WO2004006933A2 - Crystal forms of olanzapine and processes for their preparation - Google Patents

Crystal forms of olanzapine and processes for their preparation Download PDF

Info

Publication number
WO2004006933A2
WO2004006933A2 PCT/SI2003/000024 SI0300024W WO2004006933A2 WO 2004006933 A2 WO2004006933 A2 WO 2004006933A2 SI 0300024 W SI0300024 W SI 0300024W WO 2004006933 A2 WO2004006933 A2 WO 2004006933A2
Authority
WO
WIPO (PCT)
Prior art keywords
olanzapine
solvate
methylene chloride
diffraction pattern
acetonitrile
Prior art date
Application number
PCT/SI2003/000024
Other languages
French (fr)
Other versions
WO2004006933A3 (en
Inventor
Berta Kotar Jordan
Franc Vrecer
Marija Grcman
Original Assignee
Krka, D.D., Novo Mesto
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
Priority to AU2003256242A priority Critical patent/AU2003256242A1/en
Priority to US10/521,646 priority patent/US7745429B2/en
Priority to SI200332341T priority patent/SI1551414T1/en
Priority to CA002493370A priority patent/CA2493370C/en
Priority to UAA200501303A priority patent/UA83633C2/en
Priority to YU20050023A priority patent/RS53474B/en
Application filed by Krka, D.D., Novo Mesto filed Critical Krka, D.D., Novo Mesto
Priority to EP03764287.3A priority patent/EP1551414B1/en
Priority to EA200500188A priority patent/EA008055B1/en
Publication of WO2004006933A2 publication Critical patent/WO2004006933A2/en
Publication of WO2004006933A3 publication Critical patent/WO2004006933A3/en
Priority to HRP20050039AA priority patent/HRP20050039B1/en
Priority to NO20050720A priority patent/NO20050720L/en

