutical Industries Ltd. Crystal forms, methods for their preparation and method for preparation of olanzapine
US7329747B2 (en) 2004-01-27 2008-02-12 Synthon Ip Inc. Synthesis of olanzapine and intermediates thereof
US7459449B2 (en) 2004-01-27 2008-12-02 Rolf Keltjens Stable salts of olanzapine

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AU2003243153A8 (en) 2003-11-10
AU2003243153A1 (en) 2003-11-10
WO2003091260A9 (fr) 2004-06-03

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