Field of the Invention:
The present invention relates to a process for the preparation of anhydrous Type I crystals of aripiprazole compound of formula-1. Aripiprazole is chemically known as 7-[4-[4-(2,3-dichlorophenyl)-l-piperazinyI]butoxy]-3,4-dihydro-2(IH)-quinoIinone, which is represented by the following structural formula,

Aripiprazole is a dopamine D2 and serotonin 5HTi partial agonist and serotonin 5HT2 antagonist. It is useful for treating schizophrenia. Aripiprazole is commercially available under the brand name of Abilify®.
Background of the Invention:
Aripiprazole and its pharmaceutically acceptable salts were first disclosed in US 5006528. The disclosed process involves the usage of ethanol for the recrystallisation of crude aripiprazole and the obtained aripiprazole having a melting point of 139-139.5°C.
An article titled "Study on Crystal Transformation of Aripiprazole" in The Fourth Japan-Korean Symposium on Separation Technology, 937, 1996 disclosed that the aripiprazole obtained from the crystallization fi-om ethanol is an anhydrous crystal and designated as Type I crystals. The said article also teaches the conversion of Type I crystal to Type II crystals by heating the type I crystals at 130-140°C for 15 hours. The type II crystal is also an anhydrous having a mehing point of 150°C. When both Type I and Type II aripiprazole were recrystallized from an alcoholic solvent containing water upto 20%, provides the hydrated form which is designated as Type III.
EP 1330249 disclosed the seven crystalline forms of aripiprazole (A to G), where in anhydrous form B of aripiprazole is a non-hygroscopic crystalline form i.e., less than

0.4% water uptake in 24 hours. The said patent also disclosed the method of analysis for hygroscopicity and also disclosed that the prior art anhydrous aripiprazole type I crystals exhibited hygroscopicity of 1.78% after placing it in a desiccator set at a humidity 100% and left for 24 hours.
Apart form the above, number of patent literatures disclosed the different processes for the preparation of aripiprazole type I and type II anhydrous crystals. But the reported process for the preparation of type I crystals does not provide the anhydrous type I crystals consistently. Hence there is a need in the art for a process which consistently provides the anhydrous aripiprazole type I crystals.
Brief Description of the Invention:
The present invention relates a process for the preparation of anhydrous type I crystals of aripiprazole compound of formula-1.
The first aspect of the present invention is to provide a process for the preparation of anhydrous type I crystals of aripiprazole, which comprise of the following steps;
a) Dissolving the aripiprazole in a suitable alcoholic solvent at reflux temperature,
b) treating the solution with carbon,
c) stirring the reaction mixture at reflux,
d) filtering the reaction mixture and washing with a suitable solvent,
e) cooling the filtrate to room temperature and stirring,
f) filtering the solid and washed with suitable solvent,
g) the obtained wet solid transferred in to a autoclave in a suitable solvent, h) heating the reaction mixture to 80-85°C in autoclave,
i) stirring the reaction mixture,
j) cooling the reaction mixture and stirring,
k) filtering, washing the solid with suitable solvent,
1) drying the solid to get the anhydrous type I crystals of aripiprazole.

The second aspect of the present invention is to provide a process for the preparation of anhydrous type I crystals of aripiprazole by crystallizing the aripiprazole from a suitable solvent, characterized in that the reaction take place in an autoclave in a closed condition.
The third aspect of the present invention is to provide a process for the preparation of anhydrous type I crystals of aripiprazole, which comprises of the following steps
a) taking aripiprazole and a suitable solvent in a autoclave,
b) heating the reaction mixture to 50-90°C in autoclave,
c) stirring the reaction mixture,
d) cooling the reaction mixture and stirring,
e) filtering, washing the solid with suitable solvent,
f) drying the solid to get the anhydrous type I crystals of aripiprazole.
Brief Description of the drawings:
Figure-1: Illustrates the Powder X-ray diffractogram of anhydrous type I crystals of
aripiprazole
Figure-2: Illustrates the Infra red spectrum of anhydrous type I crystals of aripiprazole
Detailed Description of the Invention:

Formula-1
The present invention relates to a process for the preparation of anhydrous type I crystals of aripiprazole compound of formula-1. Aripiprazole compound of formula-1 is represented by the following structural formula

The first aspect of the present invention provides a process for the preparation of anhydrous type I crystals of aripiprazole compound of formula-1, which comprise of the following steps;
a) Dissolving the aripiprazole in a suitable alcoholic solvents selected from methanol, ethanol, isopropanol, n-propanol, butanol or mixture thereof at reflux temperature,
b) subjecting the obtained solution to carbon treatment,
c) stirring the reaction mixture at reflux,
d) filtering the reaction mixture through hyflow and washing with a suitable alcohol solvent,
e) cooling the filtrate to room temperature and stirred,
f) filtering, washing the solid with suitable alcohol solvent,
g) taking the obtained wet solid in a suitable alcoholic solvent selected from methanol, ethanol, isopropanol, n-propanol, butanol or mixture thereof in an autoclave,
h) heating the reaction mixture to 50-90°C, preferably 80-85°C in an autoclave,
i) stirring the reaction mixture,
j) cooling the reaction mixture and stirring,
k) filtering, washing solid with suitable alcoholic solvent,
1) drying the solid to get the anhydrous type I crystals of aripiprazole.
In a preferred embodiment of the present invention, the process for the preparation of anhydrous type I crystals of aripiprazole compound of formula-1 comprises of the following steps,
a) Dissolving the aripiprazole in isopropanol at 75-85°C,
b) subjecting the obtained solution to carbon treatment,
c) stirring the reaction mixture at 75-85°C for 45 minutes,
d) filtering the reaction mixture through hyflow and washing with isopropanol at 75-80°C,
e) cooling the filtrate to 25-30°C and stirred for an hour,
f) filtering the solid and washing with isopropanol,

g) taking the obtained wet solid in methanol in an autoclave,
h) heating the reaction mixture to 80-85°C in autoclave,
i) stirring the reaction mixture for 1.5 hours at 80-85°C
j) cooling the reaction mixture to 25-30°C and stirring for 15 minutes,
k) filtering, washing the solid with methanol,
1) drying the solid at 60-70°C to get the anhydrous type I crystals of aripiprazole.
The second aspect of the present invention provides a process for the preparation of anhydrous type 1 crystals of aripiprazole compound of formula-1, which comprises of crystallizing the aripiprazole from a suitable alcoholic solvent selected from methanol, ethanol, isopropanol, n-propanol, butanol or mixtures there of, at a temperature from 50°C to reflux temperature of the solvent, characterized in that the crystallization take place in an autoclave in a closed condition.
In a preferred embodiment, the aripiprazole and methanol is taken in an autoclave, heating the reaction mixture to 80-85°C and stirring for 90 minutes, cooling the reaction mixture to 25-30°C, separating the solid by filtration and finally drying the solid at 60-70°C to get the anhydrous type I crystals of aripiprazole.
The third aspect of the present invention provides a process for the preparation anhydrous type I crystals of aripiprazole, which comprise of the following steps,
a) taking the aripiprazole and a suitable alcoholic solvent selected from methanol, ethanol, isopropanol, n-propanol, butanol or mixture thereof in an autoclave,
b) heating the reaction mixture to 50-90°C, preferably 80-85°C in autoclave,
c) stirring the reaction mixture,
d) cooling the reaction mixture and stirring,
e) filtering, washing solid with suitable alcoholic solvent,
f) drying the solid to get the anhydrous type I crystals of aripiprazole.
In a preferred embodiments of the present aspect of the invention, a process for the preparation of aripiprazole comprise of the following steps;

