WO2005085256A1 - Isopropanol water solvate of olanzapine - Google Patents
Isopropanol water solvate of olanzapine Download PDFInfo
- Publication number
- WO2005085256A1 WO2005085256A1 PCT/EP2005/002389 EP2005002389W WO2005085256A1 WO 2005085256 A1 WO2005085256 A1 WO 2005085256A1 EP 2005002389 W EP2005002389 W EP 2005002389W WO 2005085256 A1 WO2005085256 A1 WO 2005085256A1
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- WO
- WIPO (PCT)
- Prior art keywords
- olanzapine
- isopropanol
- solvate
- process according
- water
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Definitions
- the present invention belongs to the field of organic chemistry and relates to a new mixed solvate form of 2- ⁇ t ⁇ ethyl-4- (4-methyl-l-piperazinyl) -lOH-thieno [2,3-J] [1 5] benzodiazepine (hereinafter referred to by its generic name "olanzapine”) , a process for its preparation and processes for the preparation of polymorphic form I of olanzapine.
- Olanzapine has shown to have high 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.
- the British patent GB 1 533 235 discloses antipsychotically effective thienobenzodiazepines by a generic formula which also covers olanzapine.
- EP-B-733 535 claims crystalline form II olanzapine, and this polymorphic 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.
- WO 03/101997 relates to processes for preparation of form I of olanzapine by regulation of the pH-value of the solution.
- WO 03/055438 discloses the preparation of form I olanzapine by crystallization from ethanol and subsequent conversion of the obtained ethanol solvate.
- US patent 5,637,584 discloses the (mono) methylene chloride solvate form of olanzapine and a method for its conversion to the polymorphic form I of olanzapine.
- EP-B-733 634 discloses three specific solvates of olanzapine, namely the methanol, ethanol and 1-propanol solvates and a process for production of form II olanzapine by drying such a solvate.
- WO 03/097650 describes two new ⁇ mixed solvate forms, the water/methylene chloride solvate and the water/DMSO solvate, methods for preparing them, and their transformation to polymorphic form I .
- WO 2004/006933 discloses a process for the preparation of form I olanzapine, as well as various pseudopolymorphic forms, namely the isopropanol solvate, and the acetonitrile/methylene chloride/water and acetonitrile/water mixed solvates of olanzapine, and the polymorphic form A.
- the invention relates to a water/isopropanol mixed solvate which contains 2 molecules of water and 1 molecule of isopropanol per 2 molecules of olanzapine.
- the solvate according to the invention was subjected to an x- ray structure analysis.
- Single crystal x-ray diffraction data were collected at room temperature on a Nonius Kappa CCD diffractometer by means of the Nonius Collect Software.
- the structure was solved by using SIR97 (direct methods) and the refinement was performed with X'tal software.
- the crystallographic data for the olanzapine isopropanol/water mixed solvate, particularly the' interplanar distances (a, b, c) and angles ( ⁇ , ⁇ , ⁇ ) are indicated in Table 1.
- Table 1 Table 1
- the invention also relates to the isopropanol/water mixed solvate of olanzapine characterized by the x-ray structure shown in Figure 1.
- Figure 1 shows the ORTEP view of the asymmetric unit of the solvate according to the invention which corresponds to the formula C ⁇ 7 H 20 NS .
- H 2 0. is(C 3 H 7 OH) .
- the population of the disordered isopropanole molecule in Figure 1 is 0.50.
- an isopropanol molecule occurs only with every second molecule of olanzapine.
- the solvate according to the invention is characterized by a NMR spectrum in CDC1 3 showing peaks at approximately 1.20 ppm, 2.20-2.40 ppm and 4.03 ppm.
- the solvate is characterized by the NMR spectrum shown in Figure 2.
- the NMR spectra were obtained using a Varian UNITY+ 300 (300 MHz) spectrometer and CDC1 3 as solvent with tetramethylsilane as internal standard.
- Figure 2 shows the NMR spectrum of the solvate according to the invention. The peaks were assigned as follows ( 1 H NMR; CDC1 3 , 300 MHz) :
- the solvate according to the invention is prepared by a process which comprises crystallizing it from a solvent mixture comprising isopropanol and water in a ratio of at least 9 to 1, preferably at least 20 to 1 and most preferred at least 35 to 1 parts by volume.
- the olanzapine used as a starting material for the preparation of the water/isopropanol mixed solvate according to the invention can be in any form, e.g. it can be used when it is contained in a reaction s.olution or in a filtrate in combination- with other solvents, ,• or -Lt can be in crude, anhydrous or any solvated or hydrated form or a mixture thereof.
