WO2008020453A2 - A process for the preparation of a novel crystalline polymorph of aripiprazole - Google Patents
A process for the preparation of a novel crystalline polymorph of aripiprazole Download PDFInfo
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- WO2008020453A2 WO2008020453A2 PCT/IN2007/000023 IN2007000023W WO2008020453A2 WO 2008020453 A2 WO2008020453 A2 WO 2008020453A2 IN 2007000023 W IN2007000023 W IN 2007000023W WO 2008020453 A2 WO2008020453 A2 WO 2008020453A2
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- WIPO (PCT)
- Prior art keywords
- aripiprazole
- preparation
- crystalline
- solvent
- crystalline polymorph
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- 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
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
Definitions
- the present invention provides a process for the preparation of a novel crystalline polymorph of the psychotropic drug aripiprazole.
- aripiprazole which is useful for the treatment of schizophrenia.
- US patent number 5,006,528 discloses a process for the preparation of aripiprazole. Crude aripiprazole was recrystallized twice from ethanol (no XRD, DSC or TGA data given).
- aripiprazole crystals can be prepared by recrystallizing aripiprazole from ethanol.
- the invention encompasses anhydrous aripiprazole crystalline form which is non- hygroscopic and which maintain compound stability during storage and method for preparing the non-hygroscopic aripiprazole crystalline form.
- One embodiment of the invention encompasses a crystalline anhydrous aripiprazole form characterized by X-ray powder diffraction (figure l)peaks at 5.84, 8.76, 11.68, 11.85, 15.82, 16.33, 17.75, 18.64, 20.14, 22.33, 20.47, 20.72, 22.12, 23.41, 24.98, 25.38, 26.45, 30.79, 31.01, and 31.41 degrees two-theta.
- the method for the preparation of the anhydrous aripiprazole crystalline form comprises dissolving aripiprazole in a solvent like 1,4-dioxane, to from a clear solution at temperature from 4O 0 C to 50 0 C, preferably at 48 0 C to 50 0 C then adding a co- solvent/reprecipitating solvent like MTBE (t-butyl methyl ether) at temperature from 4O 0 C to 5O 0 C, preferably at 48 0 C to 50 0 C. Then cooling the mixture to about 1O 0 C to 35 0 C, preferably at 3O 0 C to 32 0 C and the precipitate is collected by filtration or centrifugation.
- MTBE t-butyl methyl ether
- the crystals then dried for 24 to 65 hours, preferably for 60-65 hours at temperature from 4O 0 C to 70 0 C preferably at 70 0 C.
- aripiprazole used in the process is from the prior art US patent number 5,006,528].
- the amount of solvent added should be sufficient to dissolve the amount of aripiprazole used ( ⁇ ?. g. 1Og aripiprazole was dissolved in 25-50ml 1,4-dioxane).
- Conditions that affect the amount of solvent include, but are not limited to, the amount of aripiprazole to be crystallized and the purity of the starting aripiprazole.
- the aripiprazole crystalline form encompassed by the invention is characterized by at least one of TGA (thermo gravimetric analysis), XRPD (X-ray powder diffraction), DSC (differential calorimetry), or IR spectroscopy (infra red spectroscopy).
- TGA thermo gravimetric analysis
- XRPD X-ray powder diffraction
- DSC differential calorimetry
- IR spectroscopy infra red spectroscopy
- One embodiment of the invention encompasses a crystalline anhydrous aripiprazole form, herein defined as "Form U", having about ⁇ 0.16% moisture by weight as measured by Karl Fischer or TGA (figure 2).
- Form U is characterized by X-ray powder diffraction (figure 1) peaks at 5.84, 8.76, 11.68, 11.85, 15.82, 16.33, 17.75, 18.64, 20.14, 22.33, 20.47, 20.72, 22.12, 23.41, 24.98, 25.38, 26.45, 30.79, 31.01, and 31,41 degrees two-theta.
- Form U is characterized by a melting endotherm at about 135 0 C to 139 0 C (peak at 136.35 0 C) as measured by DSC (figure 3) and IR spectrum (figure 4). Further in order to study the non-hygroscopic nature of the above mentioned crystalline anhydrous aripiprazole form was subjected to the exposure of humidity (75%) at 4O 0 C for 65 hours. However there is no change in the XElPD, DSC or TGA data was observed. Similarly in order to study the thermal stability of the above mentioned crystalline anhydrous aripiprazole form was subjected to drying in a oven at 70 0 C for 48 hours. However there is no change in the XRPD, DSC or TGA data was observed. It will be apparent to those skilled in the art that many modifications, both to materials and methods may be practiced without departing from the scope of the invention.
- X-ray diffraction (XRD) data was obtained using X-ray diffractometer model PreFIX-
- DSC Differential scanning calorimetric
- TGA Thermogravimetric analysis
- Infra Red (IR) spectrum was recorded using Perkin Elmer-Spectrum One.
