FORM 2
THE PATENTS ACT, 1970
(Act 39 of 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See Section 10 & rule 13)
"A PROCESS FOR THE PREPARATION OF ARIPIPRAZOLE AND ITS CRYSTAL FORM THEREOF"
ZCL CHEMICALS LIMITED
'A'-806/807,
215 ATRIUM CHAKALA,
ANDHERI (EAST), MUMBAI-400 059,
MAHARASHTRA, INDIA.
(An Indian Organization)
The following specification particularly describes the invention and the manner in which it is to be performed.

"A PROCESS FOR THE PREPARATION OF ARIPIPRAZOLE AND ITS CRYSTAL FORM THEREOF"
FIELD OF THE INVENTION
The present invention relates to an improved and industrially applicable process for the preparation of aripiprazole and its crystal form of formula I thereof,

BACKGROUND OF THE INVENTION
Aripiprazole is an atypical antipsychotic and antidepressant used in the treatment of schizophrenia, bipolar disorder, and clinical depression. Aripiprazole is chemically designated as 7-{4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy}-3,4-dihydroquinolin-2(lH)-one or 7-[4-[4-(2,3-dichlorophenyl)-l-piperazinyl] butoxy]-3,4-dihydrocarbostyril and the chemical structure thereof is represented by formula (I). Aripiprazole has been approved by the FDA for the treatment of schizophrenia in 2, 5, 10, 15, 20 and 30 mg tablets for oral administration and is currently marketed under the brand name of Abilify®. The commercially marketed product contains the aripiprazole as the free base and not as an aripiprazole salt.
Aripiprazole and related compounds were first disclosed in US patent 5,006,528 (herein referred as US '528). It discloses various salts of aripiprazole and their preparation. The patent discloses double re-crystallization of crude aripiprazole from ethanol resulting in colorless crystals having a melting point 139-139.5°C.
US application 2007/0213535 discloses process for the preparation of aripiprazole by condensing 7-(4-bromobutoxy)-3,4-dihydro-2(lH)-quinolinone or 7-(4-chlorobutoxy)-3,4-dihydro-2(lH)-quinolinone with l-(2,3-dichlorophenyl) piperazine mono hydrochloride in the presence of potassium carbonate, in toluene/water, optionally in the presence of phase transfer catalyst to get the crude aripiprazole resulted in just 65% yield having purity just 98%. The patent application is disclosing purity 99.6% after crystallizing aripiprazole twice from the

ethanol which results in further extensive yield loss. However the patent is silent about yield obtained.
US application 2007/238876 discloses process for the preparation of aripiprazole by condensing 7-(4-halobutoxy)-3,4-dihydro-2(lH)-quinolinone with l-(2,3-dichlorophenyl) piperazine hydrochloride in water and in the presence of organic base. The patent application is disclosing HPLC purity 99%.
Different polymorphs exhibit different physicochemical properties such as solubility, dissolution rate, bioavailability and chemical and physical stabilities. So, polymorphism has become a topic of great interest for pharmaceutical industries as it has the potential to significantly affect the physical properties of a compound. In addition to this, process for preparing such polymorph should be robust and efficient in producing commercial quantity of crystalline compounds. This question arises because sometimes the most suitable polymorph is difficult to produce. Further particle size of the drug molecule also affects its physicochemical properties and in case of aripiprazole it is especially important for effective formulation. So, it is of greatest importance for pharmaceutical industry to ensure reliable, robust, cost effective as well as efficient process for synthesis of crystalline aripiprazole of desired purity and good yield as well.
Polymorphism of aripiprazole has been disclosed in an article, Study on Crystal Transformation of Aripiprazole, presented at the Fourth Japan-Korea Symposium on Separation Technology, p. 937 (1996). According to this reference, aripiprazole anhydride crystals may exist as Type-I, Type-II and Type-Ill crystals. This article designate aripiprazole crystal prepared by US '528 as Type I aripiprazole and identified as an anhydrate. It discloses that anhydrate crystals of aripiprazole can be prepared by re-crystallization of aripiprazole from ethanol or by heating aripiprazole hydrate (Type- III) at a temperature of 80°C. Type-II aripiprazole crystals can be prepared by heating Type-I crystals at 130°C to 140°C for 15 hours. This process of heating is not easily applied to an industrial scale preparation of anhydride aripiprazole Type-II.
US patent application publication 2004/0058935 discloses several polymorphic forms of aripiprazole namely hydrate A, crystal B, type C, D, E, F &

