Title of Invention

A PROCESS FOR THE PREPARATION OF STABLE FORM OF ARIPRAZOLE

Abstract A stable form of Aripiprazole of Formula (I) is disclosed. Said compound has the following characteristics: d) XRPD of stable form consists of characteristic peaks in difractogram at 29 = 10.7°, 14.1°, 20.1°, 21.8° and 26.4° with ± 0.2° variation (Figure-3). e) DSC of stable form has sharp endotherm at 140.39 °C (Figure-1). f) IR spectrum has peaks at 2945 cm"1, 2810 cm"1, 1676 cm"1, 1625 cm"1, 1521 cm"1, 1446 cm"1, 1379 cm"1, 1274 cm"1, 1199 cm"1, 1174 cm"1, 856 cm"1 and 715 cm"1.(Figure-5).
Full Text COMPLETE AFTER PROVISIONAL
FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
" A STABLE FORM OF ARIPIPRAZOLE "
We, CADILA HEALTHCARE LTD., a company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Roads, Ahmedabad - 380 015, Gujarat, India.




The following specification particularly describes the nature of the invention and the manner in which it is performed:

A Stable Form of Aripiprazole Field of Invention:
The present invention relates to a stable polymorph of Aripiprazole and process for preparing it. The molecular structure of Aripiprazole is represented by formula (I).

Formula (I)
Background of the invention:
Aripiprazole, which is chemically known as 7-{4-[4-(2,3-dichlorophenyl)-l-piperazinyl]-butoxy}-3,4-dihydrocarbostyryl or as 7-{4-{4-2,3-dichloro phenyl)-l-piperazinyl]-butoxy}-3,4-dihydro-2(lH)-quiinolinone having the formula (I) is an atypical anti-psychotic agent useful as a central nervous controlling agent, preferably for the treatment of schizophrenia.
U.S. Patent 4,734,416 discloses the process for the preparation of anti-psychotically effective carbostyril derivatives including Aripiprazole. U.S. patent 5,006,528 discloses preparation of Aripiprazole comprising the crystallization process from ethanol, affording product having melting point 139°C to 139.5°C
EP 1145711 discloses granules for the production of flash-melt pharmaceutical oral dosage forms of Aripiprazole.
US 2004/0058935A1 discloses that anhydrous Aripiprazole crystals 'type-I' and 'type-IP are state of art disclosed in 1996 at "4th Japanese-Korean Symposium". But, the characterization by XRPD for crystal 'type-T and 'type-II' are not documented in any slate or the art or in US patent 2004/0058935 A1.
Moreover US patent 2004/0058935Al patent refers to the unit operations to prepare crystalline forms of Aripiprazole. In other term this patent evidences change in polymorphic form of Aripiprazole when it is subjected to physical operations. Such nature is not favorable for stability, shelf-life of API, and formulation process of API etc. and consequently for efficacy of the drug product.
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Object of the Invention:
According to the principal object of the present invention, there is to provide a stable form of Aripiprazole.
Another object of the present invention is to provide the process for the preparation of stable form of Aripiprazole, which devoids of crystallization of Aripiprazole in the mixture of organic solvent and anti-solvent in the appropriate proportion and volume respectively.
DSC thermograms (Figure-1 and Figure-2) and XRPD patterns (Figure-3 and Figure-4) are self explanatory about the stability of this new morph of Aripiprazole, during unit operations (like milling etc).
Summary of Invention:
The present invention provides a new crystalline "Stable Form" of Aripiprazole and its economically viable and plant operation friendly preparation thereby to overcome the drawback about the stability of polymorphs as disclosed in prior art. These polymorphs change into another during heating and unit operations.
The state of the art for preparing crystal 'type-I' is either by crystallizing any form of Aripiprazole from an ethanolic solution or by heating Aripiprazole monohydrate at 80°C. By performing the same state of the art, we found that obtained crystalline Aripiprazole has characteristic XRPD matching with non-hygroscopic form-B of 'Aripiprazole' (Example 5 and 6 as disclosed in patent US 2004/0058935A1). However, the art disclosed for preparation of non-hygroscopic form-B of 'Aripiprazole' of the patent US 2004/0058935 Al are similar to the state of the art disclosed in "/* Japanese-Korean Symposium".
The stable form of Aripiprazole is obtained by crystallization of Aripiprazole from a mixture of organic solvents, specifically, any polymorphic form of Aripiprazole is dissolved in a suitable aromatic organic solvent upon heating and addition of another organic anti-solvent in hot condition. Thus obtained solution is cooled, and crystals separated by centrifuge or filtration to afford the crystals of stable form of Aripiprazole.
When the wet cake is dried in vacuum oven at ambient temperature or at elevated temperature below 100°C the form of Aripiprazole is same by XRPD.
The stable crystalline form of Aripiprazole does not change form during unit operations such as drying, milling, and heating ( 3

