DESC:TITLE OF THE INVENTION
An improved process for the preparation of Aripiprazole monohydrate.

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of 7-[4-[4-(2,3- dichlorophenyl)-1-piperazinyl] butoxy]-3,4 dihydrocarbostyril monohydrate having formula (I). The compound of formula (I) has adopted name “Aripiprazole monohydrate”.

BACK GROUND OF THE INVENTION

Aripiprazole monohydrate is disclosed in US 8,399,469 assigned to Otsuka pharmaceutical Co Ltd. Aripiprazole monohydrate is an atypical antipsychotic indicated for the treatment of Schizophrenia. Aripiprazole monohydrate is marketed under the name of ABILIFY.

Process for the preparation crystalline Aripiprazole monohydrate is disclosed in US 8,399,469 and WO 2012077134.

Aripiprazole monohydrate (hydrate A) has been obtained by milling Aripiprazole hydrate, milling is performed by an atomizer using a rotational speed of 5000-15000 rpm for the main axis, a feed rotation of 10-30 rpm and a screen hole size of 1-5 mm. This is not feasible at industrial scale.

In view of all these disadvantages, there is need to develop process which is cost effective, eco-friendly and industrially viable.

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to an improved process for the preparation of Aripiprazole monohydrate of formula (I),

which comprises:
a) dissolving Aripiprazole anhydrous form-B in a solvent selected from the ethanol, acetone, water and mixtures thereof;
b) reaction mixture is heated to 65-75 °C;
c) filter the reaction mass and wash with ethanol;
d) cool the reaction mass to 5-15 °C;
e) circulate the reaction mixture through high shear wet miller;
f) stir the reaction mass through high shear wet miller at 5-15 °C;
g) filter the reaction mass and wash with acetone;
h) isolating Aripiprazole monohydrate.

In another aspect the present process is cost effective with higher yield.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure-1 illustrates the X-ray diffraction of Aripiprazole monohydrate.
Figure-2 illustrates the PSD of Aripiprazole monohydrate.
Figure-3 illustrates the High Shear Wet Miller Instrument.

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, the present invention provides a process for the preparation of Aripiprazole monohydrate of formula (I),

Scheme-I illustrates the process for the preparation Aripiprazole monohydrate.

In step a) dissolving Aripiprazole anhydrous form-B in ethanol, acetone, water and mixtures thereof;

In step b) reaction mixture is heated to 60-85 °C and stirred for 20-30 minutes, till complete dissolution; preferably reaction condition is 60-80 °C, most preferably 65-75 °C.

In step c) filter the reaction mass and wash with ethanol;

In step d) cool the reaction mass to 5-20 °C, preferably 5-15 °C;

In step e) the above obtained reaction mass is circulated through high shear wet miller to get the desired particle size;

In the above step, at flow rate is 0.1 L/min to 40 L/min, preferably flow rate is 2.2 L/min to 33.0 L/min & rotational speed is 1000 to 14000 rpm, preferably 5000 to 9500 rpm and temperature of the reaction medium is 5°C to 10 °C.

In step-f) filter the reaction mass and wash with acetone under the vacuum;

Aripiprazole monohydrate is characterized by X-ray powder diffraction pattern (XRPD) depicted in Figure.1 and water content is between 3.4 - 4.3 w/w%.

The X-ray powder diffraction patterns of the Aripiprazole monohydrate is obtained using X-pert pro Panalytical Discover powder diffractometer equipped with a goniometer of T/2T configuration and Xclerator Eye detector. The Cu-anode X-ray tube was operated at 45 kV and 40 mA. The experiments were conducted over the 2T range of 2.0 ° - 50.0 °, 0.020 ° step size, 20 seconds step time.

“Particle Size Distribution (PSD)” means the cumulative volume size distribution of equivalent spherical diameters as determined by laser diffraction in Malvern Master Sizer 3000 equipment and having PSD Histogram pattern substantially the same as that shown in Figure 2.

Advantages:
1) Avoid loss of material;
2) Higher yield;
3) Easily scalable process for any batch size;
4) Environment friendly process by voiding dust formation.

Example 1:
Process for the preparation of Aripiprazole monohydrate
Aripiprazole anhydrous form B (150 grams) was dissolved in a mixture of ethanol (144 Lts), water (36 Lts) and acetone (135 Lts) and heated to 65-75 °C to get the clear solution. The solution was filtered and washed with ethanol. Cool the reaction mass to 5-15 °C, circulated through high shear wet miller with 9000 RPM at 5-15 °C and filtered off solid and washed with acetone. The obtained solid was filtered and dried at 25-35 °C for 6 hours to give title compound.

S. No. D10 (µm) D50 (µm) D90 (µm)
1 12.13 30.76 61.08
2 12.60 33.51 66.90

,CLAIMS:

1. A process for the preparation of Aripiprazole monohydrate of formula (I),

which comprises:
a) dissolving Aripiprazole anhydrous form-B in a solvent selected from the ethanol, acetone, water and mixtures thereof;
b) reaction mixture is heated to 65-75 °C;
c) filter the reaction mass and wash with ethanol;
d) cool the reaction mass to 5-15 °C;
e) circulate the reaction mixture through high shear wet miller;
f) stir the reaction mass through high shear wet miller at 5-15 °C;
g) filter the reaction mass and wash with acetone; and
h) isolating Aripiprazole monohydrate.

2. The process claimed in claim 1, wherein the high shear wet miller is carried out at flow rate is 0.1 Liters/Minute to 40 Liters/Minute.

3. The process claimed in claim 3, wherein the high shear wet miller is carried out at flow rate is preferably 2.2 Liters/Minute to 33.0 Liters/Minute.

4. The process claimed in claim 1, wherein the high shear wet miller is carried out at rotational speed is 1000 to 14000 rpm.

5. The process claimed in claim 4, wherein the high shear wet miller is carried out at rotational speed of 5000 to 9000 rpm.

6. The process claimed in claim 1, wherein Aripiprazole monohydrate is having particle size of D50 less than 50 µm, D(90) less than 150 µm & D(99) less than 250 µm.