- Aripiprazole (1Og) was dissolved in 1,4-dioxane (35ml) at 48 0 C to 5O 0 C to obtain a clear solution. Then slowly' MTBE (t-butyl methyl ether, 35ml) was added at 48 0 C to 50 0 C. Mixture was then cooled slowly to 30 0 C to 32 0 C (Crystal formation was observed at around 40 0 C to 42 0 C). Mixture was then further stirred at 30 0 C to 32 0 C for one and half hours. The resulting crystalline form was collected by filtration, dried and studied (XRD, DSC and TGA).
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a novel crystalline polymorph of the psychotropic drug aripiprazole and a process for its preparation.
Description
A PROCESS FOR THE PREPARATION OF A NOVEL CRYSTALLINE POLYMORPH OF ARIPIPRAZOLE
FIELD OF INVENTION
The present invention provides a process for the preparation of a novel crystalline polymorph of the psychotropic drug aripiprazole.
BACKGROUND OF THE INVENTION
7-[4-[4-(2,3-Dichlorophenyl)-l-piperazinyl]butoxy]-3,4-dihydro-2(i//)-quinolinone, is having formula, .
Various crystalline forms of aripiprazole were disclosed in WO 03/026659, WO 05/058835, WO 04/042976, Japnese Unexamined Patent publication No. 191256/1990. The proceedings of the 4th Japanese-Korean Symposium on Separation Technology - (October 6-8, 1996) disclosed that aripiprazole anhydride crystals may exist as Type-I and Type-II crystals. WO 04/042976 discloses Type-I aripiprazole crystals can be prepared by recrystallizing aripiprazole from ethanol.
SUMMARY OF THE INVENTION
The invention encompasses anhydrous aripiprazole crystalline form which is non- hygroscopic and which maintain compound stability during storage and method for preparing the non-hygroscopic aripiprazole crystalline form.
One embodiment of the invention encompasses a crystalline anhydrous aripiprazole form characterized by X-ray powder diffraction (figure l)peaks at 5.84, 8.76, 11.68, 11.85,
15.82, 16.33, 17.75, 18.64, 20.14, 22.33, 20.47, 20.72, 22.12, 23.41, 24.98, 25.38, 26.45, 30.79, 31.01, and 31.41 degrees two-theta.
DETAILED DESCRIPTION OF THE INVENTION
The method for the preparation of the anhydrous aripiprazole crystalline form, comprises dissolving aripiprazole in a solvent like 1,4-dioxane, to from a clear solution at temperature from 4O0C to 50 0C, preferably at 480C to 50 0C then adding a co- solvent/reprecipitating solvent like MTBE (t-butyl methyl ether) at temperature from 4O0C to 5O 0C, preferably at 480C to 50 0C. Then cooling the mixture to about 1O0C to 35 0C, preferably at 3O0C to 32 0C and the precipitate is collected by filtration or centrifugation. The crystals then dried for 24 to 65 hours, preferably for 60-65 hours at temperature from 4O0C to 70 0C preferably at 70 0C. [aripiprazole used in the process is from the prior art US patent number 5,006,528].
The amount of solvent added should be sufficient to dissolve the amount of aripiprazole used (<?. g. 1Og aripiprazole was dissolved in 25-50ml 1,4-dioxane). One of ordinary skill in the art with little or no experimentation can easily determine the sufficient amount of solvent. Conditions that affect the amount of solvent include, but are not limited to, the amount of aripiprazole to be crystallized and the purity of the starting aripiprazole. The aripiprazole crystalline form encompassed by the invention is characterized by at least one of TGA (thermo gravimetric analysis), XRPD (X-ray powder diffraction), DSC (differential calorimetry), or IR spectroscopy (infra red spectroscopy). As used herein, the term "anhydrous" refers to aripiprazole crystal form with less than about 0.5% moisture.
One embodiment of the invention encompasses a crystalline anhydrous aripiprazole form, herein defined as "Form U", having about < 0.16% moisture by weight as measured by Karl Fischer or TGA (figure 2). Form U is characterized by X-ray powder diffraction (figure 1) peaks at 5.84, 8.76, 11.68, 11.85, 15.82, 16.33, 17.75, 18.64, 20.14, 22.33, 20.47, 20.72, 22.12, 23.41, 24.98, 25.38, 26.45, 30.79, 31.01, and 31,41 degrees two-theta. Form U is characterized by a melting endotherm at about 135 0C to 139 0C (peak at 136.350C) as measured by DSC (figure 3) and IR spectrum (figure 4).
Further in order to study the non-hygroscopic nature of the above mentioned crystalline anhydrous aripiprazole form was subjected to the exposure of humidity (75%) at 4O0C for 65 hours. However there is no change in the XElPD, DSC or TGA data was observed. Similarly in order to study the thermal stability of the above mentioned crystalline anhydrous aripiprazole form was subjected to drying in a oven at 700C for 48 hours. However there is no change in the XRPD, DSC or TGA data was observed. It will be apparent to those skilled in the art that many modifications, both to materials and methods may be practiced without departing from the scope of the invention.