G and processes for their preparation. In application, it is disclosed that hydrate A is useful intermediate for preparation of anhydrate forms. Aripiprazole hydrate A is prepared by milling conventional aripiprazole hydrate.
Aripiprazole anhydrous form B (also known as crystal B), which seems to be preferred crystalline form, is low hygroscopic and is a stable crystalline form. Aripiprazole form B is prepared by heating aripiprazole hydrate A at 90-125°C for about 3 to 50 hours. Aripiprazole form B is also prepared by heating conventional hygroscopic aripiprazole anhydrous crystals or conventional aripiprazole hydrate at 100°C or 120°C for 3 to 50 hours.
It is observed that process described above does not show consistent results. There are several other processes for preparation of hydrate A, form B and Type II of aripiprazole known in art which have one or more disadvantages, some are described herein.
US patent 7,642,353 discloses a process for preparation of aripiprazole form B by dissolving aripiprazole in a suitable solvents like 1-propanol, 2-propanol, 1-butanol, ethyl acetate, acetonitrile and mixture thereof at reflux temperature, adding seed crystals of aripiprazole form B to the solution, cooling the mixture and isolating crystals of aripiprazole form B. Process requires seeding with aripiprazole form B and silent about the mode to get seeding material.
Most of prior art processes for preparation of aripiprazole hydrate A and form B either require special conditions such as seeding, milling or require special equipment which makes the final product costly and eventually makes the process not attractive for industrial production. Also some of the processes do not yield reproducible results, are lengthy and do not provide consistency in particle size of aripiprazole produced. In addition to above, prior art methods for the preparation of crystalline type II also necessitate the optimization of experimental conditions such as temperature along with that of the selection of solvents, require heating procedure and does not give reproducible results and/or result in mixture of polymorph. Numerous factors effect crystallization conditions, and they are well known to one of skill in the art.

In view of above, it is desirable to develop an alternate to meet the pharmacopoeial or regulatory requirements whereas above prior art processes resulted in purity around 99% which is not acceptable as per pharmacopoeial limits. Moreover that there is need to design economically advantageous process to prepare aripiprazole. Accordingly, there is a need in the art for processes which can ameliorate at least one of the disadvantages of the existing prior art processes.
Thus, present invention fulfills the need of the art and provides an improved and industrially applicable process for preparation of aripiprazole and its crystal form, which provides aripiprazole in high purity and good yield.
OBJECTIVE OF THE INVENTION
The principal objective of the present invention is to provide a process for preparation of aripiprazole and its crystal form to overcome or ameliorate one of the disadvantages of the prior art processes.
Yet another objective of the invention is to provide an efficient, improved and industrially advantageous process for preparation of aripiprazole and its crystal form which is conveniently applicable to industrial scale.
Yet another leading objective of the present invention is to provide a process the preparation of aripiprazole and its crystal form having high purity and yield as well.
Yet one more primary objective of the present invention is to provide a process for the preparation of aripiprazole and its crystal type I.
Yet additional key objective of the present invention is to provide a purification process for the preparation of aripiprazole and/or its crystal type I.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of aripiprazole or its crystal type I of formula I,

which proves to be efficient and industrially viable. The process comprises the steps of:
a), condensing formula II with formula III in mixture of suitable solvent in the presence of base, phase transfer catalyst and alkali metal halide; .

wherein X represents halogen group b). isolating crude aripiprazole; c). treating crude aripiprazole with mixture of acetonitrile, isobutanol and
ethanol; d). removing the solvent and optionally isolating aripiprazole; e). treating aripiprazole with ethanol and water; and f). isolating aripiprazole crystal type I.
Accordingly, the present invention provides an improved process for the purification of aripiprazole to isolate aripiprazole crystal type 1, the process comprises the steps of:
a), treating crude aripiprazole with mixture of acetonitrile, isobutanol and ethanol;
b). removing the solvent and optionally isolating aripiprazole;
c). treating aripiprazole with ethanol and water; and
d). isolating aripiprazole crystal type I,

Accordingly, the present invention provides an improved process for the preparation of aripiprazole crystal type I having hygroscopicity 0.5% or more after placing said drug substance for 24 hours in a desiccator maintained at a temperature of 60°C and a humidity level of 95-100%.
Accordingly, the present invention provides a process for preparing aripiprazole crystal type I having purity more than 99.8% as well as resulted in good yield.
Accordingly, the present invention provides an improved process for the preparation of phannacopoeial grade aripiprazole as depicted in below scheme:

BRIEF DESCRIPTION OF DRAWING:
FIG. 1 is a powder X-ray diffraction pattern for "crystal type I" of Aripiprazole having 2-theta values at 11.05°, 16.60°, 19.34°, 20.37° and 22.07°.
DETAILED DESCRIPTION OF THE INVENTION
All ranges recited herein include the endpoints, including those that recite a range "between" two values. Terms such as "about", "generally" and the like are to

be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
As used herein, the term "ambient temperature" describing common indoor temperatures usually falls in the range of 25 to 35°C.
The present invention provides an improved and efficient process for the preparation of aripiprazole crystal type I.
According to the embodiment of the invention provides an industrially viable process for preparation of aripiprazole starting from compound of formula II.
Stage 1:
The compound of formula II is reacted with compound of formula III in mixture of suitable solvents in the presence of base, phase transfer catalyst and alkali metal halide to prepare aripiprazole.
Suitable solvent include acetonitrile, ethanol, methanol, isopropanol, 1-butanol, 1- pentanol or water or mixture thereof. Preferably mixture of alcohol and water, more preferably mixture of ethanol and water. Suitable base include ammonia, n-butyl amine, pyrrolidine, diethyl amine, di-isopropyl amine, triethylamine, diisopropylethyl amine or mixtures thereof, preferably tri ethyl amine. Various types of phase transfer catalysts are known in the art. Suitable phase transfer catalysts include, but are not limited to, quaternary ammonium salts, quaternary phosphonium salts, crown ethers, polyethylene glycols, In particular, suitable phase transfer catalysts include tetrabutyl ammonium bromide, tetrabutyl ammonium hydrogen sulfate, benzyltriethyl ammonium chloride, tricaprylylmethyl ammonium. chloride, methyltrioctyl ammonium chloride, methyltributyl ammonium chloride, tetrabutyl phosphonium bromide, tetraphenyl phosphonium bromide, hexadecyltrimethyl ammonium bromide and sodium lauryl sulfate. Quaternary ammonium salts are preferred phase transfer catalysts. Tetrabutyl

ammonium bromide is particularly preferred. The phase transfer catalyst such as tetrabutyl ammonium bromide may be present in an amount from about 2 to about 20 % per weight. The reaction is advantageously carried out at temperature is suitably between 30-100°C for 4-15 hours, preferably at 40-85°C for 10-12 hours, more preferably at 80-85°C till completion of the reaction. To enhance the rate of reaction alkali metal halide can be added to the reaction mixture, wherein alkali metal bromides or iodides being particularly preferred.
Aripiprazole prepared by the above process can be taken to the next stage in-situ after filtration or can be isolated by cooling the reaction mixture to 25-30°C, washed with water and dried at 75-80°C to get aripiprazole having purity greater than 95% and yield around 97%.
Stage 2:
Aripiprazole from stage T is purified in suitable solvent system to get pure aripiprazole crystal type I.
According to an embodiment of the present invention, Aripiprazole is dissolved in suitable solvent or mixture of solvents, wherein solvents include alcohols, nitrile, water or mixture thereof. Preferably mixture of acetonitrile, iso-butanol and ethanol, more preferably in ratio of 50:40:10 respectively. The reaction mixture carried out at temperature 85-90° for 10-15 minutes. For the decolorization, charcoal treatment can be given to the product as known in the art. The reaction mixture is then cooled to 25-30°C followed by filtration to get wet aripiprazole. Wet aripiprazole can be dried optionally or can be taken to the next stage as such.
The advantage of the above particular embodiment is to prepare purer aripiprazole. Particularly the above step is designed in such a way which leads to removal of the major impurities and gives desired quality to fulfil the regulatory or pharmacopoeial requirements. In current scenario, existing prior art processes are not fulfilling pharmacopoeial requirements as impurity specifications are tighten by regulatory agencies.
According to another embodimenl of the present invention, wet or dried aripiprazole is then purified in suitable solvent to get aripiprazole crystal type I in

pure form. The suitable solvent include alcohol and water and mixtures thereof. Preferably the purification is carried out in mixture of ethanol and water, more preferably in ratio of 80:20 respectively. The reaction mixture is heated at temperature 80-90°C for 1-2 hours. The reaction mixture is then cooled to 0-5°C, washed with mixture of ethanol and water and dried at temperature 80-82°C for 30 hours to get aripiprazole crystal type T.
The advantage of the above particular embodiment is to prepare pharmacopoeial grade aripiprazole crystal type I having purity greater than 99.8% with good yield.
EXAMPLES:
Stage - I: Preparation of Aripiprazole from 7-(4-chlorobutoxy)-3, 4-dihydro-2(lH)-quinolinone
7-(4-chlorobutoxy)-3,4-dihydro-2( 1 H)-quinolinone (240 gm), triethylamine (210.18g), l-(2,3-dichlorophenyl) piperazine hydrochloride (DCPP HC1) (280.86 gm), Tetra-n-butyl ammonium bromide (TBAB) (24.0 gm), sodium iodide (Nal) (8.732 gm) was added in ethanol (120 ml) and water (2400ml) at ambient temperature. The reaction mixture was gradually heated up to 80-85°C and maintained for 8-12 hours. After completion of reaction, cooled the mixture up to 25-30°C and stirred for 60 minutes. Filtered the reaction mixture and washed with water (480 ml). Wet cake was added in water (1920 ml) and stirred at 25-30°C for 45-60 minutes. Filtered the mass at 25-30°C and washed with water (480 ml). The wet cake was dried at 75-80°C to get 391 gm Aripiprazole having HPLC purity: >95%.
Stage-II: Purification of Aripiprazole
Crude Aripiprazole (390 gm) was added into the mixture of Acetonitrile: Iso-Butanol: Ethanol (Ratio in % is 50:40:10) (1950 ml) at temperature 25-30°C. The reaction mass was heated up to 85-90°C and maintained for 10-15 minutes followed by addition of Activated Charcoal (39 gm) The reaction mass was maintained at 85-90°C for 30 minutes Filtered the mass at 85-90°C and washed with Acetonitrile:

Iso-Butanol: Ethanol (Ratio in % is 50:40:10) (390 ml).The filtrate mass was then cooled to 25-30°C and maintained for 60 minutes followed by filtration at 25-30°C. The obtained cake was washed with Acetonitrile: Iso-Butanol: Ethanol (Ratio in % is 50:40:10) (390 ml) and dried at 80-85°C under vacuum to get 312 gm first purified Aripiprazole having HPLC purity: >99.3%.
First purified Aripiprazole (312 gm) was added into the mixture of Ethanol: Water (Ratio in % is 80:20) (6212 ml) at temperature 25-30°C. The reaction mass was heated up to 80-90°C within 60 to 80 minutes and maintained for 10-15 minutes. The mass was then cooled to 25-30°C within 150 to 180 minutes then cooled up to 0-5°C within 60 to 80 minutes and maintained for 15 to 20 minutes followed by filtration at 0-5°C. The obtained cake was washed with mixture of Ethanol: Water (Ratio in % is 80:20) (156 ml) and dried at 80-82°C for 30 hours to get 287 gm final Aripiprazole having HPLC purity: >99.8%.
The above obtained aripiprazole preceded for hygroscopicity test. The hygroscopicity obtained is 0.5% or more after placing said drug substance for 24 hours in a desiccator maintained at a temperature of 60°C and a humidity level of 95-100%.

WE CLAIM:
1. An improved process for the preparation of aripiprazole or its crystal type I of formula 1,

comprising the steps of:
a), condensing formula II with formula 111 in mixture of suitable solvent in the presence of base, phase transfer catalyst and alkali metal halide;

wherein X represents halogen group b). isolating crude aripiprazole; c). treating crude aripiprazole with mixture of acetonitrile, isobutanol and
ethanol; d). removing the solvent and optionally isolating aripiprazole; e). treating aripiprazole with ethanol and water; and f). isolating aripiprazole crystal type I.
2. The process according to claim 1, wherein in step a) suitable solvent is selected from acetonitrile, ethanol, methanol, iso-propanol, l-butanol, 1-pentanol or water or mixture thereof, preferably mixture of alcohol and water, more preferably mixture of ethanol and water.
3. The process according to claim 1, wherein in step a) base is selected from ammonia, n-butyl amine, pyrrolidine, diethylamine, di-isopropyl amine, triethylamine, diisopropylethyl amine or mixtures thereof, preferably triethylamine.
4. The process according to claim 1, wherein in step a) phase transfer catalyst is selected from tetrabutyl ammonium bromide, tetrabutyl ammonium hydrogen sulfate, benzyltriethyl ammonium chloride, tricaprylylmethyl ammonium

chloride, methyltrioctyl ammonium chloride, methyltributyl ammonium chloride, tetrabutyl phosphonium bromide, tetraphenyl phosphonium bromide, hexadecyltrimethyl ammonium bromide and sodium lauryl sulfate, preferably tetrabutyl ammonium bromide.
5. The process according to claim 1, wherein in step a) alkali metal halide is selected from alkali metal bromides or alkali metal iodides.
6. An improved process for the purification of aripiprazole to isolate aripiprazole crystal type I, the process comprising the steps of:
a), treating crude aripiprazole with mixture of acetonitrile, isobutanol and
ethanol; b). removing the solvent and optionally isolating aripiprazole; c). treating aripiprazole with ethanol and water; and d). isolating aripiprazole crystal type I.
7. The process according to claim 1 and 3, aripiprazole crystal type I having hygroscopicity 0.5% or more after placing said drug substance for 24 hours in a desiccator maintained at a temperature of 60°C and a humidity level of 95-100%.
8. The process according to any of the preceding claim, aripiprazole crystal type I having purity more than 99.8%.