- the water/isopropanol mixed solvate according to the invention is prepared from a reaction mixture.
- a reaction mixture An example is given in the following.
- isopropanol is added first, followed by the addition of water to initiate crystallization.
- the clear solution is cooled to temperatures from boiling temperature to 10 °C, and water is added to start crystallization.
- the product is then filtered off, washed with isopropanol, dried at room temperature under vacuum to a constant weight, and the water/isopropanol mixed solvate according to the invention is obtained.
- the water/isopropanol mixed solvate of • olanzapine is prepared from mother liquors containing olanzapine and fo example methylene chloride, or from a methylene chloride . solvate. form.
- mother liquors containing olanzapine and fo example methylene chloride, or from a methylene chloride . solvate. form An example is given in the following.
- the solvent is . optionally distilled off, preferably under vacuum, and subsequently isopropanol and water are separately added in any order or a mixture thereof is added.
- isopropanol is added first, followed by the addition of water to initiate crystallization. After the crystallization has been completed, the precipitate is filtered off and dried.
- the water/isopropanol mixed solvate is prepared from crude olanzapine, or from olanzapine in anhydrous or any solvated or hydrated form, or mixtures thereof.
- An example is given in the following.
- the olanzapine is dissolved by heating in a mixture of isopropanol and water, or in either isopropanol or water with the other solvent being subsequently added.
- the obtained clear solution is cooled to temperatures from boiling temperature to 10 °C, and water is added to start crystallization.
- the product is then filtered off, washed with isopropanol, dried at room temperature under vacuum to a constant weight, and the water-isopropanol mixed solvate according to the invention is obtained.
- the water-isopropanol mixed solvate obtained by any one of the above processes can optionally be recrystallized.
- ethylenediaminotetraacetic acid disodium salt can be added and, . after stirring, undissolved material be hot filtered.
- the water-isopropanol mixed solvate according to the invention prepared by any of the above processes is of high quality and substantially free of impurities and is therefore ideally suited for the preparation of various other highly pure solvates, hydrates or anhydrous forms or mixtures thereof .
- the water-isopropanol mixed solvate according to the invention is particularly useful for the preparation of olanzapine form I in a high purity.
- the invention also relates-, to a process for the preparation of form I - olanzapine, wherein the isopropanol/water mixed solvate of olanzapine according to the invention is used.
- 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. According to the process of the present ' invention pure form I could be obtained which is in particular substantially free from form II and solvates.
- step (a) in a step (a) the isopropanol/water mixed solvate is converted to a methylene chloride solvate of olanzapine, and in a step (b) the methylene chloride solvate is converted to form I olanzapine.
- step (a) a solution of the isopropanol/water mixed solvate in methylene chloride is prepared, the solvent is partly evaporated and the remaining solution is cooled.
- step (a) a solution of the isopropanol/water mixed solvate in methylene chloride is prepared, a drying agent is added to the solution, the drying agent is removed from the mixture , and the methylene chloride solvate of olanzapine is recovered.
- the mixture is stirred for some time and filtered, and finally, the product is recovered, e. g. by crystallization after cooling.
- a particularly useful drying agent is anhydrous CaS0.
- step (a) the water- isopropanol mixed solvate according to the invention is suspended in methylene chloride and the suspension is heated until a clear solution is obtained. Then a part of the solvent is evaporated under vacuum or optionally at atmospheric pressure or a combination thereof at temperatures ranging from the boiling point of the solution to -30 °C to precipitate olanzapine methylene chloride solvate, which can be isolated by filtration. Alternatively, the heated solution can be cooled to temperatures from room temperature to -30 °C to precipitate the olanzapine methylene chloride solvate.
- step (a) the water- isopropanol mixed solvate is suspended in methylene chloride and the suspension is heated to 35 °C to obtain a clear solution. Subsequently, a drying agent, preferably Drierite (CaS0 4 anhydrous) , is added, and the desired product is recovered in conventional manner.
- a drying agent preferably Drierite (CaS0 4 anhydrous)
- a seeding with higher amounts of crystalline methylene chloride solvate is effected.
- olanzapine form I is a suitable seeding material. It is preferred to use as methylene chloride solvate in step
- step (b) isopropanol is added to the prepared olanzapine methylene chloride solvate in a volume (1) by weight (kg) ratio of 5:1 to 2:1, preferably 3:1 to 2:1, and the obtained suspension is stirred at a temperature of 15 °C to 35 °C, in particular at room temperature, for 15 to 90 mj-n, preferably from 30 to 60 min.
