EP1440074A1 - Olanzapine dihydrate-ii a process for its preparation and use thereof - Google Patents

Olanzapine dihydrate-ii a process for its preparation and use thereof

Info

Publication number
EP1440074A1
EP1440074A1 EP02778677A EP02778677A EP1440074A1 EP 1440074 A1 EP1440074 A1 EP 1440074A1 EP 02778677 A EP02778677 A EP 02778677A EP 02778677 A EP02778677 A EP 02778677A EP 1440074 A1 EP1440074 A1 EP 1440074A1
Authority
EP
European Patent Office
Prior art keywords
olanzapine
dihydrate
olanzapine dihydrate
product
methyl
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP02778677A
Other languages
German (de)
French (fr)
Inventor
Janet I. Cord
Reguri Buchi Reddy
Chakka Ramesh
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dr Reddys Laboratories Ltd
Original Assignee
Dr Reddys Laboratories Ltd
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 Reddys Laboratories Ltd filed Critical Dr Reddys Laboratories Ltd
Publication of EP1440074A1 publication Critical patent/EP1440074A1/en
Withdrawn legal-status Critical Current

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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

Definitions

  • the present invention relates to novel dihydrate form of 2-methyl-4-(4- metl ⁇ yl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine (hereinafter referred to as Olanzapine dihydrate-II), a process for its preparation and its conversion to Olanzapine Form-II.
  • the present invention also relates to compositions containing Olanzapine dihydrate II and the use of Olanzapine dihydrate II and compositions containing Olanzapine dihydrate II for treating disorders of the central nervous system.
  • Olanzapine is represented by the following structure:
  • Olanzapine is useful for treating psychotic patients and patients with mild-anxiety states.
  • Preparation of Olanzapine and its acid addition salts, having pharmaceutical properties, particularly in the treatment of disorders of the central nervous system is disclosed in U.S. 5,229,382.
  • EP 733635B1 discloses Olanzapine Form-II and designates the product obtained according to the process described in U.S. 5,229,382 as Olanzapine Form-I characterizing both Form-I and Form-II with their XRD patterns.
  • 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 dihydrate.
  • the patent discloses the preparation of a series of dihydrates of Olanzapine namely Dihydrate B, Dihydrate D and Dihydrate E characterized by their XRD pattern which serve as intermediates for the preparation of Olanzapine Form-II.
  • the present invention hence provides a novel Olanzapine dihydrate-II, which is useful in the preparation of Olanzapine Form-II.
  • the Olanzapine dihydrate-II is prepared using an eco-friendly process. Conversion of Olanzapine dihydrate-II to Olanzapine Form-II, is specially advantageous since the novel Olanzapine dihydrate-II is prepared in water and subsequently dried to provide Olanzapine Form-II, thus providing assurance that the Form-II material is substantially free from all organic solvent residues.
  • the present invention is directed to novel Olanzapine dihydrate-II.
  • the present invention further provides an eco-friendly and a commercially viable process for the preparation of novel Olanzapine dihydrate-II, comprising stirring Olanzapine form-I with water, followed by filtration and drying to afford the novel Olanzapine dihydrate -II.
  • the present invention also provides a process for the conversion of novel Olanzapine dihydrate-II to Olanzapine Form-II comprising further drying of Olanzapine dihydrate-II to constant weight, thereby yielding Olanzapine Form-II.
  • the present invention also provides for the use of Olanzapine dihydrate- II for treating disorders of the central nervous system and for the use of Olanzapine dihydrate-II in compositions.
  • Fig 1 is an X Ray Powder Diffractogram of novel Olanzapine dihydrate- II.
  • Fig 2 is an Infrared Absorption Spectrum of Olanzapine dihydrate-II.
  • Fig 3 is a Differential Scanning Calorimetry Thermogram of Olanzapine dihydrate-II.
  • Fig 4 is an X Ray Powder Diffractogram of Olanzapine Form-II obtained from novel Olanzapine dihydrate —II. Detailed Description Of The Invention
  • the Olanzapine dihydrate-II of the present invention can be prepared by the treatment of Form I of 2-methyl-4-(4-methyl-l- ⁇ iperazinyl)-10H-thieno[2,3- b][l,5]benzodiazepine i.e. Olanzapine Form-I with water by stirring at 25 - 35°C for 72 to 120 hours. Subsequent filtration and drying the product renders the desired Olanzapine dihydrate-II. The drying can be achieved under vacuum at 25-50°C for 1 - 2 hours, in an oven at 60-70°C for 1-2 hours, or air-drying at ambient temperature for 5- 24 hours.