The Aripiprazole produced by the process disclosed herein, when subjected to milling we found it so stable that even though a low intense peak in XRPD at 29, 9.2 ± 0.2° remains unchanged before milling (Figure-3) and after milling (Figure-4).
Thus the present invention discloses stable form of Aripiprazole having lower particle size, which is very stable towards unit operations such as milling, heating etc. that avoids the problems associated with previous inventions.
Description of Figures:
Figure-1 : DSC of Stable Form of Aripiprazole having DSC endotherm
Peak at l41°C
Figure-2 : DSC of the milled stable form of Aripiprazole having DSC
endotherm peak at 141 °C
Figure-3 : XRPD pattern of stable form of Aripiprazole
Figure-4 : XRPD pattern of the milled stable form of Aripiprazole Figure-5 : FT-IR spectrograph of stable form of Aripiprazole Detailed Description of the Invention:
According to first embodiment present invention is to provide "Stable Form" of Aripiprazole wherein said "Stable Form" has a X-ray powder diffractogram, as shown in Figure-3, having characteristic peaks at 26 = 10.7°, 14.1°, 20.1°, 21.8°, and 26.4° with ± 0.2° variation.
The said "Stable Form" has characteristic infrared absorption bands at 2945cm1, 2810 cm-1, 1676 cm-1,1625 cm"1,1521 cm"1,1446 cm-1, 1379 cm"1, 1274 cm-1, 1199 cm"1, 1174 cm"1, 856 cm"1 and 715 cm"1. The Infrared (KBr) spectrum is shown in Figure-5.
The said "Stable Form" has characteristic endothermic peak on 140.79°C and 141.35°C DSC thermogram (heating rate 10°C/minute) which is shown in Figure-1, 2.
According to another embodiment the "Stable Form" of Aripiprazole has a mean particle size 25mm or below.
The Figures of DSC thermograms (Figure-1 and Figure-2) and XRD patterns (Figure-3 and Figure-4) are self explanatory that when the stable form is subjected to unit operations (like milling), it does not change its form.
Preparation of stable form of Aripiprazole:
According to the embodiment of the present invention, the stable form of Aripiprazole is prepared by crystallization of any form of Aripiprazole from a mixture of organic solvents. Specifically, Aripiprazole is suspended in a suitable aromatic organic solvent of 1-20 volumes, preferably 10 volumes with that of Aripiprazole, followed by
4

heating to get clear solution and addition of another organic anti-solvent of 1-50 volumes with that of Aripiprazole taken for crystallization, preferably 20 volumes, having straight, branched or cyclic structure of C4 to Cs carbons in hot condition. Thus obtained solution is cooled, and crystals separated by centrifuge or filtration to afford the crystals of stable form of Aripiprazole.
The scope of the present invention is not limited by the description, examples described herein and modification can be made without departing from the spirit of the invention. For example, other methods may be produced utilizing the process of the invention beyond those examplified herein.
Example: 1
A mixture of 92.0 g of Aripiprazole and 920 mL of toluene, is heated to 75°C to 80°C to get clear solution. 1800 mL of cyclohexane is slowly added to the above clear solution of Aripiprazole in toluene at the same temperature over a duration of 30 to 90 minutes. The mixture is then brought to ambient temperature (25°C to 30°C) and stirred for 1.0 hour at the same temperature. The crystals are filtered and washed with 92 ml of cyclohexane. The obtained crystals are dried in an vacuum oven or oven at temperature below 100°C till constant weight (88.0 g) to afford the desired Stable polymorph. Melting point = 139.5°C to 142°C
DSC and XRPD patterns are similar to Figure-1 and Figure-3 respectively. DSC and XRPD patterns are similar to Figure-2 and Figure-4 respectively (after milling).
Example: 2
A mixture of 10.0 g of Aripiprazole and 100.0 mL of xylene, is heated to 75°C to 80°C to get clear solution. 200.0 mL of n-hexane is slowly added in the above clear solution of Aripiprazole in xylene at the same temperature over a duration of 30 to 90 minutes. The mixture is then brought to ambient temperature (25°C to 30°C) and stirred for 1.0 hour at the same temperature. The cirystals are filtered and washed with 10 mL of n-hexane. The obtained crystals are dried in an vacuum oven or oven at temperature below 100°C till constant weight (9.5 g) to afford the desired stable polymorph. Melting point = 139.5°C to 142°C
DSC and XRPD patterns are similar to Figure-1 and Figure-3 respectively. DSC and XRPD patterns are similar to Figure-2 and Figure-4 respectively (after milling). Advantages of invention:
1) Stable form of Aripiprazole of formula I is stable in unit operation at plant scale.
2) It is easily manufactured on commercial scale using any form of Aripiprazole.
5:

3) The product obtained from the crystallization has particle size below 25mm. It will be very useful for good formulation.