- seeding with form I olanzapine can be used.
- the filtered product is dried under vacuum at a temperature from room temperature to 50 °C until a constant weight is achieved.
- methylene chloride solvate is . suspended in isopropanol at a weight (kg) by volume (1) ratio of 1:30 to 1:2, preferably 1:15 to 1:3, which has been presaturated with olanzapine.
- the obtained suspension is stirred at a temperature of 5°C to 50>°C, in particular at room temperature, for 15 to 90 min, preferably from 30 to 60 min.
- the product is filtered off and dried under vacuum at room temperature to a constant weight, and then at 50 °C to a constant weight.
- Form I olanzapine is isolated.
- methylene chloride solvate is first dried under vacuum at a temperature of 30 to 55°C .for 6 to 36 hours.
- the obtained product is suspended in isopropanol at a weight (kg) by volume (1) ratio of 1:5 to 1:2, preferably 1:3 to 1:2.
- the obtained suspension is stirred at a ' temperature of 15°C to 35 °C, in particular at room temperature, for 15 to 60 min, preferably from 15 to 30 min.
- the product is filtered off and dried under vacuum at room temperature to a constant weight, and then at 50 °C to a constant weight.
- solid isopropanol/water mixed solvate of olanzapine according ' to the invention is mixed with solid olanzapine of form. I and the particle size of the mixture is reduced. . :
- the mixing and the size-reduction take place in a single step by for example grinding or milling the mixture. Grinding can take place in a mortar and for milling usual milling machines can be .used.
- the mixture preferably comprises up to 10% and in particular up to 5% by weight of form I olanzapine.
- the obtained material is usually dried to give the desired form I olanzapine.
- the drying is preferably conducted in a vacuum drier at temperatures ranging from room temperature to ' 80 °C, preferably from room temperature to 60 °C and most preferred from 40 to 50°C.
- the dried material is preferably suspended in isopropanol in a weight (kg) to volume (1) ratio of 1:5 to 1:2, in particular 1:3 to 1:2.
- the suspension is preferably stirred • at a temperature of 15 to
- the drying is preferably conducted under vacuum at room temperature to a constant weight and then at 50 °C to a constant weight.
- the invention also relates to a process for the preparation of any other solvate or hydrate forms of olanzapine, or mixtures ' thereof, wherein the isopropanol/water mixed solvate of olanzapine according to the invention is used.
- the invention also relates to a process for the preparation of anhydrous forms of olanzapine, wherein the isopropanol/water mixed solvate of olanzapine according to the invention is used.
- the invention therefore also relates to a process for preparing form I olanzapine wherein at least one of (a) precursors for olanzapine for ' I and (b) olanzapine form I is crystallized or precipitated from a liquid medium which medium is present in a container wherein the surfaces of the container contacting the medium are comprising at least one polymer, preferably are consisting of at least one polymer. It was unexpectedly found out that such polymer surfaces in particular diminish the likelihood of formation of the undesired form II of olanzapine, especially when using elevated temperatures . This is very beneficial since the form II is an impurity which is very difficult to be removed, if possible at all, and even small amounts thereof may function as seeding crystals which lead to formation of further amounts of the undesired form II olanzapine.
- the precursors and/or the olanzapine form I are prepared using the isopropanol/water mixed solvate according to the invention. This leads to highly pure olanzapine form I .
- the liquid medium can be a solution or dispersion which upon crystallization or precipitation leads to form I olanzapine or a precursor of form I olanzapine.
- At least one crystallization or precipitation step of a precursor is carried out such that the liquid medium is contacting the mentioned polymer surface.
- a precursor is the methylene chloride hemisolvate of olanzapine. It was found out that in particular in the crystallization or precipitation of the methylene chloride hemisolvate the likelihood of formation of the undesired form II olanzapine is diminished if carried in contact with the polymer surfaces .
- the methylene chloride hemisolvate has been prepared- by using the very pure isopropanol/water mixed solvate according to the invention. This accomplishes the preparation of very pure olanzapine of form I. ' -.
- the container can be any equipment, like a vessel or reactor, wherein a crystallization or precipitation occurs.
- polystyrene resin contains fluorine.
- Preferred examples are selected from polytetrafluoroethylene, e.g available under the brand Teflon, fluorinated ethylene propylene copolymer, perfluoro alkoxy polymer, or ethylene terafluoroethylene copolymer.
- the surfaces contacting the liquid medium are comprising polymer or are consisting of polymer, but typically the whole container is made of polymer, preferably made of polytetrafluoroethylene.
- the invention is in the following illustrated by means of examples .