a) taking aripiprazole and isopropylalochol in a autoclave,
b) heating the reaction mixture to 80-85°C in autoclave,
c) stirring the reaction mixture for 1.5 hours at 80-85°C
d) cooling the reaction mixture to 25-30°C and stirring for 15 minutes,
e) filtering, washing the solid with isopropanol,
f) drying the solid at 60-70°C to get the anhydrous type I crystals of aripiprazole.
Aripiprazole which is used as input in the present invention is prepared as per the process disclosed in US 5006528 or as per the example-1 of the present application. As used here in the present invention the anhydrous type I crystals of aripiprazole means the anhydrous type I crystals of aripiprazole which is disclosed in The Fourth Japan-Korean Symposium on Separation Technology, 937,1996.
The PXRD and IR of anhydrous type I crystal of aripiprazole is similar to the anhydrous type I crystal which is disclosed in the article titled "Study on Crystal Transformation of Aripiprazole" in The Fourth Japan-Korean Symposium on Separation Technology, 937,1996.
Anhydrous type I crystals of aripiprazole can be micronized or milled to get the desired fine particle size.
PXRD analysis of anhydrous type I crystal of aripiprazole was carried out using SIEMENS/D-5000 X-Ray diffractometer using Cu, Ka radiation of wavelength 1.54 A° and continuous scan speed of 0.045°/min. FT-IR spectrum of anhydrous type I crystal of aripiprazole was recorded on Thermo model Nicolet-380 as KBr pellet.

The process described in the present invention was dehionstrated in examples illustrated below. These examples are provided as illustration purpose only and therefore should not be construed as limitation of the scope of the present invention.
Examples:
Exainple-1: Preparation of Aripiprazole compound of formula-1:
A mixture of 7-(4-bromobutoxy)-3,4-dihydro-2(lH)-quinolinone (40 grams), l-(2,3-dichlorophenyl)piperazine hydrochloride (39.17 grams), triethylamine (30 grams) and methanol (200 ml) was heated to reflux temperature and stirred up to completion of reaction. The reaction mixture was cooled, filtered the solid and washed with methanol. The obtained wet solid was taken in autoclave and methanol was added to it then heated to 80-85°C in a closed condition. The reaction mixture is stirred for 90 minutes at 80-85°C. The reaction mixture was cooled to 25-35°C, stirred and filtered. Water (400 ml) was added to the obtained wet solid and stirred for 60 minutes at 25-35°C. The solid was filtered, washed with water and dried at 60-70°C to get aripiprazole. Yield: 75 grams. Moisture content: < 1.0 % w/w
Example-2: Preparation of anhydrous type I crystal of aripiprazole:
A mixture of aripiprazole (50 grams) and isopropanol (550 ml) was heated to reflux temperature. The obtained solution was treated with carbon and stirred for 45 minutes at reflux. The reaction mixture was filtered through hyflow, washed with isopropanol at 75-80°C. The filtrate was cooled to 25-30°C and stirred for an hour. The solid formed was filtered and washed with isopropanol. The obtained solid was taken in autoclave and methanol (500 ml) was added to it and heated to 80-85°C in a closed condition. The reaction mixture is stirred for 90 minutes at 80-85°C in an autoclave. The reaction mixture was then cooled to 25-3 5°C, stirred for 10 minutes. The solid was filtered, washed with methanol and dried at 60-70°C to get the anhydrous type I crystal of aripiprazole. The obtained type I crystals characterized by its PXRD and IR and the same has represented in figure 1 and 2 respectively. Yield: 40 grams Water content: < 1.0% w/w

ExampIe-3: Preparation of anhydrous type I crystal of aripiprazole:
Aripiprazole (40 grams) was taken in autoclave and methanol (500 ml) was added to it then the reaction mixture was heated to 80-85°C in a closed condition. The reaction mixture is stirred for 90 minutes at 80-85°C in an autoclave. The reaction mixture was then cooled to 25-35°C and stirred for 10 minutes. The solid was filtered, washed with methanol and dried at 60-70°C to get the anhydrous type I crystal of aripiprazole. Yield: 38 grams Water content: < 1.0% w/w Particle Size Distribution: D(0.5): 3.7^m; D(0.9): 8.83 ^m; D [4,3]: 4.58 ^mi
Exaniple-4: Preparation of anhydrous type I crystal of aripiprazole:
Aripiprazole (40 grams) was taken in autoclave and isopropanol (500 ml) was added to it then the reaction mixture was heated to 80-85°C in a closed condition. The reaction mixture is stirred for 90 minutes at 80-85°C in an autoclave. The reaction mixture was then cooled to 25-3 5°C and stirred for 10 minutes. The solid was filtered, washed with isopropanol and dried at 60-70°C to get the anhydrous type I crystal of aripiprazole. Yield: 35 grams Water content: < 1.0% w/w