We claim:
1. A stable form of Aripiprazole of Formula (I)

having the following characteristics:
a) XRPD of stable form consists of characteristic peaks in difractogram at 29 = 10.7°, 14.1°, 20.1°, 21.8° and 26.4° with ± 0.2° variation (Figure-3).
b) DSC of stable form has sharp endotherm at 140.39 °C (Figure-1).
c) IR spectrum has peaks at 2945 cm"1, 2810 cm"1, 1676 cm"1, 1625 cm"1, 1521 cm"1, 1446 cm"1, 1379 cm"1, 1274 cm"1, 1199 cm"1, 1174 cm'1, 856 cm"1 and 715 cm'1. (Figure-5).
2. A process of preparation of stable form of Aripiprazole if Formula (1)

which comprises:
a) dissolving Aripiprazole in suitable volume of aromatic hydrocarbon solvent at an appropriate temperature.
b) adding suitable anti-solvent at appropriate temperature in the solution obtained in step a).
c) filtering and drying solid obtained in step b) at a suitable temperature.
3. A process as claimed in claim 2 wherein said aromatic solvent is selected from the group of benzene, toluene, xylene and most preferred solvent are Toluene and Xylene.
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4. A process as claimed in claim 2 or 3 wherein said solvent is employed in a volume of up to 20 times, preferably, 1 to 10 times the volume of Aripiprazole.
5. A process as claimed in any one of claims 2 to 4 wherein said suitable temperature is 25-130°C, preferably is 65-130°C, more preferably, 75-80°C.

6. A process as claimed in any one of claims 2 to 5, wherein the suitable organic anti-solvent is selected from group of C4 to C7 aliphatic cyclic or acyclic saturated hydrocarbons or a mixture thereof most preferably are cyclohexane and n-hexane.
7. A process as claimed in any one of claims 2 to 6, wherein the volume of suitable solvent is 1-50 times with that of Aripiprazole, but most preferred is 1-20 volume.
8. A process as claimed in any one of claims 2 to 7, wherein the anti-solvent added at a suitable temperature of 25-130°C, preferably 65-130°C, more preferably 75-80°C.
9. A stable form of Aripiprazole has a mean particle size less than 50 um., preferably less than 25 um.
10. A process for preparing stable form of Aripiprazole of formula (I) such as herein described is in accordance with accompanying drawings and foregoing examples.
Dated this 18th day of February 2006

8

ABSTRACT
A stable form of Aripiprazole of Formula (I) is disclosed.

Said compound has the following characteristics:
d) XRPD of stable form consists of characteristic peaks in difractogram at 29 = 10.7°, 14.1°, 20.1°, 21.8° and 26.4° with ± 0.2° variation (Figure-3).
e) DSC of stable form has sharp endotherm at 140.39 °C (Figure-1).
f) IR spectrum has peaks at 2945 cm"1, 2810 cm"1, 1676 cm"1, 1625 cm"1, 1521 cm"1, 1446 cm"1, 1379 cm"1, 1274 cm"1, 1199 cm"1, 1174 cm"1, 856 cm"1 and 715 cm"1.(Figure-5).


Documents:

