FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
A PROCESS FOR THE PREPARATION OF A NOVEL CRYSTALLINE POLYMORPH OF ARIPIPRAZOLE
UNICHEM LABORATORIES LIMITED, A COMPANY
REGISTERED UNDER THE INDIAN COMPANY ACT, 1956,
HAVING ITS REGISTERED OFFICE LOCATED AT UNICHEM
BHAVAN, PRABHAT ESTATE, OFF. S V.ROAD, JOGESHWARI
(WEST), MUMBAI-400 102. MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.
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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(7//)-quinolinone, is
having formula,

is called aripiprazole, which is useful for the treatment of schizophrenia. In the available prior art 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).
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,
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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 40°C to 50 °C, preferably at 48°C to 50 °C then adding a co-solvent/reprecipitating solvent like MTBE (t-butyl methyl ether) at temperature from 40°C to 50 °C, preferably at 48°C to 50 °C. Then cooling the mixture to about 10°C to 35 °C, preferably at 30°C to 32 °C 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 40°C to 70 °C preferably at 70 °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 (e. 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 °C to 139 °C (peak at 136.35 °C) as measured by DSC (figure 3) and IR spectrum (figure 4).
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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 40°C for 65 hours. However there is no change in the XRPD, 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°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.
Example:
X-ray diffraction (XRD) data was obtained using X-ray diffractometer model PreFIX-
X'pertPROa (PANalytical) and copper radiation of 1.54 °A.
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 48 °C to 50 °C to obtain a clear solution. Then slowly MTBE (t-butyl methyl ether, 35ml) was added at 48 °C to 50 °C. Mixture was then cooled slowly to 30 °C to 32 °C (Crystal formation was observed at around 40 °C to 42 °C). Mixture was then further stirred at 30 °C to 32 °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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We claim:
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 °C to 139 °C (peak at 136.35 °C) as measured by DSC (figure 2).
3. The process for the preparation of aripiprazole crystalline Form U as defined in claim 1, which comprises:
3a) Dissolving the crystalline Type-I form in a ether solvent, preferably 1,4-dioxane,
3 b) The dissolution of the crystalline Type-I form of aripiprazole in ether at temperature
from 40°C to 50 °C, preferably at 48°C to 50 °C,
3 c) Then adding a co-solvent/reprecipitating solvent like MTBE (t-butyl methyl ether) at
temperature from 40°C to 50 °C, preferably at 48°C to 50 °C,
3d) Then isolating the aripiprazole crystalline Form U, by cooling the mixture to about
10°C to 35 °C, preferably at 30°C to 32 °C 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 40°C to 70 °C preferably at 70 °C
3f) The crystalline polymorph of aripiprazole "Form U", having about < 0.16% moisture
content by weight.
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ABSTRACT:
The present invention provides a novel crystalline polymorph of the psychotropic drug aripiprazole and a process for its preparation.



Santosh Kumar Nair
G.M. - Legal & Company Secretary