We Claim:
1. A process for the preparation of anhydrous type I crystal of aripiprazole compound of
formula-1, which comprise of the following steps,
a) Dissolving the aripiprazole in a suitable alcoholic solvents at reflux temperature,
b) subjecting the obtained solution to carbon treatment,
c) stirring the reaction mixture at reflux,
d) filtering the reaction mixture through hyflow and washing with a suitable alcohol solvent,
e) cooling the filtrate to room temperature and stirred,
f) filtering the solid and washing with a suitable alcoholic solvent,
g) taking the obtained wet solid in a suitable alcoholic solvent in an autoclave,
h) heating the reaction mixture to 80-85°C in autoclave,
i) stirring the reaction mixture,
j) cooling the reaction mixture and stirring,
k) filtering, washing the solid with suitable alcoholic solvent'
1) drying the solid to get the anhydrous type I crystals of aripiprazole.
2. A process according to claim 1, where in the alcoholic solvents is selected from methanol, ethanol, isopropanol, n-propanol, butanol and mixtures thereof.
3. A process according to claim 1, wherein the alcoholic solvent is methanol.
4. A process according to claim 1, where in the alcbholic solvent is isopropanol.
5. A process for the preparation of anhydrous type I crystals of aripiprazole compound of formula-1, which comprises of crystallizing the aripiprazole from a suitable solvent, at a temperature from 50°C to reflux temperature of the solvent, characterized in that the crystallization take place in an autoclave in a closed condition.

6. A process according to claim 5, where in the suitable solvent is alcoholic solvent and is selected from methanol, ethanol, isopropanol, n-propanol, butanol and mixtures thereof.
7. A process for the preparation of anhydrous type I crystal of aripiprazole compound of formula-1, which comprises of the following steps,

a) Dissolving the aripiprazole in isopropanol at 75-85°C,
b) subjecting the obtained solution to carbon treatment,
c) stirring the reaction mixture at 75-85°C for 45 minutes,
d) filtering the reaction mixture through hyflow and washing with isopropanol at 75-80°C,
e) cooling the filtrate to 25-30°C and stirred for an hour,
f) filtering the solid and washing with isopropanol,
g) taking the obtained wet solid in methanol in an autoclave,
h) heating the reaction mixture to 80-85°C in autoclave,
i) stirring the reaction mixture for 1.5 hours at 80-85°C j) cooling the reaction mixture to 25-30°C and stirring for 15 minutes, k) filtering, washing the solid with methanol,
1) drying the compound at 60-70°C to get the anhydrous type I crystals of aripiprazole.
8. A process for the preparation of anhydrous type I crystal of aripiprazole compound of
formula-1, which comprises of;
a) taking aripiprazole and a suitable alcoholic solvent selected from methanol, ethanol, isopropanol, n-propanol, butanol or mixture thereof in an autoclave,
b) heating the reaction mixture to 50-90°C in autoclave,
c) stirring the reaction mixture,
d) cooling the reaction mixture and stirring,
e) filtering, washing solid with suitable alcoholic solvent,
f) drying the solid to get the anhydrous type I crystals of aripiprazole.

9. Anhydrous type I crystals of aripiprazole particles having D90 is in the range of
2-50 xm and mean particle in the range of 2-70 10. The particles according to claim 9, the anhydrous type I crystals of aripiprazole
particles having D90 is in the range of 2-30 m and mean particle in the range of 2-45 pm.