  • This isolated Olanzapine dihydrate-II on further drying in oven at 60-70°C, to constant weight, renders Olanzapine Form-II.
  • the novel Olanzapine dihydrate-II of the present invention is well distinguished from the crystal modifications reported in the prior art.
  • Form-I used in the preparation of Olanzapine dihydrate-II can be prepared as per the process disclosed in U.S. 5,229,382, Indian Patent Application No. 709/MAS/2000 or PCT Application No. WO 02/18390A1, the subject matter of which is incorporated herein by reference.
  • Olanzapine dihydrate II can be used as a drug and in compositions, including compositions that can be administered to mammals including humans.
  • Pharmaceutical compositions of this invention can contain and/or comprise a therapeutically effective amount of the active ingredient, together with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers or excipients, which are suitable for enteral, for example oral, parenteral or topical administration.
  • the pharmaceutical 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.
  • compositions are formulated in unit dosage form, each dosage containing from 0.1 mg to 20 mg or 0.5 to 10 mg of active ingredient.
  • the dosage of Olanzapine dihydrate II depends on various factors, such as method of administration, species, age and/or individual condition.
  • the doses to be administered daily are between 0.5 mg and about 100 mg, preferably between 1 mg to
  • compositions of this invention can be used to treat disorders of the central nervous system including schizophrenia and psychosis.
  • Olanzapine Form-I (25.0 g) and water (125 ml) were stirred at 25 - 30°C for 120 hours. It was then filtered and dried under vacuum at 32 - 44°C for about 1-2 hours to render the desired Olanzapine dihydrate - II.
  • the Olanzapine dihydrate-II (5.0g) obtained as per Example 1 is dried in oven at 60-70°C to constant weight rendering Form II of Olanzapine.
  • TGA 0.310%.
  • Olanzapine Form-I (25.0 g) and water (125 ml) were stirred at 25 - 30°C for 120 hours.
  • the remaining part was air dried for about 6-7 hours at ambient temperature, to render the desired Olanzapine dihydrate - H.
  • Fig. 1 is a characteristic X-Ray powder diffraction pattern of Olanzapine dihydrate-II (Vertical axis: Intensity (CPS); Horizontal axis: Two Theta (degrees). The significant d values obtained are 9.9949, 9.5838, 9.4007, 7.6884, 7.4184, 5.2052, 4.9678, 4.8756, 4.7767, 4.4271, 4.3881, 4.3414, 4.2752, 4.1145, 3.7762 and 3.3682.
  • Fig. 2 is a characteristic infrared absorption spectrum in potassium bromide of Olanzapine dihydrate-II [Vertical axis, Transmission (%); Horizontal axis:
  • Fig. 3 is a characteristic of differential scanning calorimetry thermogram of Olanzapine dihydrate-II. Vertical axis ' : mW; Horizontal axis: Temperature (°C). The
  • DSC thermogram exhibits a significant endo - endo pattern at 69.50-195.38°C, which is characteristic of Olanzapine dihydrate-II.
  • the heating rate is 5°C/minute.
  • Fig 4 is an X ray powder diffractogram of Olanzapine Form-II obtained from novel Olanzapine dihydrate - II.
  • Vertical axis Intensity (CPS); Horizontal axis: Two Theta (degrees).
  • the significant d values obtained are 10.3696, 8.6314, 7.1668, 5.2296, 4.7869, 4.4937, 4.2468, 4.1526, 4.0046, 3.7324 and 3.5449.
  • the present invention therefore provides novel Olanzapine dihydrate-II and a process for the preparation thereof.
  • the novel Olanzapine dihydrate-II of the present invention is an important intermediate for the preparation of Olanzapine Form- II, which is disclosed as the most stable anhydrous form of Olanzapine, providing a stable anhydrous formulation with pharmaceutically desired characteristics.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to novel dihydrate form of 2-methyl-4-(4-methyl-1-piperazinyl)-10Hthieno[2,3-b][1,5]benzodiazepine (hereinafter referred to as Olanzapine dihydrate-II), a process for its preparation and its conversation to Olanzapine Form-II. The present invention also relates to compositions containing Olanzapine dihydrate II and the use of Olanzapine dihydrate II and compositions containing Olanzapine dihydrate II for treating disorders of the central nervous system.

