WO2010106551A2 - Procédé pour la fabrication de forme b d'aripiprazole anhydre pure - Google Patents

Procédé pour la fabrication de forme b d'aripiprazole anhydre pure Download PDF

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Publication number
WO2010106551A2
WO2010106551A2 PCT/IN2010/000132 IN2010000132W WO2010106551A2 WO 2010106551 A2 WO2010106551 A2 WO 2010106551A2 IN 2010000132 W IN2010000132 W IN 2010000132W WO 2010106551 A2 WO2010106551 A2 WO 2010106551A2
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WIPO (PCT)
Prior art keywords
aripiprazole
range
process according
temperature
dsc
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.)
Ceased
Application number
PCT/IN2010/000132
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English (en)
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WO2010106551A3 (fr
Inventor
Arul Ramkrishnana
Pamujula Srinivasulu
Chittala Venkata Subramanyam
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Neuland Laboratories Ltd
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Neuland Laboratories Ltd
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Publication date
Application filed by Neuland Laboratories Ltd filed Critical Neuland Laboratories Ltd
Publication of WO2010106551A2 publication Critical patent/WO2010106551A2/fr
Anticipated expiration legal-status Critical
Publication of WO2010106551A3 publication Critical patent/WO2010106551A3/fr
Ceased legal-status Critical Current

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    • 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

Definitions

  • the present invention relates to a novel, industrially viable and cost effective process for manufacturing a substantially pure anhydrous Form B of 7-[4-[4-(2,3-dichlorophenyl)-l- piperazinyl]butoxy]-3,4-dihydro-carbostyril also known as Aripiprazole.
  • Aripiprazole, 7-[4-[4-(2,3-dichlorophenyl)-l -piperazinyl]butoxy]-3,4-dihydro-carbostyril of formula I is a psychotropic drug available in the brand name of Ability® and is useful for the treatment of schizophrenia.
  • Schizophrenia is a common type of psychosis characterized by delusions, hallucinations and extensive withdrawal from others. It is more prevalent than Alzheimer's disease, multiple sclerosis, insulin-dependent diabetes and muscular dystrophy. Early diagnosis and treatment can lead to significantly improved recovery and outcome. Moreover, early therapeutic intervention can avert costly hospitalization.
  • Aripiprazole anhydride crystals are manufactured by heating Aripiprazole hydrate at 8O 0 C.
  • the Aripiprazole anhydride crystals obtained by the aforementioned methods have the disadvantage of being significantly hygroscopic.
  • Aripiprazole anhydride crystals exist as type-I crystals and type-II crystals; the type-I crystals of Aripiprazole anhydride can be prepared by recrystallizing from an ethanol solution of Aripiprazole, or by heating Aripiprazole hydrate at 8O 0 C; and the type-II crystals of Aripiprazole anhydride can be prepared by heating the type-I crystals of Aripiprazole anhydride at 130 to 14O 0 C for 15 hours.
  • Aripiprazole form B obtained by most of these processes have almost the same XRD pattern but in case of DSC some has two endothermic peaks or some has three endothermic peaks which indicates that it is not a pure polymorph Form B it is contaminated by other form or a solvate form.
  • the principal aspect of the present invention is to provide a process for the preparation of anhydrous Aripiprazole form B which gives a single endothermic peak in the range of 138-14O 0 C by DSC, which comprises: a) heating Aripiprazole in an alcoholic solvent to make a clear solution; b) cooling the contents at a temperature over a period of time; c) centrifuging the product and washing with an alcoholic solvent to obtain wet material; d) drying the obtained wet material under vacuum; e) sieving the obtained dry material without crushing and separating out the sieve tops; f) further drying the sieved material.
  • Anhydrous Crystalline Form-B Another aspect of the present invention is to provide anhydrous Aripiprazole form B having a single endothermic peak in the range of 138-14O 0 C by DSC.
  • FIG. 1 is a differential scanning calorimetry thermogram of the Anhydrous Aripiprazole Form B.
  • FIG. 2 is a powder x-ray diffraction diagram of the Anhydrous Aripiprazole Form B.
  • the present invention relates to a process for the preparation of anhydrous Aripiprazole form B having a single endothermic peak in the range of 138- 14O 0 C by DSC.
  • mixing of Aripiprazole in step (a) is carried out in a suitable alcoholic solvent selected from the group consisting of methanol, n-propanol, ethanol, isobutanol, n-butanol and the like by heating to the reflux temperature of the solvent.
  • a suitable alcoholic solvent selected from the group consisting of methanol, n-propanol, ethanol, isobutanol, n-butanol and the like by heating to the reflux temperature of the solvent.
  • Aripiprazole in step (a) is preferably mixed in ethanol and heated to reflux temperature (78-80 0 C) to make a clear solution.
  • cooling of contents in step (b) is carried out at a suitable temperature in the range of 0-10°C; preferably in the range of 0-5 0 C over a period 30 minutes to 90 minutes and maintained for one hour.
  • centrifuging and washing is carried out in step (c) with a suitable chilled alcoholic solvent selected from the group consisting of methanol, n- propanol, ethanol, isobutanol, n-butanol and the like; and mixtures thereof, preferably with ethanol.
  • a suitable chilled alcoholic solvent selected from the group consisting of methanol, n- propanol, ethanol, isobutanol, n-butanol and the like; and mixtures thereof, preferably with ethanol.
  • drying is carried out in step (d) under vacuum at a suitable temperature in the range of 40-45°C; preferably in the range of 43-47°C.
  • sieving in step (e) is carried out by using sifter (40 mesh) without crushing and further separating out the sieve tops.
  • drying in step (f) is carried out at a suitable temperature in the range of 80-90°C preferably 83-87°C by hot water circulation under vacuum to obtain anhydrous Aripiprazole Form B having a single endothermic peak in the range of 138-14O 0 C by DSC.
  • Aripiprazole can be prepared by the process mentioned in product patent US 5,006,528 or by other processes available in the prior art.
  • Anhydrous Aripiprazole Form B has a powder x-ray diffraction spectrum which is substantially the same as the powder x-ray diffraction spectrum shown in fig.2. Specifically, they have characteristic peaks at d-spacing [A] 8.00849, 7.33222, 6.16414, 5.949, 5.33806, 4.58549, 4.35752, 4.02380, 3.15271, 2.83466. They exhibit an endothermic peak which is substantially the same as given in Fig.l i.e. about 138.5 0 C in differential scanning calorimetry.
  • Aripiprazole (10 Kg) was mixed with ethanol (220 L) and heated to reflux at 78-80°C to make a clear solution. The contents were cooled to 0-5°C over a period and maintained for some time. The product was centrifuged and washed with chilled ethanol (20 L). The obtained wet material was dried under vacuum at 43-47°C. The obtained dry material was sieved using sifter (40 mesh) without crushing and separated out the sieve tops. The sieved material was again dried at 83- 87°C (bath temperature) under vacuum till the LOD is complies (LOD limit: NMT 0.5%w/w).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Quinoline Compounds (AREA)

Abstract

La présente invention concerne un nouveau procédé industriellement viable et économique de fabrication de la forme B anhydre sensiblement pure de 7-[4-[4-(2,3-dichlorophényl)-1-pipérazinyl]butoxy]-3,4-di-hydrocarbostyrile également connu sous le nom d'Aripiprazole.
PCT/IN2010/000132 2009-03-09 2010-03-09 Procédé pour la fabrication de forme b d'aripiprazole anhydre pure Ceased WO2010106551A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN518CH2009 2009-03-09
IN518/CHE/2009 2009-03-09

Publications (2)

Publication Number Publication Date
WO2010106551A2 true WO2010106551A2 (fr) 2010-09-23
WO2010106551A3 WO2010106551A3 (fr) 2013-02-07

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PCT/IN2010/000132 Ceased WO2010106551A2 (fr) 2009-03-09 2010-03-09 Procédé pour la fabrication de forme b d'aripiprazole anhydre pure

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WO (1) WO2010106551A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014021652A1 (fr) * 2012-08-02 2014-02-06 주식회사 에스텍파마 Cristaux d'aripiprazole anhydres et leur procédé de production
CN104230799A (zh) * 2013-06-21 2014-12-24 江苏豪森药业股份有限公司 制备阿立哌唑晶型的方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5006528A (en) * 1988-10-31 1991-04-09 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivatives
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

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014021652A1 (fr) * 2012-08-02 2014-02-06 주식회사 에스텍파마 Cristaux d'aripiprazole anhydres et leur procédé de production
CN104230799A (zh) * 2013-06-21 2014-12-24 江苏豪森药业股份有限公司 制备阿立哌唑晶型的方法

Also Published As

Publication number Publication date
WO2010106551A3 (fr) 2013-02-07

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