EP1934183A1 - Methods of preparing anhydrous aripiprazole form ii - Google Patents
Methods of preparing anhydrous aripiprazole form iiInfo
- Publication number
- EP1934183A1 EP1934183A1 EP06825291A EP06825291A EP1934183A1 EP 1934183 A1 EP1934183 A1 EP 1934183A1 EP 06825291 A EP06825291 A EP 06825291A EP 06825291 A EP06825291 A EP 06825291A EP 1934183 A1 EP1934183 A1 EP 1934183A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- aripiprazole
- slurry
- acetone
- temperature
- mixture
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the invention encompasses methods of preparing anhydrous aripiprazole Form II.
- Schizophrenia is the most common type of psychosis caused by excessive neurotransmission activity of the dopaminergic nervous system in the central nervous system.
- a number of drugs which block the neurotransmission of dopaminergic receptor in the central nervous system have been developed for use in treating schizophrenia.
- drugs developed are phenothiazine-type compounds such as chlorpromazine, butyrophenone-type compounds such as haloperidol, and benzamide-type compounds such as sulpiride. These drugs improve so-called positive symptoms in the acute period of schizophrenia such as hallucinations, delusions, and excitations.
- Aripiprazole is a pyschotropic drug that exhibits high affinity for dopamine D 2 and D 3 , serotonin 5-HT 1A and 5-HT 2A receptors; moderate affinity for dopamine D 4 , serotonin 5-HT 2 c and 5-HT 7 , ⁇ -adrenergic and histamine H 1 receptors; and moderate affinity for the serotonin reuptake site.
- Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors.
- the mechanism of action of aripiprazole, as with other drugs having efficacy in schizophrenia, is unknown. It has been proposed, however, that the efficacy of aripiprazole is mediated through a combination of partial agonist activity at D 2 and 5-HT 1 A receptors and antagonist activity at 5-HT 2A receptors.
- Type-I aripiprazole crystals can be prepared by recrystallizing aripiprazole from an ethanol solution or by heating aripiprazole hydrate at 80°C.
- Type-II aripiprazole crystals can be prepared by heating the Type-I crystals at 130°C to 140°C for 15 hours. This process is not easily applied to an industrial scale preparation of anhydride aripiprazole.
- PCT publication WO 03/26659 discloses the preparation of anhydrous aripiprazole Type I and crystalline Forms A, B, C, D, E, F. and G.
- the powder x-ray diffraction spectrum for aripiprazole Form C has characteristic peaks at 12.6°, 13.7°, 15.4°, 18.1°, 19.0°, 20.6°, 23.5°, and 26.4° 2-theta.
- the process for preparing the crystalline forms comprises heating crystalline anhydrous aripiprazole.
- the process is cumbersome because it requires crystalline anhydrous aripiprazole as the starting material.
- the process can include drying or heating the aripiprazole which may affect the distribution of crystalline forms and/or crystalline purity, if drying causes crystalline transformation from one crystalline form to another.
- the methods of the invention provide procedures that consistently and reproducibly yield Form II consistently to increase the arsenal of crystalline forms available to the skilled artisan in preparing pharmaceutical formulations.
- One embodiment of the invention encompasses a method of preparing anhydrous aripiprazole Form II comprising slurrying aripiprazole in a solvent selected from the group consisting of: C 3 -C 8 ketones, THF, acetonitrile, butyl-acetate, dimethyl formamide (DMF), a mixture of tetrahydrofuran (THF) and IPA, water, diethyl ether (DEE) and acetone; heating the slurry; and isolating anhydrous aripiprazole Form II from the slurry.
- the method can further comprise seeding the slurry with aripiprazole Form II prior to the heating step.
- Another embodiment of the invention encompasses a method of preparing anhydrous aripiprazole Form II comprising providing a mixture of aripiprazole in acetone; heating the mixture at a temperature of about 56 0 C; cooling the mixture to room temperature; maintaining the mixture at a temperature of about 4 0 C for about 15 hours to obtain anhydrous aripiprazole Form II; providing a slurry of starting aripiprazole in acetone; seeding the slurry with the anhydrous aripiprazole Form II obtained from the mixture; heating the slurry at a temperature of about 25°C to about 5O 0 C; and isolating aripiprazole Form II.
- Another embodiment of the invention encompasses a method of preparing anhydrous aripiprazole Form II comprising: providing a mixture of aripiprazole in a solvent selected from the group consisting of: C 3 -C 8 ketones, THF, acetonitrile, butyl- acetate, dimethyl formamide (DMF), a mixture of tetrahydrofuran (THF) and IPA, water, diethyl ether (DEE) and acetone; heating the mixture at a temperature of about 45 0 C to about the reflux temperature; cooling the mixture to a temperature of about 1O 0 C to about -2O 0 C; maintaining the mixture for about 15 minutes to about 60 hours to obtain anhydrous aripiprazole Form II; isolating the anhydrous aripiprazole Form II; providing a slurry of aripiprazole in a solvent selected from the group consisting of: C 3 -C 8 ketones, THF, acetonit
- Another embodiment of the invention encompasses a method of preparing aripiprazole Form II comprising: combining aripiprazole and acetone to obtain a slurry; and seeding the slurry with aripiprazole Form II.
- Figure 1 illustrates the powder X-ray diffraction pattern for Form II.
- the process of the invention describes slurrying aripiprazole from a low boiling solvent such as acetone.
- a low boiling solvent such as acetone.
- the process is reproducible and consistent such that it can be applied in the large scale manufacture of crystalline aripiprazole.
- the slurry in acetone reduces the amounts of solvent used during crystallization, thus yielding a significant economical and ecological advantage.
- Aripiprazole Form II prepared by the method of the invention, is disclosed in WO 05/058835, hereby incorporated by reference. As disclosed therein, aripiprazole Form II is characterized by X-ray powder diffraction peaks at 16.5, 18.7, 21.9, 22.4 and 23.5 degrees two-theta ⁇ 0.2 degrees two-theta.
- the aripiprazole crystalline Form II used for seeding can be made in situ or obtained as described in the PCT publication WO 05/058835.
- Aripiprazole Form XII and Compound 2 are also disclosed in WO 05/058835.
- aripiprazole Form XII is characterized by X-ray powder diffraction peaks at 17.4, 18.2, 19.7 and 24.5 degrees two-theta ⁇ 0.2 degrees two-theta; and aripiprazole compound 2 is characterized by X-ray powder diffraction peaks at 8.8, 14.5, 17.8, 20.5 and 22.2 degrees two-theta ⁇ 0.2 degrees two-theta.
- the invention encompasses a method of preparing anhydrous aripiprazole Form II comprising slurrying a starting aripiprazole in a solvent selected from the group consisting of: C 3 -C 8 ketones, THF, acetonitrile, butyl-acetate, dimethyl formamide (DMF), a mixture of tetrahydrofuran (THF) and IPA, water, diethyl ether (DEE) and acetone; heating the slurry; and isolating anhydrous aripiprazole Form II from the slurry.
- the method can further comprise seeding the slurry with aripiprazole Form II prior to the heating step.
- the amount of aripiprazole Form II used for seeding is about 0.05% to 5% by weight of the aripiprazole.
- the starting aripiprazole is selected from the group consisting of: crystalline aripiprazole Form XII, Compound 2, Form C, anhydrate, hydrate, solvate and mixtures thereof.
- the solvent is acetone.
- the amount of the solvent should be sufficient to form a slurry with the aripiprazole.
- the ratio of starting aripiprazole to acetone is about 3:1 to about 20:1 ml of acetone per gram of aripiprazole. More preferably, the ratio of starting aripiprazole to acetone is about 3:1 to about 6:1 ml of acetone to gram of aripiprazole.
- 30 g of aripiprazole 90 to 180 mL of acetone can be used.
- the slurry is heated to a temperature of about 25°C to about 5O 0 C. More preferably, the slurry is heated to a temperature of about 3O 0 C to about 5O 0 C.
- the slurry is maintained at the temperature for at least 1 hour, preferably from about 2 hours to about 22 hours.
- the anhydrous aripiprazole Form II can be isolated by any method known in the art.
- the anhydrous aripiprazole Form II can be separated by filtering the slurry or decanting the solvent from the slurry.
- the isolating method can further comprise washing and drying the anhydrous aripiprazole Form II.
- the anhydrous aripiprazole Form II is dried at a temperature of about 3O 0 C to about 6O 0 C, more preferably, at a temperature of about 4O 0 C to about 53 0 C under reduced pressure.