Example:
X-ray diffraction (XRD) data was obtained using X-ray diffractometer model PreFIX-
X'pertPRO (PANalytical) and copper radiation of 1.54 0A.
Differential scanning calorimetric (DSC) analysis was performed using Pyris 6 DSC
(Perkin-Elmer) differential scanning calorimeter.
Thermogravimetric analysis (TGA) was performed using Pyris 6 TGA (Perkin-Elmer) thermogravimeter.
Infra Red (IR) spectrum was recorded using Perkin Elmer-Spectrum One.
Preparation of the anhydrous aripiprazole crystalline form:
Aripiprazole (1Og) was dissolved in 1,4-dioxane (35ml) at 480C to 5O 0C to obtain a clear solution. Then slowly' MTBE (t-butyl methyl ether, 35ml) was added at 48 0C to 50 0C. Mixture was then cooled slowly to 30 0C to 32 0C (Crystal formation was observed at around 400C to 420C). Mixture was then further stirred at 300C to 320C for one and half hours. The resulting crystalline form was collected by filtration, dried and studied (XRD, DSC and TGA).
Claims
1. A novel crystalline polymorph of the psychotropic drug aripiprazole.
2, A process for the preparation of aripiprazole comprising:
Form U is characterized by X-ray powder diffraction (figure 1) peaks at 5.84, 8.76, 11.68, 11.85, 15.82, 16.33, 17.75, 18.64, 20.14, 22.33, 20.47, 20.72, 22.12, 23.41, 24.98, 25.38, 26.45, 30.79, 31.01, and 31.41 degrees two-theta.
2. Form U is characterized by a melting endotherm at about 135 0C to 139 0C (peak at 136.350C) as measured by DSC (figure 2).
3. The process for the preparation of aripiprazole crystalline Form U as defined in claim 1, which comprises:
3 a) Dissolving the crystalline Type-I form in a ether solvent, preferably 1,4-dioxane,
3 b) The dissolution of the crystallineType-I form of aripiprazole in ether at temperature from 4O0C to 500C, preferably at 480C to 500C,
3 c) Then adding a co-solvent/reprecipitating solvent like MTBE (t-butyl methyl ether) at temperature from 400C to 500C, preferably at 480C to 5O0C,
3d) Then isolating the aripiprazole crystalline Form U, by cooling the mixture to about
1O0C to 35 0C, preferably at 3O0C to 320C and the precipitate is collected by filtration or centrifugation.
3e) The crystals then dried for 24 to 65 hours, preferably for 60-65 hours at temperature from 4O0C to 700C preferably at 700C
3f) The crystalline polymorph of aripiprazole "Form U", having about < 0.16% moisture content by weight.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1287/MUM/2006 | 2006-08-17 | ||
| IN1287MU2006 | 2006-08-17 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2008020453A2 true WO2008020453A2 (en) | 2008-02-21 |
| WO2008020453A3 WO2008020453A3 (en) | 2009-05-28 |
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| Application Number | Title | Priority Date | Filing Date |
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| PCT/IN2007/000023 Ceased WO2008020453A2 (en) | 2006-08-17 | 2007-01-19 | A process for the preparation of a novel crystalline polymorph of aripiprazole |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7714129B2 (en) | 2003-12-16 | 2010-05-11 | Teva Pharmaceutical Industries Ltd. | Methods of preparing anhydrous aripiprazole form II |
| KR20120070353A (en) * | 2010-12-21 | 2012-06-29 | 대봉엘에스 주식회사 | Method of producing related substance of olmesartan medoxomil |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004083183A1 (en) * | 2003-03-21 | 2004-09-30 | Hetero Drugs Limited | Novel crystalline forms of aripiprazole |
| EP1618103A2 (en) * | 2003-04-25 | 2006-01-25 | Cadila Healthcare Ltd. | Polymorphs of aripiprazole |
| JP5546717B2 (en) * | 2003-12-16 | 2014-07-09 | テバ ファーマシューティカル インダストリーズ リミティド | Method for preparing aripiprazole crystalline form |
| WO2006012237A2 (en) * | 2004-06-25 | 2006-02-02 | Shanghai Institute Of Pharmaceutical Industry | Aripiprazole crystaline forms and associated methods |
-
2007
- 2007-01-19 WO PCT/IN2007/000023 patent/WO2008020453A2/en not_active Ceased
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7714129B2 (en) | 2003-12-16 | 2010-05-11 | Teva Pharmaceutical Industries Ltd. | Methods of preparing anhydrous aripiprazole form II |
| KR20120070353A (en) * | 2010-12-21 | 2012-06-29 | 대봉엘에스 주식회사 | Method of producing related substance of olmesartan medoxomil |
| KR101696851B1 (en) | 2010-12-21 | 2017-01-17 | 대봉엘에스 주식회사 | Method of Producing Related Substance of Olmesartan Medoxomil |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2008020453A3 (en) | 2009-05-28 |
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