WO2004006933A2 - Crystal forms of olanzapine and processes for their preparation - Google Patents
Crystal forms of olanzapine and processes for their preparation Download PDFInfo
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- 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
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- WIPO (PCT)
- Prior art keywords
- olanzapine
- solvate
- methylene chloride
- diffraction pattern
- acetonitrile
- Prior art date
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- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 title claims abstract description 164
- 229960005017 olanzapine Drugs 0.000 title claims abstract description 163
- 238000000034 method Methods 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 239000013078 crystal Substances 0.000 title description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 81
- 239000012453 solvate Substances 0.000 claims abstract description 73
- 239000011877 solvent mixture Substances 0.000 claims abstract description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 165
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 123
- 239000002904 solvent Substances 0.000 claims description 43
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 21
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 238000001704 evaporation Methods 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000000243 solution Substances 0.000 description 46
- 239000000047 product Substances 0.000 description 22
- 239000000725 suspension Substances 0.000 description 17
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 15
- 229940049706 benzodiazepine Drugs 0.000 description 15
- 238000001035 drying Methods 0.000 description 14
- 239000007858 starting material Substances 0.000 description 9
- 238000001816 cooling Methods 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 8
- 238000002329 infrared spectrum Methods 0.000 description 7
- 238000002441 X-ray diffraction Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 238000003828 vacuum filtration Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 238000010899 nucleation Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 150000004677 hydrates Chemical class 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- FUOBHGGXKJHKDF-UHFFFAOYSA-N 2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine dihydrate Chemical compound O.O.C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 FUOBHGGXKJHKDF-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 2
- 208000028017 Psychotic disease Diseases 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000006748 scratching Methods 0.000 description 2
- 230000002393 scratching effect Effects 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- DQHIXWWYDHOZKI-UHFFFAOYSA-N 2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine hydrate Chemical group O.CN1CCN(CC1)C1=Nc2ccccc2Nc2sc(C)cc12 DQHIXWWYDHOZKI-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010026749 Mania Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 150000004683 dihydrates Chemical group 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 150000004682 monohydrates Chemical group 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
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).
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- Neurology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
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 |
US10/521,646 US7745429B2 (en) | 2002-07-15 | 2003-07-14 | Crystal forms of olanzapine and processes for their preparation |
AU2003256242A AU2003256242A1 (en) | 2002-07-15 | 2003-07-14 | Crystal forms of olanzapine and processes for their preparation |
EA200500188A EA008055B1 (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 |
SI200332341T SI1551414T1 (en) | 2002-07-15 | 2003-07-14 | Process for preparing the crystal form I of olanzapine |
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 |
---|---|---|---|
SIP-200200175 | 2002-07-15 | ||
SI200200175A SI21270A (en) | 2002-07-15 | 2002-07-15 | Crystal forms of olanzapine and procedures for their preparation |
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)
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)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7323459B2 (en) * | 2002-12-24 | 2008-01-29 | Teva Pharmaceutical Industries Ltd. | Crystal forms, methods for their preparation and method for preparation of olanzapine |
Citations (5)
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)
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---|---|---|---|---|
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 |
CA2266444C (en) | 1996-09-23 | 2007-01-09 | Eli Lilly And Company | Olanzapine dihydrate d |
ZA978515B (en) | 1996-09-23 | 1999-03-23 | Lilly Co Eli | Intermediates and process for preparing olanzapine |
WO1999016312A1 (en) * | 1997-09-30 | 1999-04-08 | Eli Lilly And Company | Method for treating sexual dysfunction |
NZ519926A (en) | 1999-12-28 | 2004-02-27 | Cipla Ltd | New polymorphic forms of olanzapine |
-
2002
- 2002-07-15 SI SI200200175A patent/SI21270A/en not_active IP Right Cessation
-
2003
- 2003-07-14 EA EA200500188A patent/EA008055B1/en not_active IP Right Cessation
- 2003-07-14 US US10/521,646 patent/US7745429B2/en not_active Expired - Fee Related
- 2003-07-14 UA UAA200501303A patent/UA83633C2/en unknown
- 2003-07-14 SI SI200332341T patent/SI1551414T1/en unknown
- 2003-07-14 AU AU2003256242A patent/AU2003256242A1/en not_active Abandoned
- 2003-07-14 CA CA002493370A patent/CA2493370C/en not_active Expired - Fee Related
- 2003-07-14 RS YU20050023A patent/RS53474B/en unknown
- 2003-07-14 EP EP03764287.3A patent/EP1551414B1/en not_active Expired - Lifetime
- 2003-07-14 WO PCT/SI2003/000024 patent/WO2004006933A2/en not_active Application Discontinuation
- 2003-07-14 PL PL373845A patent/PL217081B1/en unknown
-
2005
- 2005-01-14 HR HRP20050039AA patent/HRP20050039B1/en not_active IP Right Cessation
- 2005-02-10 NO NO20050720A patent/NO20050720L/en unknown
Patent Citations (5)
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)
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 |
---|---|
PL217081B1 (en) | 2014-06-30 |
RS20050023A (en) | 2007-06-04 |
PL373845A1 (en) | 2005-09-19 |
EA200500188A1 (en) | 2005-06-30 |
HRP20050039B1 (en) | 2014-10-10 |
EP1551414A2 (en) | 2005-07-13 |
CA2493370A1 (en) | 2004-01-22 |
SI21270A (en) | 2004-02-29 |
US7745429B2 (en) | 2010-06-29 |
CA2493370C (en) | 2009-09-29 |
EP1551414B1 (en) | 2013-11-27 |
US20060040920A1 (en) | 2006-02-23 |
NO20050720L (en) | 2005-02-10 |
UA83633C2 (en) | 2008-08-11 |
RS53474B (en) | 2014-12-31 |
SI1551414T1 (en) | 2014-04-30 |
WO2004006933A3 (en) | 2004-04-01 |
EA008055B1 (en) | 2007-02-27 |
HRP20050039A2 (en) | 2005-08-31 |
AU2003256242A1 (en) | 2004-02-02 |
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