Links

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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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 belongs to the field of organic chemistry and relates to a new polymorphic form A of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine (hereinafter referred to by its generic name "olanzapine”) and some pseudopolymo ⁇ hic forms, namely solvates of olanzapine, a method for production thereof and a method for preparation of polymo ⁇ hic form I of olanzapine.
  • olanzapine 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine
  • pseudopolymo ⁇ hic forms namely solvates of olanzapine, a method for production thereof and a method for preparation of polymo ⁇ hic form I of olanzapine.
  • Olanzapine has shown to have activity with regard to the central nervous system and is also useful for the treatment of schizophrenia, schizophreniform disorders, acute mania, mild anxiety states and psychosis.
  • solvents like methylene chloride and acetonitrile, are used for the crystallization of form I of olanzapine.
  • these solvents are not recommended for use in the preparation of pharmaceutical products, as they are harmful.
  • haloge- nated solvents such as methylene chloride are not environmentally friendly and therefore their use should be limited.
  • olanzapine is highly soluble in methylene chloride and therefore the yields are not satisfactory for large-scale industrial production.
  • the invention also relates to a new polymo ⁇ hic form of olanzapine which is designated "form A of olanzapine", a process for its preparation as well as pharmaceutical compositions comprising it.
  • the British patent GB 1 533 235 discloses antipsychotically effective thienobenzodiazepines by a generic formula which also covers olanzapine.
  • EP-B-733 635 claims crystalline form II olanzapine and this polymo ⁇ hic form is said to be more stable than the material obtained according to US 5,229,382 which is designated "form I olanzapine". Both the form I and the form II of olanzapine are characterized by e.g. x-ray data.
  • the preparation of the more stable form II of olanzapine is effected by dissolving technical grade olanzapine in ethyl acetate and crystallization from the resulting solution by any conventional process such as seeding, cooling, scratching the glass of the reaction vessel or other common techniques.
  • WO 02/18390 discloses the monohydrate form I and the dihydrate form I of olanzapine, a process for production thereof and a process for production of form I of olanzapine which comprises the steps of stirring olanzapine monohydrate form I or crude olanzapine or form II of olanzapine in methylene chloride at reflux, cooling, filtering and drying. It is also described that a repeating of the process described in US 5,229,382 Example 1, subexample 4 did not lead to formation of form I of olanzapine.
  • EP-B-733 634 relates to three specific solvates of olanzapine namely the methanol, ethanol and 1-propanol solvates and a process for production technical grade olanzapine by drying the corresponding solvate.
  • EP-B-831 098 relates to processes for preparation of form II of olanzapine by drying olanzapine dihydrate intermediates in a vacuum oven.
  • EP-A-831 097 relates to olanzapine dihydrate D.
  • WO 01/47933 three new polymorphic forms designated as form HI, IN and V and methods for preparing them are disclosed.
  • the processes involve a dissolving of form I or form II of olanzapine in aqueous organic or anorganic acid and precipitating the desired material by neutralisation.
  • US patent application 20020086993 discloses new polymo ⁇ hic form designated as form X of olanzapine and a method for its preparation.
  • Fig. 1 shows the powder x-ray diffraction pattern of form A of olanzapine
  • Fig. 2 shows the powder x-ray diffraction pattern of olanzapine acetonitrile/methylene chloride/water mixed solvate
  • Fig. 3 shows the powder x-ray diffraction pattern of olanzapine acetonitrile/water mixed solvate
  • Fig. 4 shows the powder x-ray diffraction pattern of olanzapine methylene chloride IA solvate
  • Fig. 5 shows the powder x-ray diffraction pattern of olanzapine methylene chloride IB solvate
  • Fig. 6 shows the powder x-ray diffraction pattern of olanzapine 2-propanol solvate Detailed description of the invention
  • the process according to the invention for the preparation of form I of olanzapine is characterized by crystallization of olanzapine from the solvent 2-propanol or from a solvent mixture which comprises 2-propanol.
  • the solvent mixture also comprises at least one further solvent in which olanzapine is soluble and this further solvent is aprotic, in particular selected from the group consisting of tetrahy- drofuran, methylene chloride, acetone, toluene, N, N-dimethylformamide, dimethylsulfoxide, and chloroform.
  • the solvent mixture comprises 2-propanol and the at least one further solvent in a ratio of 1:0.1 to 5 parts, more preferably 1:0.3 to 3 and most preferably 1:0.5 to 1.5 by volume.
  • the olanzapine used as a starting material can be in any form, e.g. it can be in reaction solution, crude or in anhydrous or solvated form.
  • a hydrate is used as olanzapine starting material or an aqueous solvent is employed, then formation of hydrates in the final product is very likely to occur. Since the product in form of hydrates is not desirable, it is preferred to avoid hydrates as starting material and aqueous solvents.
  • the final form I of olanzapine obtained will therefore be preferably substantially free from hydrates.
  • Form I of olanzapine obtained by the process of this invention contains preferably less than 0.5%, more preferably less than 0.2% and most preferably less than 0.1% by weight of associated water.
  • the process for preparing form I of olanzapine usually involves dissolving of olanzapine starting material in a solvent mixture which comprises 2-propanol, and then crystallizing and recovering the product by conventional processes.
  • the process preferably involves a heating of the mixture of the olanzapine starting material and the solvent until a clear solution is obtained, in particular a heating to temperatures from 30°C to the boiling point of the solvent, preferably from 50 to 55°C.
  • a part of the solvent is evaporated under vacuum at temperatures ranging from room temperature to 60°C, preferably at 30 to 35°C. It is preferred that the evaporated part of the solvent makes up 20 to 70%, based on the total volume of solvents.
  • a seeding of the remaining solution with crystals of form I of olanzapine is conducted. Seeding with higher amounts of polymorph form I, such as for example 10 %, increases the speed of crystallization.
  • the product can then be isolated by conventional processes including further vacuum evaporation at the same temperature so that the total volume of the solvent is reduced by 30 to 90% or by cooling the solution to about room temperature, i.e. about 20°C. At temperatures below room temperature, the formation of solvates is favoured.
  • the process according to the invention is carried out by using the olanzapine starting material in form of a solvate of olanzapine.
  • the solvate is at least one of the group consisting of a methylene chloride solvate, a 2-propanol solvate and an acetonitrile mixed solvates of olanzapine.
  • the mixed solvates have inco ⁇ orated acetonitrile and water (acetonitrile/water mixed solvate) or acetonitrile, methylene chloride and water (acetonitrile/methylene chloride/water mixed solvate).
  • crystallisation of form I of olanzapine is performed at a temperature of 15 to 35°C, in particular at room temperature.
  • Form I of olanzapine is rather difficult to be prepared in substantially pure form, because formation of the thermodynamically more stable form II is favoured.
  • substantially pure form I free from form ⁇ and solvates could be obtained.
  • a further aspect of the present invention are specific solvates of olanzapine, a process for the preparation thereof and their use in the preparation of in particular anhydrous forms of form I of olanzapine.
  • the solvates can be transformed to forms I, II , HI, IN, N, X, to the new form A of olanzapine or to the mixture thereof, described hereinafter.
  • Powder x-ray diffraction patterns were measured on a Siemens D-5000 diffractometer with Cu K ⁇ radiation, 2-theta range from 7 to 30 degree, step 0.034 degree 2-theta, divergent slit 20 mm and receiving slit 0.6 mm.
  • the characteristic powder diffraction peaks are expressed in degrees 2-theta.
  • vs refers to very strong relative intesity up to 50 %
  • s refers to strong relative intensity from 25 to 50 %
  • m refers to medium relative intensity from 10 to 25 %
  • w refers to weak relative intensity from 5 to 10 %
  • vw refers to very weak relative intensity from 0 to 5 %.
  • FT-IR Infrared
  • the acetonitrile/methylene chloride/water mixed solvate is characterized by the following data:
  • Typical X-ray diffraction pattern is represented by following 2-theta degrees accompanied with intensities: 2-theta int.
  • the acetonitrile/methylene chloride/water mixed solvate is prepared by dissolving olanzapine in any form in a solvent mixture of acetonitrile and methylene chloride and by heating to a temperature of about 50°C until a clear solution is obtained, cooling the solution to a temperature of below 10°C, and optionally removing a part of the solvents by evaporation in order to enhance yields.
  • the acetonitrile/methylene chloride/water mixed solvate can be converted to form A of olanzapine by removing the solvent by drying.
  • the acetonitrile/water mixed solvate of olanzapine according to the invention is characterized by the following data:
  • Typical X-ray diffraction pattern is represented by following 2-theta degrees accompanied with intensities:
  • Preferably it is characterised by the following 2-theta degrees: 8.76, 9.10, 14.05, 19.37, 20.10, 24.55, 25.92, 27.96.
  • the acetonitrile/water mixed solvate is prepared by dissolving olanzapine in any form in acetonitrile or in a mixture of acetionitrile with aqueous ammonia, heating the mixture to a temperature from 30°C to the boiling point to obtain a clear solution, cooling the solution, preferably to temperatures of from 10°C to -30°C, or evaporating a part of the solvent, and isolating the product by conventional means.
  • This form of acetonitrile/water mixed solvate can, for example, be converted to form II of olanzapine by drying.
  • the 2-propanol solvate of olanzapine is characterized by the following data:
  • Typical X-ray diffraction pattern is represented by following 2-theta degrees accompanied with intensities:
  • Preferably it is characterized by the following 2-theta degrees: 8.74, 14.05, 19.38, 22.65, 23.03, 24.46, 25.92, 28.36.
  • the 2-propanol solvate of olanzapine according to the invention is prepared by suspending olanzapine in a mixture of 2-propanol and a further solvent in which olanzapine is soluble, such as tetrahydrofuran or methylene chloride, heating the mixture to obtain a clear solution, cooling the solution preferably to temperatures from 10°C to -30°C, or evaporating a part of the solvent, and isolating the product by conventional processes.
  • a further solvent in which olanzapine is soluble such as tetrahydrofuran or methylene chloride
  • the 2-propanol solvate can be converted to mixed form I and II of olanzapine by removing the solvent by drying.
  • Typical X-ray diffraction pattern is represented by following 2-theta degrees accompanied with intensities:
  • Preferably it is characterized by the following 2-theta degrees: 10.80, 14.25, 19.22, 22.78, 24.53.
  • Typical X-ray diffraction pattern is represented by following 2-theta degrees accompanied with intensities: 2-theta int.
  • Preferably it is characterized by the following 2-theta degrees: 9.30, 10.80, 14.25, 14.98, 15.94, 19.23, 20.04.
  • Both of methylene chloride solvates are prepared by dissolving olanzapine in methylene chloride, optionally with heating to obtain a clear solution. In case the solvent mixture is partly evaporated and cooled or completely evaporated, then form IB of methylene chloride solvate is obtained. In case the crystallisation mixture is rapidly cooled to temperatures about 0°C form IA of methylene chloride solvate is obtained.
  • the aforementioned solvates according to the invention can be used for preparing other forms and in particular anhydrous forms of olanzapine. They are preferably used for preparing anhydrous olanzapine form I, ⁇ , HI, IV, V, X, Aor mixture thereof.
  • a further aspect of the invention is a new polymo ⁇ hic form of olanzapine, designated as form A of olanzapine.
  • This form A of olanzapine is characterized by the following data: Typical X-ray diffraction pattern is represented by following 2-theta degrees accompanied with intensities: 2-theta int.
  • Preferably it is characterised by the following 2-theta degrees: 11.52, 12.00, 13.35, 13.56, 14.21, 15.47, 16.69, 19.16, 20.25, 20.69, 22.12, 24.33, 26.88, 27.13.
  • the form A of olanzapine is prepared by suspending olanzapine in a mixture of acetonitrile with a solvent in which olanzapine is soluble or alternatively by dissolving olanzapine in a solvent where olanzapine is soluble, heating the mixture to obtain a clear solution, optionally filtration and partly evaporation of the solvent, and recovering the product by conventional procedures such as seeding, cooling, scratching the glass vessel or other common technique.
  • the olanzapine used as starting material can be either crude olanzapine, olanzapine in any anhydrous form or any solvate form of olanzapine including the abovementioned solvates of acetonitrile, 2-propanol and methylene chloride according to the invention.
  • Preferred solvents in which olanzapine is soluble are e.g. methylene chloride, tetrahydrofuran, acetone, toluene, N, N-dimethylformamide, dimethylsulfoxide and chloroform.
  • the ratio of acetonitrile to other possible solvents is preferably 1:0.1 to 5 parts, preferably 1:0.1 to 3.0 and most preferred 1:0.2 to 1.5.
  • the mixture is usually heated to a temperature of from 30°C to the boiling point of the mixture, preferably 40-60°C, to obtain the clear solution. It is further preferred to evaporate solvent from the clear solution under vacuum at temperatures ranging from 0°C to 60°C, preferably 30 to 40°C. The evaporated part of the solvent should make up from 10 to 70% based on the total volume of solvents.
  • the desired fo ⁇ n A of olanzapine can be recovered by cooling or seeding of the solution with crystals of form A. The product can then be further dried in vacuum.
  • This new polymo ⁇ hic form A is stable and therefore particularly suited for inco ⁇ oration in pharmaceutical preparations.
  • the invention therefore also relates to a pharmaceutical composition comprising form A of olanzapine.
  • the polymo ⁇ hic form A of olanzapine can be formulated in a pharmaceutical composition in combination with one or more pharmaceutical acceptable excipients which can be either solid, semisolid or liquid.
  • Pharmaceutical formulation can be prepared by any conventional techniques such as direct compression, dry and wet granulation, with or without final coating of the dosage form.
  • the final dosage form including form A of olanzapine can be in any conventional unit dosage forms such as granules, pellets, tablets, film coated tablets, fast dispersible tablets, capsules, suspensions and solutions for oral use, transdermal patches, suppositories, parenteral products, etc.
  • olanzapine 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine
  • acetonitrile 30 ml
  • the suspension was heated to 50°C and methylene chloride (35 ml) was added to obtain a clear solution.
  • the methylene chloride was then evaporated under vacuum at 40 °C.
  • To the resulting solution a few seed crystals of form A of olanzapine were added and the mixture was stirred for one hour at 40°C.
  • the product was filtered off and dried under vacuum at 60°C to obtain form A of olanzapine (6.5 g).
  • olanzapine 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine
  • acetonitrile 10 ml
  • the suspension was heated to 50°C and toluene (2 ml) was added to obtain a clear solution.
  • Approximately half of the solvent was evaporated under vacuum at 35 to 40°C, and then the remaining solution was seeded with the crystals of form A of olanzapine.
  • the product was recovered by filtration and dried at 50 °C to obtain form A of olanzapine (0.76 g).
  • olanzapine 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2 : ,3-b][l,5]benzodiazepine
  • olanzapine 2-methyI-4-(4-methyl-l-piperazinyl)-10/ -thieno[2,3-b][l,5]benzodiazepine
  • Olanzapine starting materials anhydrous polymo ⁇ hic forms or 2-propanol, methylene chloride or acetonitrile solvates of olanzapine.
  • olanzapine 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine
  • olanzapine 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine
  • olanzapine 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine
  • 2-propanol 30 ml
  • methylene chloride 20 ml
  • Approximately half of the solvent was evaporated under vacuum at 30-35°C, and then the solution was seeded with crystals of form I of olanzapine and evaporation at this temperature was continued.
  • the product was recovered by filtration and dried at 60 °C and shown to be form I of olanzapine (7.6 g).
  • olanzapine 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine
  • 2-propanol 30 ml
  • acetone 45 ml
  • Approximately half of the solvent was evaporated under vacuum at 30-35°C, and then the solution was seeded with the crystals of form I of olanzapine and vacuum distillation at this temperature was continued for further 15 minutes.
  • the product was recovered by filtration and dried at 60 °C to obtain form I of olanzapine (7.2 g).

Abstract

The invention relates to a process for the preparation of form I of olanzapine, crystallized from a solvent mixture which comprises 2-propanol, some pseudopolymorphic forms, namely solvates of olanzapine, a new polymorphic form A of olanzapine, and processes for the preparation thereof.

Description

CRYSTAL FORMS OF OLANZAPINE AND PROCESSES FOR THEIR PREPARATION
Technical field
The present invention belongs to the field of organic chemistry and relates to a new polymorphic form A of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine (hereinafter referred to by its generic name "olanzapine") and some pseudopolymoφhic forms, namely solvates of olanzapine, a method for production thereof and a method for preparation of polymoφhic form I of olanzapine.
Olanzapine has shown to have activity with regard to the central nervous system and is also useful for the treatment of schizophrenia, schizophreniform disorders, acute mania, mild anxiety states and psychosis.
Technical problem
According to prior art processes, solvents, like methylene chloride and acetonitrile, are used for the crystallization of form I of olanzapine. However, these solvents are not recommended for use in the preparation of pharmaceutical products, as they are harmful. Moreover, haloge- nated solvents such as methylene chloride are not environmentally friendly and therefore their use should be limited. Finally, olanzapine is highly soluble in methylene chloride and therefore the yields are not satisfactory for large-scale industrial production.
Moreover, the prior art processes often do not lead to satisfactory yields of the form I of olanzapine.
Consequently, there is a need for an improved process to prepare form I of olanzapine.
Further, there is a need for precursors which allow the easy preparation of polymoφhic forms of olanzapine or the conversion to other forms of olanzapine.
These problems are solved by the present invention. The invention also relates to a new polymoφhic form of olanzapine which is designated "form A of olanzapine", a process for its preparation as well as pharmaceutical compositions comprising it.
Background of the invention
The British patent GB 1 533 235 discloses antipsychotically effective thienobenzodiazepines by a generic formula which also covers olanzapine.
US patent 5,229,382 describes olanzapine explicitly. The described process for its production involves a crystallization from acetonitrile, determining the melting point of that crystallized compound at 195°C.
EP-B-733 635 claims crystalline form II olanzapine and this polymoφhic form is said to be more stable than the material obtained according to US 5,229,382 which is designated "form I olanzapine". Both the form I and the form II of olanzapine are characterized by e.g. x-ray data. The preparation of the more stable form II of olanzapine is effected by dissolving technical grade olanzapine in ethyl acetate and crystallization from the resulting solution by any conventional process such as seeding, cooling, scratching the glass of the reaction vessel or other common techniques.
WO 02/18390 discloses the monohydrate form I and the dihydrate form I of olanzapine, a process for production thereof and a process for production of form I of olanzapine which comprises the steps of stirring olanzapine monohydrate form I or crude olanzapine or form II of olanzapine in methylene chloride at reflux, cooling, filtering and drying. It is also described that a repeating of the process described in US 5,229,382 Example 1, subexample 4 did not lead to formation of form I of olanzapine.
EP-B-733 634 relates to three specific solvates of olanzapine namely the methanol, ethanol and 1-propanol solvates and a process for production technical grade olanzapine by drying the corresponding solvate. EP-B-831 098 relates to processes for preparation of form II of olanzapine by drying olanzapine dihydrate intermediates in a vacuum oven.
EP-A-831 097 relates to olanzapine dihydrate D.
In WO 01/47933 three new polymorphic forms designated as form HI, IN and V and methods for preparing them are disclosed. The processes involve a dissolving of form I or form II of olanzapine in aqueous organic or anorganic acid and precipitating the desired material by neutralisation.
US patent application 20020086993 discloses new polymoφhic form designated as form X of olanzapine and a method for its preparation.
Brief description of drawings
Fig. 1 shows the powder x-ray diffraction pattern of form A of olanzapine
Fig. 2 shows the powder x-ray diffraction pattern of olanzapine acetonitrile/methylene chloride/water mixed solvate
Fig. 3 shows the powder x-ray diffraction pattern of olanzapine acetonitrile/water mixed solvate
Fig. 4 shows the powder x-ray diffraction pattern of olanzapine methylene chloride IA solvate
Fig. 5 shows the powder x-ray diffraction pattern of olanzapine methylene chloride IB solvate
Fig. 6 shows the powder x-ray diffraction pattern of olanzapine 2-propanol solvate Detailed description of the invention
It has unexpectedly been found that the preparation of form I of olanzapine can easily be accomplished if olanzapine is crystallized by using the non-harmful solvent mixture which comprises 2-propanol.
The process according to the invention for the preparation of form I of olanzapine is characterized by crystallization of olanzapine from the solvent 2-propanol or from a solvent mixture which comprises 2-propanol.
The solvent mixture also comprises at least one further solvent in which olanzapine is soluble and this further solvent is aprotic, in particular selected from the group consisting of tetrahy- drofuran, methylene chloride, acetone, toluene, N, N-dimethylformamide, dimethylsulfoxide, and chloroform.
It is preferred that the solvent mixture comprises 2-propanol and the at least one further solvent in a ratio of 1:0.1 to 5 parts, more preferably 1:0.3 to 3 and most preferably 1:0.5 to 1.5 by volume.
The olanzapine used as a starting material can be in any form, e.g. it can be in reaction solution, crude or in anhydrous or solvated form. We have observed that in case a hydrate is used as olanzapine starting material or an aqueous solvent is employed, then formation of hydrates in the final product is very likely to occur. Since the product in form of hydrates is not desirable, it is preferred to avoid hydrates as starting material and aqueous solvents. The final form I of olanzapine obtained will therefore be preferably substantially free from hydrates. Form I of olanzapine obtained by the process of this invention contains preferably less than 0.5%, more preferably less than 0.2% and most preferably less than 0.1% by weight of associated water. The process for preparing form I of olanzapine usually involves dissolving of olanzapine starting material in a solvent mixture which comprises 2-propanol, and then crystallizing and recovering the product by conventional processes.
In the following preferred embodiments of the process are described.
The process preferably involves a heating of the mixture of the olanzapine starting material and the solvent until a clear solution is obtained, in particular a heating to temperatures from 30°C to the boiling point of the solvent, preferably from 50 to 55°C. After the clear solution is obtained, a part of the solvent is evaporated under vacuum at temperatures ranging from room temperature to 60°C, preferably at 30 to 35°C. It is preferred that the evaporated part of the solvent makes up 20 to 70%, based on the total volume of solvents. After evaporation, a seeding of the remaining solution with crystals of form I of olanzapine is conducted. Seeding with higher amounts of polymorph form I, such as for example 10 %, increases the speed of crystallization. The product can then be isolated by conventional processes including further vacuum evaporation at the same temperature so that the total volume of the solvent is reduced by 30 to 90% or by cooling the solution to about room temperature, i.e. about 20°C. At temperatures below room temperature, the formation of solvates is favoured.
In a further preferred embodiment, the process according to the invention is carried out by using the olanzapine starting material in form of a solvate of olanzapine. Preferably, the solvate is at least one of the group consisting of a methylene chloride solvate, a 2-propanol solvate and an acetonitrile mixed solvates of olanzapine. The mixed solvates have incoφorated acetonitrile and water (acetonitrile/water mixed solvate) or acetonitrile, methylene chloride and water (acetonitrile/methylene chloride/water mixed solvate).
When using a solvate of olanzapine as starting material, then it is preferred that the crystallisation of form I of olanzapine is performed at a temperature of 15 to 35°C, in particular at room temperature.
Form I of olanzapine is rather difficult to be prepared in substantially pure form, because formation of the thermodynamically more stable form II is favoured. However, by using the above crystallization conditions, it was possible to prepare form I of olanzapine with yields higher than 70%. According to the process of the present invention substantially pure form I free from form π and solvates could be obtained.
A further aspect of the present invention are specific solvates of olanzapine, a process for the preparation thereof and their use in the preparation of in particular anhydrous forms of form I of olanzapine.
We have found out that the 2-propanol solvate, the acetonitrile solvate and the methylene chloride solvate could be formed. The latter solvate was found to exist in two forms with different molar ratio between the olanzapine and methylene chloride.
Depending on the form, the solvates can be transformed to forms I, II , HI, IN, N, X, to the new form A of olanzapine or to the mixture thereof, described hereinafter.
Powder x-ray diffraction patterns were measured on a Siemens D-5000 diffractometer with Cu Kα radiation, 2-theta range from 7 to 30 degree, step 0.034 degree 2-theta, divergent slit 20 mm and receiving slit 0.6 mm. The characteristic powder diffraction peaks are expressed in degrees 2-theta.
As used herein, the following abbreviated terms are: "vs" refers to very strong relative intesity up to 50 %, "s" refers to strong relative intensity from 25 to 50 %, "m" refers to medium relative intensity from 10 to 25 %, "w" refers to weak relative intensity from 5 to 10 % and "vw" refers to very weak relative intensity from 0 to 5 %.
Infrared (FT-IR) spectra were obtained in a KBr disk using a Perkin Elmer FT-IR spectrometer Spectrum 1000 at resolution 4 cm"1. The characteristic absoφtion bands are expressed in cm'1.
The acetonitrile/methylene chloride/water mixed solvate is characterized by the following data:
• Typical X-ray diffraction pattern is represented by following 2-theta degrees accompanied with intensities: 2-theta int.
8.76 vs
18.29 w
19.39 m
19.66 w 20.12 w
23.13 w 23.62 w 25.08 w
Preferably it is characterized by the following 2-theta degrees: 8.76, 19.39, 20.12.
IR spectra is characterised by the following characteristic peaks:
3430, 3236, 2933, 2844, 1592, 1560, 1468, 1458, 1409, 1366, 1341, 1297, 1282,
1265, 1220, 1149, 1004, 970, 850, 779, 754, 669 cm"1.
The acetonitrile/methylene chloride/water mixed solvate is prepared by dissolving olanzapine in any form in a solvent mixture of acetonitrile and methylene chloride and by heating to a temperature of about 50°C until a clear solution is obtained, cooling the solution to a temperature of below 10°C, and optionally removing a part of the solvents by evaporation in order to enhance yields.
The acetonitrile/methylene chloride/water mixed solvate can be converted to form A of olanzapine by removing the solvent by drying.
The acetonitrile/water mixed solvate of olanzapine according to the invention is characterized by the following data:
Typical X-ray diffraction pattern is represented by following 2-theta degrees accompanied with intensities:
2-theta int.
8.76 vs
9.10 m
14.05 m
14.44 m
18.30 vs
18.67 m
18.84 s
19.37 s
19.68 m
20.10 m
20.54 m
21.65 m
22.79 m
23.12 s
23.62 vs
24.55 m
25.06 s 25.92 m
27.96 m
28.44 m
Preferably it is characterised by the following 2-theta degrees: 8.76, 9.10, 14.05, 19.37, 20.10, 24.55, 25.92, 27.96.
• IR spectra is characterised by the following characteristic peaks:
3401, 3235,2930, 2843, 1592, 1561, 1467, 1458, 1409, 1366, 1341, 1282, 1265, 1219, 1148, 1004, 970, 852, 779, 754, 668 cm"1.
The acetonitrile/water mixed solvate is prepared by dissolving olanzapine in any form in acetonitrile or in a mixture of acetionitrile with aqueous ammonia, heating the mixture to a temperature from 30°C to the boiling point to obtain a clear solution, cooling the solution, preferably to temperatures of from 10°C to -30°C, or evaporating a part of the solvent, and isolating the product by conventional means.
This form of acetonitrile/water mixed solvate can, for example, be converted to form II of olanzapine by drying.
The 2-propanol solvate of olanzapine is characterized by the following data:
Typical X-ray diffraction pattern is represented by following 2-theta degrees accompanied with intensities:
2-theta int.
8.74 vs
14.05 m
14.41 m
17.77 m
18.22 vs
18.76 s
19.38 vs
19.81 m
19.95 m 20.54 m
20.96 s
21.64 m 22.26 m
22.65 m 23.03 s 23.58 vs 23.90 s 24.46 m
25.03 vs
25.39 m
25.92 m
26.63 m
27.47 m
27.95 m
28.36 m
Preferably it is characterized by the following 2-theta degrees: 8.74, 14.05, 19.38, 22.65, 23.03, 24.46, 25.92, 28.36.
IR spectra is characterized by the following characteristic peaks:
3400, 3234, 2962, 2931, 2843, 1590, 1559, 1468, 1413, 1282, 1267, 1220, 1147,
1004, 970, 846,779, 756, 667 cm"1.
The 2-propanol solvate of olanzapine according to the invention is prepared by suspending olanzapine in a mixture of 2-propanol and a further solvent in which olanzapine is soluble, such as tetrahydrofuran or methylene chloride, heating the mixture to obtain a clear solution, cooling the solution preferably to temperatures from 10°C to -30°C, or evaporating a part of the solvent, and isolating the product by conventional processes.
The 2-propanol solvate can be converted to mixed form I and II of olanzapine by removing the solvent by drying.
Two methylene chloride solvates IA and IB of olanzapine according to the invention are characterised by the following spectra, the both forms can be in particular distinguished by IR spectra:
Form IA is characterized by the following data:
Typical X-ray diffraction pattern is represented by following 2-theta degrees accompanied with intensities:
2-theta int.
8.85 vs
10.80 m
12.89 m
14.09 m
14.25 m
18.37 vs
18.81 s
19.22 s
19.41 s 19.57 s
20.07 m
20.80 m
21.00 m
21.71 s
22.06 m
22.25 m
22.78 m
23.14 s
23.62 s
24.03 s
24.53 m
25.04 s
25.43 m
26.67 m
27.51 m
28.00 m
28.45 m
28.70 m
Preferably it is characterized by the following 2-theta degrees: 10.80, 14.25, 19.22, 22.78, 24.53.
• IR spectra is characterized by the following characteristic peaks:
3435, 3237, 2918, 2842, 1590, 1560, 1467, 1413, 1366, 1343, 1282, 1266, 1219, 1147, 1004, 970, 846, 780, 757, 668 cm'1.
Form IB is characterized by the following data:
Typical X-ray diffraction pattern is represented by following 2-theta degrees accompanied with intensities: 2-theta int.
8.43 m
8.86 vs
9.30 m
14.25 m
14.98 m
10.80 s
15.94 m
16.88 s
17.79 m
18.40 vs
18.57 vs
18.83 s
19.23 vs
19.57 vs
20.04 s
20.79 m 21.01 m 21.68 vs 22.06 s 22.23 s 23.57 s
24.02 vs 24.89 m 25.12 m 25.46 m 26.38 m 26.56 m 27.50 s 28.06 m 28.71 m 29.02 m
Preferably it is characterized by the following 2-theta degrees: 9.30, 10.80, 14.25, 14.98, 15.94, 19.23, 20.04.
IR spectra is characterized by the following characteristic peaks:
3274, 2943, 2916, 2841, 1589, 1560, 1466, 1419, 1282, 1259, 1215, 1144, 1122,
1001, 970, 783, 759, 747, 725 cm"1.
Both of methylene chloride solvates are prepared by dissolving olanzapine in methylene chloride, optionally with heating to obtain a clear solution. In case the solvent mixture is partly evaporated and cooled or completely evaporated, then form IB of methylene chloride solvate is obtained. In case the crystallisation mixture is rapidly cooled to temperatures about 0°C form IA of methylene chloride solvate is obtained.
By drying and optionally compression or grinding of any one of methylene chloride solvate IA or IB, form I of olanzapine is obtained.
Generally, the aforementioned solvates according to the invention can be used for preparing other forms and in particular anhydrous forms of olanzapine. They are preferably used for preparing anhydrous olanzapine form I, π, HI, IV, V, X, Aor mixture thereof.
A further aspect of the invention is a new polymoφhic form of olanzapine, designated as form A of olanzapine. This form A of olanzapine is characterized by the following data: Typical X-ray diffraction pattern is represented by following 2-theta degrees accompanied with intensities: 2-theta int.
11.52 m
11.83 m
12.00 m
13.35 m
13.56 m
14.21 vs
15.47 w
16.69 m
17.83 s
19.16 s
20.25 s
20.69 vs
21.65 s
22.12 m
23.21 s
24.33 m
26.88 s
27.13 m
28.57 m
Preferably it is characterised by the following 2-theta degrees: 11.52, 12.00, 13.35, 13.56, 14.21, 15.47, 16.69, 19.16, 20.25, 20.69, 22.12, 24.33, 26.88, 27.13.
IR spectra is characterised by the following characteristic peaks:
3216, 2912, 2846, 2804, 1592, 1469, 1450, 1395, 1369, 1286, 1257, 1217, 1143,
1006, 964, 853, 752, 674 cm"1.
The form A of olanzapine is prepared by suspending olanzapine in a mixture of acetonitrile with a solvent in which olanzapine is soluble or alternatively by dissolving olanzapine in a solvent where olanzapine is soluble, heating the mixture to obtain a clear solution, optionally filtration and partly evaporation of the solvent, and recovering the product by conventional procedures such as seeding, cooling, scratching the glass vessel or other common technique. The olanzapine used as starting material can be either crude olanzapine, olanzapine in any anhydrous form or any solvate form of olanzapine including the abovementioned solvates of acetonitrile, 2-propanol and methylene chloride according to the invention. Preferred solvents in which olanzapine is soluble are e.g. methylene chloride, tetrahydrofuran, acetone, toluene, N, N-dimethylformamide, dimethylsulfoxide and chloroform. The ratio of acetonitrile to other possible solvents is preferably 1:0.1 to 5 parts, preferably 1:0.1 to 3.0 and most preferred 1:0.2 to 1.5.
The mixture is usually heated to a temperature of from 30°C to the boiling point of the mixture, preferably 40-60°C, to obtain the clear solution. It is further preferred to evaporate solvent from the clear solution under vacuum at temperatures ranging from 0°C to 60°C, preferably 30 to 40°C. The evaporated part of the solvent should make up from 10 to 70% based on the total volume of solvents. Usually, the desired foπn A of olanzapine can be recovered by cooling or seeding of the solution with crystals of form A. The product can then be further dried in vacuum.