Description

OLANZAPINE DIHYDRATE-II A PROCESS FOR ITS PREPARATION AND USE HEREOF
Field of Invention The present invention relates to novel dihydrate form of 2-methyl-4-(4- metlιyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine (hereinafter referred to as Olanzapine dihydrate-II), a process for its preparation and its conversion to Olanzapine Form-II. The present invention also relates to compositions containing Olanzapine dihydrate II and the use of Olanzapine dihydrate II and compositions containing Olanzapine dihydrate II for treating disorders of the central nervous system. Background of Invention
Olanzapine is represented by the following structure:
Olanzapine is useful for treating psychotic patients and patients with mild-anxiety states. Preparation of Olanzapine and its acid addition salts, having pharmaceutical properties, particularly in the treatment of disorders of the central nervous system is disclosed in U.S. 5,229,382.
EP 733635B1 discloses Olanzapine Form-II and designates the product obtained according to the process described in U.S. 5,229,382 as Olanzapine Form-I characterizing both Form-I and Form-II with their XRD patterns. 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 dihydrate. In addition to this, the patent discloses the preparation of a series of dihydrates of Olanzapine namely Dihydrate B, Dihydrate D and Dihydrate E characterized by their XRD pattern which serve as intermediates for the preparation of Olanzapine Form-II.
The present invention hence provides a novel Olanzapine dihydrate-II, which is useful in the preparation of Olanzapine Form-II. The Olanzapine dihydrate-II is prepared using an eco-friendly process. Conversion of Olanzapine dihydrate-II to Olanzapine Form-II, is specially advantageous since the novel Olanzapine dihydrate-II is prepared in water and subsequently dried to provide Olanzapine Form-II, thus providing assurance that the Form-II material is substantially free from all organic solvent residues. Summary of the Invention
The present invention is directed to novel Olanzapine dihydrate-II. The present invention further provides an eco-friendly and a commercially viable process for the preparation of novel Olanzapine dihydrate-II, comprising stirring Olanzapine form-I with water, followed by filtration and drying to afford the novel Olanzapine dihydrate -II.
The present invention also provides a process for the conversion of novel Olanzapine dihydrate-II to Olanzapine Form-II comprising further drying of Olanzapine dihydrate-II to constant weight, thereby yielding Olanzapine Form-II.
The present invention also provides for the use of Olanzapine dihydrate- II for treating disorders of the central nervous system and for the use of Olanzapine dihydrate-II in compositions.
Brief Description Of Accompanying Drawings Fig 1 is an X Ray Powder Diffractogram of novel Olanzapine dihydrate- II. Fig 2 is an Infrared Absorption Spectrum of Olanzapine dihydrate-II.
Fig 3 is a Differential Scanning Calorimetry Thermogram of Olanzapine dihydrate-II.
Fig 4 is an X Ray Powder Diffractogram of Olanzapine Form-II obtained from novel Olanzapine dihydrate —II. Detailed Description Of The Invention
The Olanzapine dihydrate-II of the present invention can be prepared by the treatment of Form I of 2-methyl-4-(4-methyl-l-ρiperazinyl)-10H-thieno[2,3- b][l,5]benzodiazepine i.e. Olanzapine Form-I with water by stirring at 25 - 35°C for 72 to 120 hours. Subsequent filtration and drying the product renders the desired Olanzapine dihydrate-II. The drying can be achieved under vacuum at 25-50°C for 1 - 2 hours, in an oven at 60-70°C for 1-2 hours, or air-drying at ambient temperature for 5- 24 hours. This isolated Olanzapine dihydrate-II on further drying in oven at 60-70°C, to constant weight, renders Olanzapine Form-II. The novel Olanzapine dihydrate-II of the present invention is well distinguished from the crystal modifications reported in the prior art.
The Form-I used in the preparation of Olanzapine dihydrate-II can be prepared as per the process disclosed in U.S. 5,229,382, Indian Patent Application No. 709/MAS/2000 or PCT Application No. WO 02/18390A1, the subject matter of which is incorporated herein by reference.
U.S. 5,229,382, Example 1 (4) discloses preparation of Olanzapine
Form-I wherein crude 4-amino-2-methyl-10H-thieno-[2,3b] [1,5] benzodiazepine ΗC1 was refluxed in a mixture of N-methylpiperazine, DMSO and toluene under nitrogen atmosphere for 20 hours. The mixture was cooled to 50°C, water added and the product allowed to crystallize at 5°C overnight. The product was filtered and crystallized from acetonitrile to give 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5] benzodiazepine which was later designated in EP 733635B1 as Olanzapine Form-I. Indian Application, 709/MAS/2000 and WO 02/18390A1 disclose preparation of Olanzapine Form-I from Olanzapine by dissolving Olanzapine in Cι-C3 haloalkane solvent selected from dichloromethane, 1,2-dichloroethane and chlorofonn, preferably dichloromethane at reflux, cooling the reaction solution, filtering the precipitate obtained by conventional methods, and drying the product to obtain the desired Olanzapine Form-I. Olanzapine Form-I can be prepared by any other known method. hi addition to using Olanzapine dihydrate II to prepare Olanzapine Form- I, Olanzapine dihydrate II can be used as a drug and in compositions, including compositions that can be administered to mammals including humans. Pharmaceutical compositions of this invention can contain and/or comprise a therapeutically effective amount of the active ingredient, together with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers or excipients, which are suitable for enteral, for example oral, parenteral or topical administration. The pharmaceutical 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. Preferably, the compositions are formulated in unit dosage form, each dosage containing from 0.1 mg to 20 mg or 0.5 to 10 mg of active ingredient. The dosage of Olanzapine dihydrate II depends on various factors, such as method of administration, species, age and/or individual condition. The doses to be administered daily are between 0.5 mg and about 100 mg, preferably between 1 mg to
40 mg daily for warm-blooded species. The pharmaceutical compositions of this invention can be used to treat disorders of the central nervous system including schizophrenia and psychosis.
The present invention is described in detail with examples given below that are provided by way of illustration only and therefore, should not be construed to limit the scope of the invention. EXAMPLES
Preparation of Olanzapine dihydrate-II
Example 1