- Another embodiment of the invention encompasses a method of preparing anhydrous aripiprazole Form II comprising: providing a mixture of aripiprazole in a solvent selected from the group consisting of: C 3 -C 8 ketones, THF, acetonitrile, butyl- acetate, dimethyl formamide (DMF), a mixture of tetrahydrofuran (THF) and IPA, water, diethyl ether (DEE) and acetone; heating the mixture at a temperature of about 45 0 C to about the reflux temperature; cooling the mixture to a temperature of about 1O 0 C to about -20 0 C; maintaining the mixture for about 15 minutes to about 60 hours to obtain anhydrous aripiprazole Form II; isolating the anhydrous aripiprazole Form II; providing a slurry of aripiprazole in a solvent selected from the group consisting of: C 3 -C 8 ketones, THF, acetonitrile
- the aripiprazole used in the process is selected from the group consisting of: crystalline aripiprazole Form XII, Compound 2, Form C, anhydrate, hydrate, solvate and mixtures thereof.
- the solvent is acetone.
- the mixture is heated to a temperature of about 56 0 C.
- the cooling is to a temperature of about 4°C.
- the cooled mixture is maintained for about 15 hours.
- the amount of aripiprazole Form II used for seeding is about 0.05% to 5% by weight of the starting aripiprazole.
- the ratio of acetone to aripiprazole in the slurry is about 3:1 to about 20:1 ml of acetone per gram of aripiprazole. More preferably, the ratio of acetone to aripiprazole in the slurry is about 3:1 to about 6:1 ml of acetone per gram of aripiprazole.
- the slurry can be prepared using the conditions and reagents described above.
- Aripiprazole Form II can be isolated using the methods described above.
- Another embodiment of the invention encompasses a method of preparing aripiprazole Form II comprising: combining aripiprazole and acetone to obtain a slurry; and seeding the slurry with aripiprazole Form II.
- the starting aripiprazole in crystalline form (30 g), acetone (90-180 ml) and aripiprazole Form II (0.015 to 1.5 g) were introduced into a 250 ml reactor.
- the mixture was heated at 25 0 C to 5O 0 C and stirred for at least 1 hr. Then, the mixture was cooled to room temperature and stirred for at least 10 min.
- the precipitate, wet aripiprazole Form II was collected by filtration and washed with 30 ml of acetone.
- the wet aripiprazole Form II was dried under vacuum at 40 0 C to 53 0 C overnight. Dry aripiprazole Form II was obtained.
- Table 1 The results are summarized in Table 1.
- Example 14 Preparation of Aripiprazole Form II by slurry in acetone including seeding of Aripiprazole Form II
- Aripiprazole Form XII (10.8 Kg wet or 10 Kg dry), acetone (40 L) and aripiprazole Form II (200 g) were introduced into 100 L reactor. The mixture was heated to 48 0 C and stirred for 2 hr. Then, the mixture was cooled to room temperature and stirred for 1 hour. Aripiprazole Form II was collected by filtration and washed with 10 L of acetone. The wet aripiprazole Form II was dried under vacuum at 49 0 C for 4 hours. 9.5 Kg of dry aripiprazole Form II was obtained.
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Psychiatry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US72261605P | 2005-09-29 | 2005-09-29 | |
US72645605P | 2005-10-12 | 2005-10-12 | |
US73709205P | 2005-11-15 | 2005-11-15 | |
PCT/US2006/038279 WO2007041414A1 (en) | 2005-09-29 | 2006-09-29 | Methods of preparing anhydrous aripiprazole form ii |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1934183A1 true EP1934183A1 (en) | 2008-06-25 |
Family
ID=37670930
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP06825291A Withdrawn EP1934183A1 (en) | 2005-09-29 | 2006-09-29 | Methods of preparing anhydrous aripiprazole form ii |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP1934183A1 (ko) |
JP (1) | JP2008521835A (ko) |
KR (1) | KR20070088750A (ko) |
BR (1) | BRPI0606163A2 (ko) |
IL (1) | IL186278A0 (ko) |
MX (1) | MX2007006368A (ko) |
WO (1) | WO2007041414A1 (ko) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101340214B1 (ko) * | 2011-03-31 | 2013-12-10 | 주식회사 대웅제약 | 무수 아리피프라졸 ⅱ형 결정의 제조방법 |
CN102850268B (zh) * | 2011-06-27 | 2015-07-15 | 上海中西制药有限公司 | 阿立哌唑ⅰ型微晶、阿立哌唑固体制剂及制备方法 |
KR101372840B1 (ko) * | 2012-08-02 | 2014-03-12 | 주식회사 에스텍파마 | 무수 아리피프라졸 결정의 제조방법 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5006528A (en) | 1988-10-31 | 1991-04-09 | Otsuka Pharmaceutical Co., Ltd. | Carbostyril derivatives |
JP2608788B2 (ja) | 1988-10-31 | 1997-05-14 | 大塚製薬 株式会社 | 精神分裂病治療剤 |
AR033485A1 (es) | 2001-09-25 | 2003-12-26 | Otsuka Pharma Co Ltd | Sustancia medicinal de aripiprazol de baja higroscopicidad y proceso para la preparacion de la misma |
PL1613598T3 (pl) * | 2003-12-16 | 2012-03-30 | Teva Pharma | Sposób wytwarzania krystalicznych form aripiprazolu |
-
2006
- 2006-09-29 KR KR1020077014806A patent/KR20070088750A/ko active Search and Examination
- 2006-09-29 WO PCT/US2006/038279 patent/WO2007041414A1/en active Application Filing
- 2006-09-29 BR BRPI0606163-0A patent/BRPI0606163A2/pt not_active IP Right Cessation
- 2006-09-29 EP EP06825291A patent/EP1934183A1/en not_active Withdrawn
- 2006-09-29 MX MX2007006368A patent/MX2007006368A/es not_active Application Discontinuation
- 2006-09-29 JP JP2007543630A patent/JP2008521835A/ja active Pending
-
2007
- 2007-09-25 IL IL186278A patent/IL186278A0/en unknown
Non-Patent Citations (1)
Title |
---|
See references of WO2007041414A1 * |
Also Published As
Publication number | Publication date |
---|---|
IL186278A0 (en) | 2008-01-20 |
JP2008521835A (ja) | 2008-06-26 |
MX2007006368A (es) | 2007-07-11 |
BRPI0606163A2 (pt) | 2009-05-26 |
WO2007041414A1 (en) | 2007-04-12 |
KR20070088750A (ko) | 2007-08-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4700813B2 (ja) | テルミサルタンの多形体、その調製方法及び医薬組成物の調製のためのその使用 | |
EP2093217B1 (en) | Process for preparing Form X of aripiprazole | |
CA2595334C (en) | Polymorphic forms of aripiprazole and processes for making | |
EP2951158B1 (en) | Process for the preparation of ivacaftor and solvates thereof | |
US9273044B2 (en) | Crystalline form of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate | |
CA2550726A1 (en) | Methods of preparing aripiprazole crystalline forms | |
AU2016384921A1 (en) | Crystalline form of BTK kinase inhibitor and preparation method thereof | |
EP3337485B1 (en) | Crystalline forms of ibrutinib | |
EP1812397A1 (en) | Process of making crystalline aripiprazole | |
US20050277650A1 (en) | Process for preparing aripirazole hydrate | |
EP1765782A1 (en) | Method of making 7-(4-bromobutoxy)-3,4-dihydrocarbostyril | |
WO2016131431A1 (en) | Solid forms of empagliflozin | |
HRP20050039A2 (en) | Crystal forms of olanzapine and processes for their preparation | |
EP1934183A1 (en) | Methods of preparing anhydrous aripiprazole form ii | |
WO2015014984A1 (en) | A process for preparing rifaximin k | |
WO2004085426A1 (en) | Novel crystalline forms of candesartan cilexetil | |
US7714129B2 (en) | Methods of preparing anhydrous aripiprazole form II | |
AU2012204839A1 (en) | Method for resolution of 4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1,2,2-trimethyl-piperazine and 1-((1R,3S)-6-chloro-3-phenyl-indan- 1-yl)-3,3-dimethyl-piperazine | |
WO2011153221A1 (en) | Solid state forms of ixabepilone | |
JP7236458B2 (ja) | トリアゾロキナゾリノンの合成 | |
WO2008130534A1 (en) | Crystalline forms of topotecan hydrochloride and processes for making the same | |
WO2008038143A2 (en) | Novel solid forms of rimonabant and synthetic processes for their preparation | |
US20120267533A1 (en) | Processes for the preparation of form i and form ii of palonosetron hydrochloride | |
KR101489062B1 (ko) | 고순도의 올란자핀 및 이의 결정형 ii의 제조방법 | |
KR101340214B1 (ko) | 무수 아리피프라졸 ⅱ형 결정의 제조방법 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20070522 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR |
|
DAX | Request for extension of the european patent (deleted) | ||
17Q | First examination report despatched |
Effective date: 20080716 |
|
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20120301 |