If the solution is rapidly cooled to temperatures under 5°C, then an acetonitrile/methylene chloride/water mixed solvate is usually formed. This solvate can, however, be transformed to form A of olanzapine by drying.
This new polymoφhic form A is stable and therefore particularly suited for incoφoration in pharmaceutical preparations. The invention therefore also relates to a pharmaceutical composition comprising form A of olanzapine.
The polymoφhic form A of olanzapine can be formulated in a pharmaceutical composition in combination with one or more pharmaceutical acceptable excipients which can be either solid, semisolid or liquid. Pharmaceutical formulation can be prepared by any conventional techniques such as direct compression, dry and wet granulation, with or without final coating of the dosage form.
The final dosage form including form A of olanzapine can be in any conventional unit dosage forms such as granules, pellets, tablets, film coated tablets, fast dispersible tablets, capsules, suspensions and solutions for oral use, transdermal patches, suppositories, parenteral products, etc.
The invention is in the following further illustrated by examples. Examples
Preparation of form A of olanzapine
Example 1
10.0 g of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine ("olanzapine") was suspended in a mixture of 50.0 ml methylene chloride and 50.0 ml acetonitrile. The obtained suspension was heated to 45 to 50°C to obtain a clear solution. The solution was filtered and the solvent was evaporated under vacuum at 0 to 5°C. The product was recovered by vacuum filtration to obtain an acetonitrile/methylene chloride/water mixed solvate.
Upon drying under vacuum at 60°C, this solvate was converted to form A of olanzapine (8.94 g).
Example 2
10.0 g of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine ("olanzapine") was suspended in acetonitrile (30 ml). The suspension was heated to 50°C and methylene chloride (35 ml) was added to obtain a clear solution. The methylene chloride was then evaporated under vacuum at 40 °C. To the resulting solution a few seed crystals of form A of olanzapine were added and the mixture was stirred for one hour at 40°C. The product was filtered off and dried under vacuum at 60°C to obtain form A of olanzapine (6.5 g).
Example 3
1.0 g of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine ("olanzapine") was suspended in acetonitrile (10 ml). The suspension was heated to 50°C and toluene (2 ml) was added to obtain a clear solution. Approximately half of the solvent was evaporated under vacuum at 35 to 40°C, and then the remaining solution was seeded with the crystals of form A of olanzapine. The product was recovered by filtration and dried at 50 °C to obtain form A of olanzapine (0.76 g). Example 4
1.0 g of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2:,3-b][l,5]benzodiazepine ("olanzapine") was suspended in 6.0 ml of methylene chloride. The obtained suspension was heated to the boiling point to obtain a clear solution which was heated at this temperature for 3 hours. The solution was left at room temperature until the solvent evaporated. To the residue 6.0 ml of methylene chloride was added, the suspension was heated to 40°C, undissolved product was filtered and dried at room temperature to obtain olanzapine form A (0.4 g).
Preparation of solvates
Acetonitrile/water mixed solvate of olanzapine
Example5
10.0 g of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine
("olanzapine") was suspended in acetonitrile (110 ml), and the suspension was heated to reflux at a temperature of 82°C. The obtained clear solution was filtered hot. The filtrate was cooled to 0-5°C and stirred under vacuum for 30 minutes. The product was isolated by vacuum filtration and dried under ambient conditions for 12 hours. Yield: 10.1 g.
Loss on drying (determined by TGA): 11.5%.
Assay of water (KF): 6.5 %.
Molar ratio among olanzapine / acetonitrile / water (confirmed by 1H NMR analysis) is
1:V2:1.
Example 6
5.0 g of 2-methyI-4-(4-methyl-l-piperazinyl)-10/ -thieno[2,3-b][l,5]benzodiazepine ("olanzapine") was suspended in acetonitrile (210 ml), and the suspension was heated to 40°C to obtain a clear solution. To this solution 2.4 ml 25% aqueous ammonia was added and the mixture was cooled to -30°C within 20 minutes. The product was filtered and dried under vacuum for 1 hour at 50°C. Yield: 5.3 g. Acetonitrile / methylene chloride /water mixed solvate of olanzapine
Example 7
1.0 g of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine ("olanzapine") was suspended in a mixture of methylene chloride (5.0 ml) and acetonitrile (5.0 ml). The suspension was heated to 45-50°C to obtain a clear solution. The solution was filtered and the solvent was evaporated under vacuum at 0-5°C. The product was recovered by vacuum filtration and dried under ambient conditions. Yield: 0.80 g. Loss on drying (determined by TGA): 13.2%. Assay of water (KF): 6.6 %.
Molar ratio among olanzapine / acetonitrile / methylene chloride / water (confirmed by 1H NMR analysis) is lΛ/2 Λ/6±
2-Propanol solvate of olanzapine
Example 8
10.0 g of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine
("olanzapine") was suspended in an mixture of 2-propanol (30 ml) and tetrahydrofuran (30 ml). The suspension was heated to 56°C to obtain a clear solution. Approximately half of the solvent was evaporated under vacuum at 35°C. The resulting solution was cooled to 0°C, and the product was recovered by vacuum filtration and dried under ambient conditions for 12 hours. Yield: 8.9 g.
Loss on drying (determined by TGA): 9.1%.
Molar ratio among olanzapine / 2-propanol (confirmed by 1H NMR analysis) is 1:V2.
Methylene chloride solvates IA and IB of olanzapine
Example 9
10.0 g of 2-methyl-4-(4-methyl-l-ρiρerazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine ("olanzapine") was suspended in methylene chloride (50 ml), and the suspension was heated to 40°C to obtain a clear solution. The solution was cooled to 0-5°C and stirred for 15 minutes. The product was isolated by vacuum filtration and dried under ambient conditions. Yield: 11.8 g.
Form IA is obtained.
Loss on drying (determined by TGA): 10.1%. Molar ratio among olanzapine / methylene chloride (confirmed by 1H NMR analysis) is 1:V2.
Example 10
5.0 g of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine ("olanzapine") was suspended in methylene chloride (25 ml), and the suspension was heated to 40°C to obtain a clear solution. The solution was filtered hot and the filtrate was stirred under vacuum for 10 minutes and cooled to 0-5 °C. The product was isolated by vacuum filtration and dried under ambient conditions. Yield: 5.33 g. Form IA is obtained.
Example 11
5.0 g of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine
("olanzapine") was suspended in methylene chloride (25 ml). The suspension was heated to
40° C to obtain a clear solution. The solvent was evaporated under vacuum at 35°C to dryness.
Yield: 5.5g.
Form IB is obtained.
Loss on drying (determined by TGA): 4.5 %.
Molar ratio among olanzapine / methylene chloride (confirmed by 1H NMR analysis) is 1:V6.
Example 12
5.0 g of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l55]benzodiazepine was suspended in methylene chloride (25 ml). The suspension was heated to 40°C to obtain a clear solution. The solvent was allowed to evaporate under air within two days. Yield: 5.3g. Form IB is obtained. Preparation of form I of olanzapine
Olanzapine starting materials: anhydrous polymoφhic forms or 2-propanol, methylene chloride or acetonitrile solvates of olanzapine.
Example 13
300.0 g of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine ("olanzapine") was suspended in a mixture of tetrahydrofuran (900 ml) and 2-propanol (900 ml). The suspension was then heated to 50-55°C to obtain a clear solution. Approximately 450 ml of the solvent was evaporated under vacuum at 30-35°C, and the resulting solution was seeded with crystals of form I of olanzapine. Further solvent was removed by with vacuum distillation at this temperature to 1/2 of the original volume. The product was recovered by filtration and dried at 50 °C and shown to be form I of olanzapine (286.7 g).
Example 14
10.0 g of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine ("olanzapine") was suspended in 2-propanol (30 ml) and heated to 50°C. To this mixture methylene chloride (20 ml) was added to obtain a clear solution. Approximately half of the solvent was evaporated under vacuum at 30-35°C, and then the solution was seeded with crystals of form I of olanzapine and evaporation at this temperature was continued. The product was recovered by filtration and dried at 60 °C and shown to be form I of olanzapine (7.6 g).
Example 15
10.0 g of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5]benzodiazepine ("olanzapine") was suspended in 2-propanol (30 ml). This suspension was heated to 50°C and acetone (45 ml) was added to obtain a clear solution. Approximately half of the solvent was evaporated under vacuum at 30-35°C, and then the solution was seeded with the crystals of form I of olanzapine and vacuum distillation at this temperature was continued for further 15 minutes. The product was recovered by filtration and dried at 60 °C to obtain form I of olanzapine (7.2 g).
Example 16
1.0 g of methylene chloride solvate of olanzapine was suspended in 2-propanol (3 ml). The suspension was stirred at room temperature for one hour. The product was filtered and dried in vacuo at 50°C. Yield: 0.86 g.