191-MUM-2005-ABSTRACT(20-2-2006).pdf

191-MUM-2005-ABSTRACT(25-1-2010).pdf

191-MUM-2005-ABSTRACT(7-12-2011).pdf

191-MUM-2005-ABSTRACT(GRANTED)-(30-12-2011).pdf

191-mum-2005-abstract-complete.doc

191-mum-2005-abstract-complete.pdf

191-MUM-2005-CANCELLED PAGES(25-1-2010).pdf

191-MUM-2005-CANCELLED PAGES(7-12-2011).pdf

191-MUM-2005-CLAIMS(20-2-2006).pdf

191-MUM-2005-CLAIMS(AMENDED)-(25-1-2010).pdf

191-MUM-2005-CLAIMS(AMENDED)-(7-12-2011).pdf

191-MUM-2005-CLAIMS(GRANTED)-(30-12-2011).pdf

191-mum-2005-claims-complete.pdf

191-MUM-2005-CORRESPONDENCE(12-2-2010).pdf

191-MUM-2005-CORRESPONDENCE(13-10-2010).pdf

191-MUM-2005-CORRESPONDENCE(15-2-2011).pdf

191-MUM-2005-CORRESPONDENCE(16-3-2009).pdf

191-MUM-2005-CORRESPONDENCE(2-11-2011).pdf

191-MUM-2005-CORRESPONDENCE(23-4-2010).pdf

191-MUM-2005-CORRESPONDENCE(23-5-2011).pdf

191-MUM-2005-CORRESPONDENCE(7-12-2011).pdf

191-MUM-2005-CORRESPONDENCE(8-6-2010).pdf

191-mum-2005-correspondence(ipo)-(16-2-2009).pdf

191-MUM-2005-CORRESPONDENCE(IPO)-(30-12-2011).pdf

191-mum-2005-correspondence-received-ver-050405.pdf

191-mum-2005-correspondence-received-ver-180206.pdf

191-mum-2005-correspondence-received-ver-210205.pdf

191-mum-2005-descripiton (complete).pdf

191-mum-2005-descripiton (provisional).pdf

191-MUM-2005-DESCRIPTION(COMPLETE)-(20-2-2006).pdf

191-MUM-2005-DESCRIPTION(GRANTED)-(30-12-2011).pdf

191-MUM-2005-DRAWING(25-1-2010).pdf

191-MUM-2005-DRAWING(GRANTED)-(30-12-2011).pdf

191-MUM-2005-DRAWING(PROVISIONAL)-(22-2-2005).pdf

191-mum-2005-drawings.pdf

191-MUM-2005-FORM 1(25-1-2010).pdf

191-MUM-2005-FORM 1(7-12-2011).pdf

191-MUM-2005-FORM 1(8-4-2005).pdf

191-mum-2005-form 18(9-1-2008).pdf

191-MUM-2005-FORM 2(COMPLETE)-(20-2-2006).pdf

191-MUM-2005-FORM 2(GRANTED)-(30-12-2011).pdf

191-MUM-2005-FORM 2(TITLE PAGE)-(25-1-2010).pdf

191-MUM-2005-FORM 2(TITLE PAGE)-(7-12-2011).pdf

191-MUM-2005-FORM 2(TITLE PAGE)-(COMPLETE)-(20-2-2006).pdf

191-MUM-2005-FORM 2(TITLE PAGE)-(GRANTED)-(30-12-2011).pdf

191-MUM-2005-FORM 2(TITLE PAGE)-(PROVISIONAL)-(22-2-2005).pdf

191-mum-2005-form-1.pdf

191-mum-2005-form-2-complete.doc

191-mum-2005-form-2-complete.pdf

191-mum-2005-form-2-provisional.doc

191-mum-2005-form-2-provisional.pdf

191-mum-2005-form-26.pdf

191-mum-2005-form-3.pdf

191-mum-2005-form-5.pdf

191-MUM-2005-REPLY TO EXAMINATION REPORT(25-1-2010).pdf

191-MUM-2005-REPLY TO HEARING (27-10-2011).pdf

191-MUM-2005-REPLY TO HEARING(3-11-2011).pdf

191-MUM-2005-SPECIFICATION(AMENDED)-(25-1-2010).pdf

abstract1.jpg


Patent Number 250379
Indian Patent Application Number 191/MUM/2005
PG Journal Number 01/2012
Publication Date 06-Jan-2012
Grant Date 30-Dec-2011
Date of Filing 22-Feb-2005
Name of Patentee CADILA HEALHCARE LIMITED
Applicant Address ZYDUS TOWER, SATELITE CROSS ROAD, AHMEDABAD.
Inventors:
# Inventor's Name Inventor's Address
1 BOKHA MAGAN CHANGANBHAI ZYDUS TOWER, SATELITE CROSS ROAD, AHMEDABAD- 380015 GUJRAT
2 DAVE PRASHANT MAHENDRABHAI ZYDUS TOWER, SATELITE CROSS ROAD, AHMEDABAD- 380015 GUJRAT
3 SHAH NIRAJKUMAR SHYAMLAL ZYDUS TOWER, SATELITE CROSS ROAD, AHMEDABAD- 380015 GUJRAT
4 RAJIV KUMAR ZYDUS TOWER, SATELITE CROSS ROAD, AHMEDABAD- 380015 GUJRAT
5 AGARWAL VIRENDRAKUMAR ZYDUS TOWER, SATELITE CROSS ROAD, AHMEDABAD- 380015 GUJRAT
PCT International Classification Number C07D401/12
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA