FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10; rule 13)

1. Title of the invention. -

NOVEL POLYMORPHIC FORMS OF 7-[4-[4-(2,3-DICHLOROPHENYL)PIPERAZIN-l-YL|BUTOXY]-l,2,3,4-TETRAHYDROQUINOLIN-2-ONE AND THEIR PREPARATION

2. Applicant(s)
(a) NAME:
(b) NATIONALITY:
(c) ADDRESS :

ALEMBIC LIMITED
An Indian Company
Alembic Campus, Alembic Road, Vadodara-390 003, Gujarat, India

3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention

Field of the Invention:
The present invention relates the novel polymorphs of 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one [formula (I)] and its preparation. 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one is also known as Aripiprazole and is useful for the treatment of Schizophrenia.

Background and Prior Art
Schizophrenia is one of the most serious mental disorders. It may include withdrawal from reality, disorders of thought processes, abnormal behavior and a gross inability to communicate with other people. It is the most common type of psychosis and affects up to one person in every hundred. Onset of schizophrenia typically occurs between the age of 16 and 25. It is commonly characterized by delusions, hallucinations and extensive withdrawal from others
7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one exhibits high affinity for dopamine D2 and D3, serotonin 5-HT1A and 5- HT2A receptors, moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha 1-adrenergic and histamine HI receptors. Aripiprazole functions as a partial agonist at the dopamine D2 and the serotonin 5-HT1A receptors, and as an antagonist at serotonin 5-HT2A receptor.
7-[4-[4-(2,3-dichlorophenyl)piperazin-l -yl]butoxy]-l ,2,3,4-tetrahydroquinolin-2-one is
broadly disclosed in US patent no. 4,734,416 and specifically disclosed in US patent no. 5,006,528. The process for the preparation of 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one is well disclosed in US patent no. 5,006,528. However, no polymorphic details are reported in these patents.
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Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes in solid state. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such melting point temperatures and/or X-Ray diffraction pattern. Polymorphs of a compound can be characterized by X-Ray diffraction pattern, Infrared Spectrum, DSC etc.
US patent application no. 2004/0058935 discloses various polymorphic forms of 7-[4-[4-(2,3-dichlorophenyl)piperazin-1 –yl]butoxy]-1,2,3,4-tetrahydroquinolin-2-one (Aripiprazole) such as anhydrous Form B, Form C, Form D, Form E and Form G and hydrated Form A. These polymorphs are prepared via crystallization from various selective solvents like toluene, acetontitrile, and acetone or by heating another polymorph of Aripiprazole. All the polymorphs are characterized by their specific properties like XRD, DSC, IR etc...
WO 2004/106322 discloses the polymorphic forms of 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one namely Form II, Form III and Form IV. All the forms are characterized by their DSC and XRD pattern.
WO 2004/083183 discloses the polymorphic forms of 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one hydrochloride salt namely Form A, form B, Form C and Form D. All the polymorphs are characterized by their XRD pattern.
OBJECT OF THE INVENTION:
The object of the invention is to provide novel polymorphic forms of 7-[4-[4-(2,3-
dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one.
Another object of the invention is to provide process for the preparation of novel
polymorphic forms of 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-
tetrahydroquinolin-2-one.
BRIEF DESCRIPTION OF THE DRAWINGS:
Figure 1 represents the powder X-ray diffraction (XRD) pattern of 7-[4-[4-(2,3-dichlorophenyl)piperazin-1 -yl]butoxy]-1,2,3,4-tetrahydroquinolin-2-one Form A
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Figure 2 represents the powder X-ray diffraction (XRD) pattern of 7-[4-[4-(2,3-dichlorophenyl)piperazin-1 –yl]butoxy]-1,2,3,4-tetrahydroquinolin-2-one Form B Figure 3 represents the powder X-ray diffraction (XRD) pattern of 7-[4-[4-(2,3-dichlorophenyl)piperazin-1 –yl]butoxy]-1,2,3,4-tetrahydroquinolin-2-one Form C
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the novel polymorphic forms of 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one and its preparation.
According to one aspect of the present invention, the novel polymorphic form of 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one designated as "Form A" is characterized by powder X-ray diffraction peaks at about 16.6, 19.4, 20.4, 22.1 and 24.4±0.2 degree two-theta.
The process for the preparation of 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one Form A comprises
(i) dissolving 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-
tetrahydroquinolin-2-one with polar aprotic solvent
(ii) adding polar protic solvent to crystallize 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-
yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one Form A
(iii) isolating 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-
tetrahydroquinolin-2-one Form A
Polar aprotic solvent can be selected from the group comprising of N,N-dimethylformamide, N,N-dimethyl acetamide, N-methyl pyrrolidine, Dimethyl sulfoxide, sulfolane and the like or mixtures thereof
Polar protic solvent can be selected from the group comprising of alcohols such as alcohols -methanol, ethanol, isoproapanol, n-propanol and the like or mixtures there of.
According to another aspect of the present invention, the novel polymorphic form of 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one designated as
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"Form B" is characterized by powder X-ray diffraction peaks at about 11.1, 16.5, 18.9, 20.8, 22.4, 23.4 and 25.0±0.2 degree two-theta.
The process for the preparation of 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one Form B comprises
(i) treating 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-
tetrahydroquinolin-2-one with aromatic hydrocarbon solvent preferably xylene
(ii) crystallizing 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-
tetrahydroquinolin-2-one Form B
(iii) isolating 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-
tetrahydroquinolin-2-one Form B
According to one aspect of the present invention, the novel polymorphic form of 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one designated as "Form C" is characterized by powder X-ray diffraction peaks at about 15.8, 16.4, 17.7, 20.3, 22.2, 23.4 and 25.0±0.2 degree two-theta.
The process for the preparation of 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one Form C comprises
(i) treating 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-
tetrahydroquinolin-2-one with halogenated solvent preferably Methylene dichloride or ethereal solvent like diethyl ether, diisopropyl ethetr, tetrahydrofuran, preferable tetrahydrofuran
(ii) adding cyclohexane to crystallize 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one Form C
(iii) isolating 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-1,2,3,4-
tetrahydroquinolin-2-one Form C
The process for the preparation of polymorphic form of 7-[4-[4-(2,3-dichlorophenyl)piperazin-1 –yl]butoxy]-1,2,3,4-tetrahydroquinolin-2-one comprises
(i) treating 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-
tetrahydroquinolin-2-one with polar solvent
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(ii) adding non polar solvent to crystallize polymorph of 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one
(iii) isolating 7-[4-[4-(2,3-dichlorophenyl)piperazin-l -yl]butoxy]-l ,2,3,4-
tetrahydroquinolin-2-one polymorph
Polar solvent can be selected from group comprising of N,N-dimethylformamide, N,N-dimethyl acetamide, N-methyl pyrrolidine, Dimethyl sulfoxide, sulfolane and the like or mixture there of
Non polar solvent can be selected from group comprises of hydrocarbon solvent like toluene, xylene; ether like diethyl ether, Diisopyopyl ether, tetrahydrofuran; methyl tert-butyl ether, dioxane and the like or mixtures thereof.
The term 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one as used herein is meant to include 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one in any form, or its solvates, hydrate and in any state of purity.
As used herein term treating is meant to include dissolving, suspending, mixing, slurring. The process of the present invention is described by the following examples, which are illustrative only and should not be construed so as to limit the scope of the invention in any manner.
Example 1:
Preparation of 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydro
quinolin-2-one Form A:
(a) l0gm of 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one is dissolved in 50ml N,N-dimethylformamide at about 40 to 50° C. It is further cooled to room temperature. 100ml Methanol is added to the solution to crystallize 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one Form A. The reaction mass is stirred for 10-15 minutes, filtered and dried at 60° C to give 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one Form A.
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(b) l0gm of 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-
2-one is dissolved in 50ml N,N-Dimethylacetamide. 100ml Methanol is added to the solution
to crystallize 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-
2-one Form A. The reaction mass is stirred for 10-15 minutes, filtered and dried at 60° C to
give 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one
Form A.
(c) l0gm of 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-
one is dissolved in 50ml N-methyl pyrrolidine. 100ml Methanol is added to the solution to
crystallize 7-[4-[4-(2,3-dichlorophenyl)piperazin-l -yl]butoxy]-l ,2,3,4-tetrahydroquinolin-2-
one Form A. The reaction mass is stirred for 10-15 minutes, filtered and dried at 60° C to give
7-[4-[4-(2,3-dichlorophenyl)piperazin-l -yl]butoxy]-l ,2,3,4-tetrahydroquinolin-2-one Form
A.
Example 2:
Preparation of 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydro
quinolin-2-one Form B:
l0gm 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one is dissolved in 60ml o-Xylene at about 70 to 75° C. It is further cooled to room temperature to crystallize 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one Form B. The reaction mass is stirred for 10-15 minutes, filtered and dried at 60° C to give 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one Form B.
Example 3:
Preparation of 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3?4-tetrahydro
quinolin-2-one Form C:
(a) l0gm 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one is dissolved in 50ml Methylene dichloride at about 25 to 30° C. 100ml of cyclohexane is added to the solution to crystallize 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one Form C. The reaction mass is stirred, filtered and dried at 60° C to give 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one Form C.
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(b) l0gm 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one is dissolved in 50ml Tetrahydrofuran at about 25 to 30° C. 100ml of cyclohexane is added to the solution to crystallize 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one Form C. The reaction mass is stirred, filtered and dried at 60° C to give 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one Form C.
Example 4:
Preparation of 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydro quinolin-2-one:
L0gm 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one is dissolved in 50ml Dimethylformamide. 100ml of xylene is added to the solution to crystallize 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one. The reaction mass is stirred, filtered and dried at 60° C to give 7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one.
Dated this 9th day of June 2005
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