Olanzapine Form-I (25.0 g) and water (125 ml) were stirred at 25 - 30°C for 120 hours. It was then filtered and dried under vacuum at 32 - 44°C for about 1-2 hours to render the desired Olanzapine dihydrate - II.
Yield: 27.4 g; Moisture content: 10.33%w/w. Weight loss of the product on TGA is 10.090%.
Preparation of Olanzapine Form-II
The Olanzapine dihydrate-II (5.0g) obtained as per Example 1 is dried in oven at 60-70°C to constant weight rendering Form II of Olanzapine.
Yield: 4.5 g Moisture content: 0.88% w/w. Weight loss of the product on
TGA is 0.310%.
Example 2
Olanzapine Form-I (25.0 g) and water (125 ml) were stirred at 25 - 30°C for 120 hours.
Approximately V_ part of the above-obtained wet cake was dried at 65°C for 90 minutes to afford the desired Olanzapine dihydrate-II.
Yield: 14.1 g; Moisture content: 11.4 %>w/w.
The remaining part was air dried for about 6-7 hours at ambient temperature, to render the desired Olanzapine dihydrate - H.
Yield: 14.3 g; Moisture content: 11.1 %w/w.
The aforementioned crystalline form in Examples 1 and 2 have been examined for their structural and analytical data viz., Powder X-Ray Diffraction, Differential Scanning Calorimetry, Infrared Absorption Spectroscopy and moisture content. The results obtained for the example are discussed in (Fig. 1-4).
The X-Ray Diffraction Pattern set out herein for Example 1 is obtained using Rigaku D / Max-2200 X-Ray Powder Diffractometer having a copper Kα radiation source of wavelength λ=1.54 A0. The samples were scanned between 3-45 degrees 2Θ.
The d values of X-Ray diffractogram for Olanzapine dihydrate-II and Olanzapine Form-II in Example- 1 are herewith enclosed (Fig. 1 & Fig. 4 respectively)
Detailed Description Of Accompanying Drawings
Fig. 1 is a characteristic X-Ray powder diffraction pattern of Olanzapine dihydrate-II (Vertical axis: Intensity (CPS); Horizontal axis: Two Theta (degrees). The significant d values obtained are 9.9949, 9.5838, 9.4007, 7.6884, 7.4184, 5.2052, 4.9678, 4.8756, 4.7767, 4.4271, 4.3881, 4.3414, 4.2752, 4.1145, 3.7762 and 3.3682. Fig. 2 is a characteristic infrared absorption spectrum in potassium bromide of Olanzapine dihydrate-II [Vertical axis, Transmission (%); Horizontal axis:
Wave number (cm-1)]. The characteristic peaks for Olanzapine dihydrate-II are indicated around 750.43 cm'l, 971.39 cm"l and 1003.70 cm'l. Fig. 3 is a characteristic of differential scanning calorimetry thermogram of Olanzapine dihydrate-II. Vertical axis': mW; Horizontal axis: Temperature (°C). The
DSC thermogram exhibits a significant endo - endo pattern at 69.50-195.38°C, which is characteristic of Olanzapine dihydrate-II. The heating rate is 5°C/minute.
Fig 4 is an X ray powder diffractogram of Olanzapine Form-II obtained from novel Olanzapine dihydrate - II. (Vertical axis: Intensity (CPS); Horizontal axis: Two Theta (degrees). The significant d values obtained are 10.3696, 8.6314, 7.1668, 5.2296, 4.7869, 4.4937, 4.2468, 4.1526, 4.0046, 3.7324 and 3.5449.
The present invention therefore provides novel Olanzapine dihydrate-II and a process for the preparation thereof. The novel Olanzapine dihydrate-II of the present invention is an important intermediate for the preparation of Olanzapine Form- II, which is disclosed as the most stable anhydrous form of Olanzapine, providing a stable anhydrous formulation with pharmaceutically desired characteristics.