- Example 6 The solution of 2 , 4-bis ( 4-metbyl-l-piperazinyl) -3- propylidene-3i7- [ 1 , 5 ] benz odiazepine ( 41 . 86 g, 0 . 11 mmol) (prepared according to WO 2004 /065390 ) , pyridinium p- toluenesulfonate (55.29 g, 0.22 -itimol) and sulfur (11.99 g, 0.374 mmol) in benzonitrile (1100 .mL) was stirred at 140°C for 11 h, cooled to 90 °C and concentrated to an oily residue.
- the wet material was suspended in isopropanol (215 ml) and heated to reflux to obtain a clear solution. The solution was hot filtered. Water (6.5 ml) was added to induce crystallization. The obtained 'suspension was cooled to 0°C, and upon completion of crystallisation, the product was filtered off and washed with isopropanol (10 ml) . The product was dried at room temperature under vacuum to a constant weight. Yield: 18.61 g. Loss on drying (140°C): 12.8 %. Water content (Karl Fischer) : 5.29 %.
- Olanzapine water-isopropanol mixed solvate (30 g) was suspended in methylene chloride (330 ml) and heated to 35°C to. obtain a clear solution.
- D ierite (CaS0 anhydrous, 45 g) was added and it was stirred for one hour. The suspension was hot filtered and concentrated under vacuum to a volume of 100 ml. During vacuum destination the solution was cooled and the product precipitated. The- product was filtered off and dried under vacuum at room temperature to a constant weight. Yield: 21.31 g. Loss on drying (140°C) : 11.3%. Water content (Karl Fischer): 0.51%. " -
- Olanzapine water-isopropanol mixed solvate 25 g was suspended in methylene chloride (300 ml) and heated to obtain a clear solution. The mixture was concentrated at 25 to 30 °C under weak vacuum to 130 ml. The mixture was hot filtered and cooled to -20 °C. The obtained suspension was filtered and the wet cake was dried under vacuum at room temperature to a constant weight. Yield: 17.7 -g. Loss on drying (140°C): 12.8%. Water content (Karl Fischer): 1.16%.
- Olanzapine water-isopropanol mixed ' solvate (30 g) was suspended in methylene chloride (360 ml) and the suspension was heated to obtain a clear solution. The solution was concentrated at 25 to 30 °C under weak . ' vacuum to 180 ml. The mixture was hot filtered into a reactor made from perfluorated polymer and evaporated ' to dryness at room temperature under vacuum. The residue was dried under vacuum at room temperature to a constant weight. Yield: 27.5 g. Loss on drying (140°C) : 12.6%. Water content (Karl Fischer): 0.41%.
- Olanzapine water-isopropanol mixed solvate 50 g was suspended in methylene chloride (600 ml) and the suspension was heated to obtain a clear solution. The solution was concentrated at 25 to 30 °C under a weak vacuum to 220 ml. The solution was then hot filtered and seeded with olanzapine form I. The suspension was cooled to -15°C and solids were filtered off. The obtained wet cake was dried under vacuum at room temperature to a constant weight. Yield: 36.15 g. Loss on drying (140°C).: 12.7%. Water content (Karl Fischer): 0.57%.
- Olanzapine methylene chloride hemisolvate (10 g) was suspended in isopropanol (20 ml) . The suspension was stirred at room temperature for one hour. The product was filtered off and dried under vacuum at room temperature to a constant weight, and then at 50°C to a.constant weight. Yield: 7.8 g.
- Olanzapine methylene chloride hemisolvate (10 g) was suspended in isopropanol (150 ' " ml, presaturated with olanzapine) . The suspension was stirred at room temperature for one hour. The product was filtered off and dried under vacuum at room temperature to a constant weight, and then at 50 °C to a constant weight. Yield: 14.3 g.
- Olanzapine methylene chloride hemisolvate (6.00 g) was homogenized with olanzapine form I (0.3O g) .
- the mixture was suspended in isopropanol (150 ml) and stirred at room temperature for 40 min.
- the suspension was filtered and the filter cake dried under vacuum at room temperature to a constant weight, and then at 50 °C to a constant weight. Yield: 4.63 g.
- Olanzapine methylene chloride ' .hemisolvate (20 g) was dried under vacuum at 50 °C for 12 hours.
- a mixture of olanzapine water-isopxopanol mixed solvate (5g) and olanzapine of form I (0.25g) was grinded in a mortar. 5.071 g of the obtained material were dried in a vacuum drier at 50°C for 16 h to yield 4.430 g of dried material. 3.5 g of the dried material were suspended in 8.8 ml of isopropanol, and the suspension was stirred at room temperature for 15 min. The obtained mixture was filtered and the separated solid was dried under vacuum until constant weight was achieved and then at 50 °C to constant weight.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP05707723A EP1730153B1 (en) | 2004-03-08 | 2005-03-07 | Isopropanol water solvate of olanzapine |
EA200601563A EA200601563A1 (en) | 2004-03-08 | 2005-03-07 | ВОДНО-ИЗОПРОПАНОЛЬНЫЙ SOLLATE OLANZAPINE |
US10/591,831 US7906642B2 (en) | 2004-03-08 | 2005-03-07 | Isopropanol water solvate of olanzapine |
PL05707723T PL1730153T3 (en) | 2004-03-08 | 2005-03-07 | Isopropanol water solvate of olanzapine |
CA002557986A CA2557986A1 (en) | 2004-03-08 | 2005-03-07 | Isopropanol water solvate of olanzapine |
SI200531386T SI1730153T1 (en) | 2004-03-08 | 2005-03-07 | Isopropanol water solvate of olanzapine |
AT05707723T ATE517109T1 (en) | 2004-03-08 | 2005-03-07 | ISOPROPANOL WATER SOLVATE OF OLNZAPINE |
NO20064484A NO20064484L (en) | 2004-03-08 | 2006-10-03 | Isopropanol-aqueous solution of olanzapine |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SI200400073A SI21746A (en) | 2004-03-08 | 2004-03-08 | Crystal forms of olanzapine and processes for their preparation |
SIP-200400073 | 2004-03-08 | ||
DE200410060412 DE102004060412A1 (en) | 2004-12-14 | 2004-12-14 | New isopropanol and water mixed solvate of olanzapine used to prepare any other solvate and/or hydrate forms of olanzapine, or anhydrous forms of olanzapine |
DE102004060412.6 | 2004-12-14 |
Publications (1)
Publication Number | Publication Date |
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WO2005085256A1 true WO2005085256A1 (en) | 2005-09-15 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2005/002389 WO2005085256A1 (en) | 2004-03-08 | 2005-03-07 | Isopropanol water solvate of olanzapine |
Country Status (9)
Country | Link |
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US (1) | US7906642B2 (en) |
EP (1) | EP1730153B1 (en) |
AT (1) | ATE517109T1 (en) |
CA (1) | CA2557986A1 (en) |
EA (1) | EA200601563A1 (en) |
NO (1) | NO20064484L (en) |
PL (1) | PL1730153T3 (en) |
SI (1) | SI1730153T1 (en) |
WO (1) | WO2005085256A1 (en) |
Cited By (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 |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2007138376A1 (en) * | 2006-06-01 | 2007-12-06 | Aurobindo Pharma Limited | An improved process for preparing olanzapine form i |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004006933A2 (en) * | 2002-07-15 | 2004-01-22 | Krka, D.D., Novo Mesto | Crystal forms of olanzapine and processes for their preparation |
-
2005
- 2005-03-07 AT AT05707723T patent/ATE517109T1/en not_active IP Right Cessation
- 2005-03-07 EA EA200601563A patent/EA200601563A1/en unknown
- 2005-03-07 PL PL05707723T patent/PL1730153T3/en unknown
- 2005-03-07 EP EP05707723A patent/EP1730153B1/en active Active
- 2005-03-07 WO PCT/EP2005/002389 patent/WO2005085256A1/en active Application Filing
- 2005-03-07 SI SI200531386T patent/SI1730153T1/en unknown
- 2005-03-07 CA CA002557986A patent/CA2557986A1/en not_active Abandoned
- 2005-03-07 US US10/591,831 patent/US7906642B2/en not_active Expired - Fee Related
-
2006
- 2006-10-03 NO NO20064484A patent/NO20064484L/en not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004006933A2 (en) * | 2002-07-15 | 2004-01-22 | Krka, D.D., Novo Mesto | Crystal forms of olanzapine and processes for their preparation |
Cited By (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 |
Also Published As
Publication number | Publication date |
---|---|
PL1730153T3 (en) | 2012-01-31 |
SI1730153T1 (en) | 2011-11-30 |
US20070191348A1 (en) | 2007-08-16 |
CA2557986A1 (en) | 2005-09-15 |
NO20064484L (en) | 2006-11-29 |
US7906642B2 (en) | 2011-03-15 |
EP1730153A1 (en) | 2006-12-13 |
EA200601563A1 (en) | 2006-12-29 |
ATE517109T1 (en) | 2011-08-15 |
EP1730153B1 (en) | 2011-07-20 |
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