Claims

Claims
1. A process for the preparation of form I of olanzapine, wherein olanzapine is crystallized from a solvent mixture which comprises 2-propanol.
2. Process according to claim 1, wherein the solvent mixture also comprises at least one further solvent selected from group consisting of tetrahydrofuran, methylene chloride, acetone, toluene, N, N-dimethylformamide, dimethylsulfoxide, and chloroform.
3. Process according to claim 2, wherein the solvent mixture comprises 2-propanol and at least one further solvent in a ratio of 1 :0.1 to 5 parts by volume.
4. Process according to any one of claims 1 to 3, wherein the olanzapine is used in form of a solvate of olanzapine.
5. Process according to claim 4, wherein the solvate is at least one of the group consisting of a methylene chloride solvate, a 2-propanol solvate, a acetonitrile/methylene chloride/water mixed solvate and acetonitrile/water mixed solvate of olanzapine.
6. Acetonitrile/methylene chloride/water mixed solvate of olanzapine characterized by an x-ray powder diffraction pattern (2 theta) as follows:
8.76, 19.39, 20.12.
7. Acetonitrile/methylene chloride/water mixed solvate of olanzapine according to claim 6, characterized by an x-ray powder diffraction pattern (2 theta) as follows: 8.76,18.29, 19.39, 19.66, 20.12, 23.13, 23.62, 25.08.
8. Acetonitrile/water mixed solvate of olanzapine characterized by an x-ray powder diffraction pattern (2 theta) as follows:
8.76, 9.10, 14.05, 19.37, 20.10, 24.55, 25.92, 27.96.
9. Acetonitrile/water mixed solvate of olanzapine according to claim 8, characterized by an x-ray powder diffraction pattern (2 theta) as follows:
8.76, 9.10, 14.05, 14.44, 18.30, 18.67, 18.84, 19.37, 19.68, 20.10, 20.54, 21.65,
22.79, 23.12, 23.62, 24.55, 25.06, 25.92, 27.96, 28.44.
10. 2-propanol solvate of olanzapine characterized by an x-ray powder diffraction pattern as follows:
8.74, 14.05, 19.38, 22.65, 23.03, 24.46, 25.92, 28.36.
11. 2-propanol solvate of olanzapine according to claim 10, characterized by an x-ray powder diffraction pattern as follows:
8.74, 14.05, 14.41, 17.77, 18.22, 18.76, 19.38, 19.81, 19.95, 20.54, 20.96, 21.64, 22.26, 22.65, 23.03, 23.58, 23.90, 24.46, 25.03, 25.39, 25.92, 26.63, 27.47, 27.95, 28.36.
12. Methylene chloride solvate IA of olanzapine characterized by an x-ray powder diffraction pattern as follows:
10.80, 14.25, 19.22, 22.78, 24.53.
13. Methylene chloride solvate IA of olanzapine according to claim 12, characterized by an x-ray powder diffraction pattern as follows:
8.85, 10.80, 12.89, 14.09, 14.25, 18.37, 18.81, 19.22, 19.41, 19.57, 20.07, 20.80, 21.00, 21.71, 22.06, 22.25, 22.78, 23.14, 23.62, 24.03, 24.53, 25.04, 25.43, 26.67, 27.51, 28.00, 28.45, 28.70.
14. Methylene chloride solvate IB of olanzapine characterized by an x-ray powder diffraction pattern as follows:
9.30, 10.80, 14.25, 14.98, 15.94, 19.23, 20.04.
15. Methylene chloride solvate IB of olanzapine according to claim 14, characterized by an x-ray powder diffraction pattern as follows:
8.43, 8.86, 9.30, 10.80, 14.25, 14.98, 15.94, 16.88, 17.79, 18.40, 18.57, 18.83, 19.23, 19.57, 20.04, 20.79, 21.01, 21.68, 22.06, 22.23, 23.57, 24.02, 24.89, 25.12, 25.46, 26.38, 26.56, 27.50, 28.06, 28.71, 29.02.
16. Process for preparing anhydrous forms of olanzapine by using at least one solvate according to any one of claims 6 to 15.
17. Process according to claim 16, wherein the anhydrous form of form I of olanzapine is prepared and wherein at least one solvate accordmg to any one of claims 12 and 15 is dried.
18. Form A of olanzapine characterized by an x-ray powder diffraction pattern as follows:
11.52, 12.00, 13.35, 13.56, 14.21, 15.47, 16.69, 19.16, 20.25, 20.69, 22.12, 24.33, 26.88, 27.13.
19. Form A of olanzapine according to claim 18, characterized by an x-ray powder diffraction pattern as follows:
11.52, 11.83, 12.00, 13.35, 13.56, 14.21, 15.47, 16.69, 17.83, 19.16, 20.25, 20.69, 21.65, 22.12, 23.21, 24.33, 26.88, 27.13, 28.57.
20. Form A of olanzapine according to claim 18 or 19, which is in essentially pure form.
21. Form A of olanzapine according to claim 18, 19 or 20, which is anhydrous.
22. Process for preparing form A of olanzapine as defined in claim 18 to 21, comprising the steps of dissolving any form of olanzapine in a mixture of acetonitrile with a solvent in which olanzapine is soluble or in a solvent in which olanzapine is soluble, heating the mixture to obtain a clear solution, optionally filtering the solution, partly evaporating the solvent and isolating the product.
23. Pharmaceutical composition which comprises form A of olanzapine according to any one of claims 18 to 21.
PCT/SI2003/000024 2002-07-15 2003-07-14 Crystal forms of olanzapine and processes for their preparation WO2004006933A2 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
US10/521,646 US7745429B2 (en) 2002-07-15 2003-07-14 Crystal forms of olanzapine and processes for their preparation
SI200332341T SI1551414T1 (en) 2002-07-15 2003-07-14 Process for preparing the crystal form I of olanzapine
CA002493370A CA2493370C (en) 2002-07-15 2003-07-14 Crystal forms of olanzapine and processes for their preparation
UAA200501303A UA83633C2 (en) 2002-07-15 2003-07-14 Process for the preparation of forms of olanzapine and solvates of olanzapine and use thereof for the preparation of anhydrous forms of olanzapine
YU20050023A RS53474B (en) 2002-07-15 2003-07-14 Processes for preparing the crystal form i of olanzapine
AU2003256242A AU2003256242A1 (en) 2002-07-15 2003-07-14 Crystal forms of olanzapine and processes for their preparation
EP03764287.3A EP1551414B1 (en) 2002-07-15 2003-07-14 Process for preparing the crystal form I of olanzapine
EA200500188A EA008055B1 (en) 2002-07-15 2003-07-14 Crystal forms of olanzapine and processes for their preparation
HRP20050039AA HRP20050039B1 (en) 2002-07-15 2005-01-14 Crystal forms of olanzapine and processes for their preparation
NO20050720A NO20050720L (en) 2002-07-15 2005-02-10 Crystal forms of olanzapine and process for their preparation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SI200200175A SI21270A (en) 2002-07-15 2002-07-15 Crystal forms of olanzapine and procedures for their preparation
SIP-200200175 2002-07-15

Publications (2)

Publication Number Publication Date
WO2004006933A2 true WO2004006933A2 (en) 2004-01-22
WO2004006933A3 WO2004006933A3 (en) 2004-04-01

Family

ID=30113490

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SI2003/000024 WO2004006933A2 (en) 2002-07-15 2003-07-14 Crystal forms of olanzapine and processes for their preparation

Country Status (12)

Country Link
US (1) US7745429B2 (en)
EP (1) EP1551414B1 (en)
AU (1) AU2003256242A1 (en)
CA (1) CA2493370C (en)
EA (1) EA008055B1 (en)
HR (1) HRP20050039B1 (en)
NO (1) NO20050720L (en)
PL (1) PL217081B1 (en)
RS (1) RS53474B (en)
SI (2) SI21270A (en)
UA (1) UA83633C2 (en)
WO (1) WO2004006933A2 (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004056833A1 (en) * 2002-12-20 2004-07-08 Adamed Sp. Z O.O. A process for the preparation of a pharmaceutically pure polymorphic form i of olanzapine
WO2005070937A1 (en) * 2004-01-27 2005-08-04 Synthon B.V. A process for making olanzapine in a polymorph form i
WO2005085256A1 (en) * 2004-03-08 2005-09-15 Krka, Tovarna Zdravil, D.D., Novo Mesto Isopropanol water solvate of olanzapine
WO2006013435A1 (en) * 2004-07-27 2006-02-09 Inke, S.A. Mixed solvate of olanzapine, method for preparing it and method for preparing form i of olanzapine therefrom
WO2007052167A2 (en) 2005-11-03 2007-05-10 Actavis Group Ptc Ehf Stable composition for a pharmaceutical formulation containing olanzapine
WO2007087555A2 (en) * 2006-01-26 2007-08-02 Sandoz Ag Novel polymorph 'form e ' of olanzapine (2-methyl-4- (4-methyl-1-piperazinyl) -10h-thieno [2, 3-b] [1, 5] benzodiazepine) and preparation of the anhydrous non-solvated crystalline polymorphic 'form i' of olanzapine from the polymorphic olanzapine 'form e'
US7329747B2 (en) 2004-01-27 2008-02-12 Synthon Ip Inc. Synthesis of olanzapine and intermediates thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1575962A1 (en) * 2002-12-24 2005-09-21 Teva Pharmaceutical Industries Limited Novel crystal forms of olanzapine, methods for their preparation and method for the preparation of known olanzapine crystal forms

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1533235A (en) 1974-11-26 1978-11-22 Lilly Industries Ltd Benzodiazepine derivatives
US5229382A (en) 1990-04-25 1993-07-20 Lilly Industries Limited 2-methyl-thieno-benzodiazepine
EP0733634B1 (en) 1995-03-24 2000-11-22 Eli Lilly And Company Process for preparing a thieno(2,3-B)(1,5) benzodiazepine derivative
EP0733635B1 (en) 1995-03-24 2001-08-16 Eli Lilly And Company Crystal forms of a thieno(2,3-B)(1,5) benzodiazepine derivative and process for their preparation
WO2002018390A1 (en) 2000-08-31 2002-03-07 Dr. Reddy's Laboratories Ltd. Process for preparation of hydrates of olanzapine and their conversion into crystalline forms of olanzapine