Claims

C L A I M S
1. Olanzapine Dihydrate-II.
2. The compound according to claim 1, which is characterized by a powder X-ray diffraction pattern (d values in A0) of about: 9.9949, 9.5838, 9.4007, 7.6884, 7.4184, 5.2052, 4.9678, 4.8756, 4.7767, 4.4271, 4.3881, 4.3414, 4.2752, 4.1145, 3.7762 and 3.3682.
3. The compound according to claim 1, characterized by infrared absorption peaks (in cm"1) at about: 750.43 cm'l, 971.39 cm'l and 1003.70 cm'l.
4. The compound according to claim 1 , characterized by a DSC thermogram having endo-endo peaks at about 69.50 and 195.38°C.
5. Olanzapine Dihydrate II according to claim 1, characterized by an X-ray diffraction pattern substantially in accordance with Figure 1.
6. Olanzapine Dihydrate II according to claim 1, characterized by a differential scanning calorimetry thermogram substantially in accordance with Figure 3.
7. Olanzapine Dihydrate II according to claim 1, characterized by an infrared absorption pattern substantially in accordance with Fig. 2
8. Olanzapine Dihydrate II according to claim 5, characterized by a differential scanning calorimetry thermogram in accordance with Figure 3.
9. A process for preparing olanzapine dihydrate II which comprises the steps of: a) stirring a mixture of Form I of 2-methyl-4-(4-methyl- 1 - piperazinyl)-10H-thieno[2,3-b][l,5] benzodiazepine and water at 25-35°C for 72 to 120 hours followed by isolation of product obtained; and b) drying the product of step a) to obtain Olanzapine Dihydrate-II.
10. The process according to claim 9, wherein the product of step a) is dried under vacuum at 25-50 °C for 1 - 2 hours to obtain Olanzapine Dihydrate-II.
11. The process according to claim 8, wherein the product of step a) is air- dried at ambient temperature for 5-24 hours to obtain Olanzapine Dihydrate-II.
12. The process according to claim 9, wherein the product of step a) is dried in an oven at 60-70°C for 1-2 hours to obtain Olanzapine Dihydrate-II.
13. A process for preparing Olanzapine Form-II which comprises the steps of: a) stirring a mixture of Form I of 2-methyl-4-(4-methyl- 1 - piperazinyl)-10H-thieno[2,3-b][l,5] benzodiazepine and water at 25-35°C for 72-120 hours followed by isolation of product obtained; b) drying the product of step a) to afford Olanzapine Dihydrate-II; and c) further drying Olanzapine Dihydrate-II to constant weight to obtain Olanzapine Form II.
14. The process according to claim 13, wherein in step c) the Olanzapine
Dihydrate-II is dried at 60-70 °C in oven to constant weight.
15. A composition comprising Olanzapine Dihydrate-II according to any one of claims 1 to 8 and a pharmaceutically acceptable excipient.
16. A composition according to claim 15 for treating disorders of the central nervous system.
17. Use of Olanzapine dihydrate-II according to any one of claims 1 to 8 for preparing a medicament for treating disorders of the central nervous system.
EP02778677A 2001-10-29 2002-10-29 Olanzapine dihydrate-ii a process for its preparation and use thereof Withdrawn EP1440074A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
INCH08772001 2001-10-29
IN877CH2001 2001-10-29
PCT/US2002/034701 WO2003037903A1 (en) 2001-10-29 2002-10-29 Olanzapine dihydrate-ii a process for its preparation and use thereof

Publications (1)

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EP1440074A1 true EP1440074A1 (en) 2004-07-28

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AU (1) AU2002340328A1 (en)
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Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE500258T1 (en) 2002-05-31 2011-03-15 Sandoz Ag METHOD FOR PRODUCING OLNZAPINE FORM I
AU2003300324A1 (en) 2002-12-24 2004-07-22 Teva Pharmaceutical Industries Ltd. Novel crystal forms of olanzapine, methods for their preparation and method for the preparation of known olanzapine crystal forms
ES2289974T1 (en) * 2004-07-14 2008-02-16 Shasun Chemicals And Drugs Limited IMPROVED METHOD TO PRODUCE THE OLANZAPINE FORM I.
SI1838716T1 (en) 2005-01-05 2011-10-28 Lilly Co Eli Olanzapine pamoate dihydrate
CN103185759A (en) * 2011-12-27 2013-07-03 天津药物研究院 Detection method for solvent residue in olanzapine and application for same
CN103848847B (en) * 2012-12-04 2018-02-06 广东东阳光药业有限公司 A kind of method that improvement prepares Olanzapine and its crystal formation II
JP6008734B2 (en) * 2012-12-20 2016-10-19 株式会社トクヤマ Olanzapine type II crystal production method

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Publication number Priority date Publication date Assignee Title
US5229382A (en) * 1990-04-25 1993-07-20 Lilly Industries Limited 2-methyl-thieno-benzodiazepine
EG23659A (en) * 1995-03-24 2007-03-26 Lilly Co Eli Process and crystal forms of methyl-thieno-benzodiazepine
ZA978515B (en) * 1996-09-23 1999-03-23 Lilly Co Eli Intermediates and process for preparing olanzapine
JP2001500878A (en) * 1996-09-23 2001-01-23 イーライ・リリー・アンド・カンパニー Olanzapine dihydrate D
SK2502003A3 (en) * 2000-08-31 2004-03-02 Reddys Lab Ltd Dr Process for preparation of hydrates of olanzapine and their conversion into crystalline forms of olanzapine

Non-Patent Citations (1)

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Title
See references of WO03037903A1 *

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WO2003037903A8 (en) 2004-02-12
AU2002340328A1 (en) 2003-05-12
CA2464306A1 (en) 2003-05-08

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