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CR5278A (en) * 1995-03-24 1996-07-04 Lilly Co Eli ORAL FORMULATION OF 2-METHYL-THENO-BENZODIACEPINE
US5631250A (en) * 1995-03-24 1997-05-20 Eli Lilly And Company Process and solvate of 2-methyl-thieno-benzodiazepine
US5776928A (en) * 1995-04-21 1998-07-07 Eli Lilly And Company Method for treating dyskinesias with olanzapine
US6506746B2 (en) * 1995-05-30 2003-01-14 Eli Lilly And Company Method for treating cognitive dysfunction
NZ334346A (en) 1996-09-23 2000-05-26 Lilly Co Eli Olanzapine dihydrate D comprising 2-methyl-4-(4-methyl-1-piperazinyl)-1OH-thieno[2,3-b][1,5]benzodiazepine and a formulation for use in treating central nervous system disorders
ZA978515B (en) 1996-09-23 1999-03-23 Lilly Co Eli Intermediates and process for preparing olanzapine
CA2304472A1 (en) * 1997-09-30 1999-04-08 Pierre Van Tran Method for treating sexual dysfunction
WO2001047933A1 (en) * 1999-12-28 2001-07-05 Cipla Limited New polymorphic forms of olanzapine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1533235A (en) 1974-11-26 1978-11-22 Lilly Industries Ltd Benzodiazepine derivatives
US5229382A (en) 1990-04-25 1993-07-20 Lilly Industries Limited 2-methyl-thieno-benzodiazepine
EP0733634B1 (en) 1995-03-24 2000-11-22 Eli Lilly And Company Process for preparing a thieno(2,3-B)(1,5) benzodiazepine derivative
EP0733635B1 (en) 1995-03-24 2001-08-16 Eli Lilly And Company Crystal forms of a thieno(2,3-B)(1,5) benzodiazepine derivative and process for their preparation
WO2002018390A1 (en) 2000-08-31 2002-03-07 Dr. Reddy's Laboratories Ltd. Process for preparation of hydrates of olanzapine and their conversion into crystalline forms of olanzapine

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004056833A1 (en) * 2002-12-20 2004-07-08 Adamed Sp. Z O.O. A process for the preparation of a pharmaceutically pure polymorphic form i of olanzapine
WO2005070937A1 (en) * 2004-01-27 2005-08-04 Synthon B.V. A process for making olanzapine in a polymorph form i
US7459449B2 (en) 2004-01-27 2008-12-02 Rolf Keltjens Stable salts of olanzapine
US7329747B2 (en) 2004-01-27 2008-02-12 Synthon Ip Inc. Synthesis of olanzapine and intermediates thereof
WO2005085256A1 (en) * 2004-03-08 2005-09-15 Krka, Tovarna Zdravil, D.D., Novo Mesto Isopropanol water solvate of olanzapine
WO2006013435A1 (en) * 2004-07-27 2006-02-09 Inke, S.A. Mixed solvate of olanzapine, method for preparing it and method for preparing form i of olanzapine therefrom
ES2253091A1 (en) * 2004-07-27 2006-05-16 Inke, S.A. Mixed solvate of olanzapine, method for preparing it and method for preparing form i of olanzapine therefrom
US7759484B2 (en) 2004-07-27 2010-07-20 Inke, S.A. Mixed solvate of olanzapine, method for preparing it and method for preparing form I of olanzapine therefrom
JP2008508254A (en) * 2004-07-27 2008-03-21 インケ、ソシエダ、アノニマ Olanzapine mixed solvate, process for producing the same, and process for producing olanzapine form I
WO2007052167A3 (en) * 2005-11-03 2008-03-13 Actavis Group Ptc Ehf Stable composition for a pharmaceutical formulation containing olanzapine
WO2007052167A2 (en) 2005-11-03 2007-05-10 Actavis Group Ptc Ehf Stable composition for a pharmaceutical formulation containing olanzapine
WO2007087555A3 (en) * 2006-01-26 2007-10-25 Sandoz Ag Novel polymorph 'form e ' of olanzapine (2-methyl-4- (4-methyl-1-piperazinyl) -10h-thieno [2, 3-b] [1, 5] benzodiazepine) and preparation of the anhydrous non-solvated crystalline polymorphic 'form i' of olanzapine from the polymorphic olanzapine 'form e'
WO2007087555A2 (en) * 2006-01-26 2007-08-02 Sandoz Ag Novel polymorph 'form e ' of olanzapine (2-methyl-4- (4-methyl-1-piperazinyl) -10h-thieno [2, 3-b] [1, 5] benzodiazepine) and preparation of the anhydrous non-solvated crystalline polymorphic 'form i' of olanzapine from the polymorphic olanzapine 'form e'
US7834176B2 (en) 2006-01-26 2010-11-16 Sandoz Ag Polymorph E of Olanzapine and preparation of anhydrous non-solvated crystalline polymorphic Form I of 2-methyl-4(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5] benzodiazepine (Olanzapine Form I) from the polymorphic Olanzapine Form E

Also Published As

Publication number Publication date
US20060040920A1 (en) 2006-02-23
RS53474B (en) 2014-12-31
EP1551414A2 (en) 2005-07-13
CA2493370C (en) 2009-09-29
US7745429B2 (en) 2010-06-29
EA200500188A1 (en) 2005-06-30
AU2003256242A1 (en) 2004-02-02
CA2493370A1 (en) 2004-01-22
RS20050023A (en) 2007-06-04
EA008055B1 (en) 2007-02-27
SI21270A (en) 2004-02-29
HRP20050039B1 (en) 2014-10-10
PL373845A1 (en) 2005-09-19
NO20050720L (en) 2005-02-10
UA83633C2 (en) 2008-08-11
HRP20050039A2 (en) 2005-08-31
EP1551414B1 (en) 2013-11-27
SI1551414T1 (en) 2014-04-30
WO2004006933A3 (en) 2004-04-01
PL217081B1 (en) 2014-06-30

Similar Documents

Publication Publication Date Title
AU2001243475A1 (en) Process for preparation of hydrates of olanzapine and their conversion into crystalline forms of olanzapine
HRP20050039A2 (en) Crystal forms of olanzapine and processes for their preparation
EP1656381B1 (en) Crystallisation of solid forms of clopidogrel addition salts
KR20110041431A (en) Solid and crystalline dutasteride and processes for preparation thereof
WO2013105106A1 (en) An improved process for the preparation of etoricoxib and polymorphs thereof
EP2850064A1 (en) Process for preparation of montelukast sodium
CA2395774C (en) New polymorphic forms of olanzapine
US7829700B2 (en) Process for preparation of a pharmaceutically pure polymorphic form I of Olanzapine
SI21850A (en) Salts of olanzapin and their transformation into free base of olanzapin
AU2009264395A1 (en) Process for the preparation of clopidogrel hydrogen sulfate crystalline form I
WO2007102167A1 (en) A process for the preparation of anhydrous polymorphic form of olanzapine
EP1730153B1 (en) Isopropanol water solvate of olanzapine
US8106188B2 (en) Process for preparing olanzapine form I
EP1716154A1 (en) Process for the preparation of olanzapine form 1 useful as antipsychotic drug
KR101489062B1 (en) Process for the preparation of high purity olanzapine and crystalline form II thereof
KR20020093090A (en) (5R)-(Methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione
WO2004007496A1 (en) Process for the preparation of imidazo(1,2-a)pyridine-3-acetamides
EP1632473A1 (en) Sertraline hydrochloride polymorphs
SI21746A (en) Crystal forms of olanzapine and processes for their preparation
WO2007096895A1 (en) Preparation of anhydrous olanzapine of form-1
ZA200301640B (en) Process for preparation of hydrates of Olanzapine and their conversion into cystalline forms of Olanzapine.

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: P-2005/0023

Country of ref document: YU

AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 2493370

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2006040920

Country of ref document: US

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 10521646

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 373845

Country of ref document: PL

Ref document number: P20050039A

Country of ref document: HR

WWE Wipo information: entry into national phase

Ref document number: 200500188

Country of ref document: EA

WWE Wipo information: entry into national phase

Ref document number: 2003764287

Country of ref document: EP

Ref document number: 184/CHENP/2005

Country of ref document: IN

WWP Wipo information: published in national office

Ref document number: 2003764287

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 10521646

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Ref document number: JP