DESC:FIELD OF THE INVENTION
The present invention relates to 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 MAINTENA.

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 conventional 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 the 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 60-80 °C;
c) filter the reaction mass and wash with ethanol;
d) cool the reaction mass to 5-20 °C;
e) filter the reaction mass and wash with acetone;
f) isolating conventional Aripiprazole monohydrate;
g) micronize the compound obtained in Step f) in micronizer;
j) collect the micronized Aripiprazole monohydrate material & sieve the material through the 10-180 mesh.

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

which comprises:
a) micronizing the crystalline material of conventional Aripiprazole monohydrate in micronizer at grinding pressure of about 4 kg/cm2 to about 14 kg/cm2, feeding pressure of about 2 kg/cm2 to about 10 kg/cm2, micronizing fluid medium is air or nitrogen, feed rate RPM is about 1 to 100;
b) collect the micronized Aripiprazole monohydrate material and sieve the material through the 10-180 mesh.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure-1 illustrates the X-ray diffraction, before and after micronization of Aripiprazole monohydrate.
Figure-2 illustrates the PSD, before and after micronization of Aripiprazole monohydrate.
Figure-3 shows the 1H-NMR spectrum of the Aripiprazole monohydrate obtained in Example 1.

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 conventional Aripiprazole monohydrate.

In step a) process, dissolving Aripiprazole anhydrous form-B in a solvent selected from the ethanol, acetone, water and mixtures thereof. The above reaction is carried in presence of room temperature;

In step b) process, reaction mixture is heated to 60-85 °C and stirred for 20-30 minutes, till complete dissolution; preferably reaction condition is 60-70 °C, most preferably 65-75 °C.

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

In step d) process, cool the reaction mass to 5-20 °C, preferably 5-15 °C stirred the contents for 60 minutes;

In step e) process, filter the reaction mass and wash with acetone under the vacuum;

In step f) process, isolating conventional Aripiprazole monohydrate and dry the material for 5- 7 hours at 25-35 °C, preferably 6 hours.

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

Conventional Aripiprazole monohydrate produced by this process (before Micronization) has shown a mean particle size of D90 greater than about 40 microns, and PSD diagram is depicted in Figure.2a. The mean particle size is determined by Malvern method.

In step g) process, micronize the compound obtained in step f) in micronizer, micronization is carried out in Midas Mikronizer model MOC-SS 316, grinding nozzle pressure of about 4 kg/cm2to about 14 kg/cm2. The feed rate of the material to be micronized is about 2 kg/cm2 to about 10 kg/cm2 and remains the same throughout the entire process. Midas Mikronizer has a grinding chamber of diameter of approximately 50 mm. It has venturi based powder injection system for delivering the powder to the milling chamber, micronizing fluid medium is air or nitrogen, feed rate RPM is about 1 to 100, capacity is about 200 gram/hour. Material manually through feed hopper in certain interval of time.

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

Scheme-II illustrates the process for the preparation of Aripiprazole monohydrate.

In step a) process, micronizing the crystalline material of conventional Aripiprazole monohydrate in micronizer at, grinding pressure of about 4 kg/cm2 to about 14 kg/cm2, feeding pressure of about 2 kg/cm2 to about 10 kg/cm2, micronizing fluid medium is air or nitrogen, feed rate RPM is about 1 to 100.

In step a) process, micronization is carried out in Midas Mikronizer model MOC-SS 316, grinding nozzle pressure of about 4 kg/cm2 to about 14 kg/cm2. The feed rate of the material to be micronized is about 2 kg/cm2 to about 10 kg/cm2 and remains the same throughout the entire process. Midas Mikronizer has a grinding chamber of diameter of approximately 50 mm. It has venturi based powder injection system for delivering the powder to the milling chamber, micronizing fluid medium is Air or Nitrogen, feed rate RPM is about 1 to 100, and capacity is about 200 gram/hr. Material manually through feed hopper in certain interval of time.

In step b) process, collect the micronized Aripiprazole monohydrate material and sieve the material through the 10-180 mesh.

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

Aripiprazole monohydrate produced by this process (after Micronization) has shown a mean particle size of D 90 greater than about 3 microns and the PSD diagram is depicted in Figure-2b. The mean particle size is determined by Malvern method.

The X-ray powder diffraction patterns of the micronized and unmicronized micronized Aripiprazole monohydrate are 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.

The 13C-NMR spectrum of the Aripiprazole monohydrate (Hydrate A) is which is substantially the same as the 13C-NMR spectrum shown in Figure.3.

Advantages:
1) Avoid the 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.
2) Micronization technique is applicable for continuous manufacturing and thereby achieving faster throughput time and lower operational and maintenance costs.
3) Micronization is cost effective, eco-friendly and industrially viable.

Examples:
Example 1:
Step 1: Process for the preparation of Conventional Aripiprazole monohydrate
A suspension of aripiprazole anhydrous form B (150 g) in a mixture of ethanol (2400 mL), water (600 mL) and acetone (2250 mL) was heated to 60-80 °C till complete dissolution. The solution was filtered and washed with ethanol. The reaction mass was cooled to 5-20 °C. The reaction mass was stirred 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.

Particle size data Aripiprazole Monohydrate (Before Micronization):
S.No D10 D50 D90
1 7.357 26.237 58.262
2 5.859 22.199 54.897
3 4.625 17.056 44.659

Step 2: Process for the preparation of Aripiprazole monohydrate
Cycle-1:
1. Ensured the cleanness of Micronizer parts
2. Assembled the Micronizer parts such that no leakage from the parts of the Micronizer
3. Ensured the leakage of Micronizer with 11 kg/cm2 grinding pressure and 6 kg/cm2 feeding pressure
4. Noted the initial weight of Aripiprazole Monohydrate and noted the value
5. Kept 4 grams of initial material for reference
6. Feeding pressure and Grinding pressure set to 6 kg/cm2 and 11 kg/cm2 respectively
7. Charged the material manually through feed hopper in certain interval of time

Cycle-2:
1. Ensured the cleanness of Micronizer parts
2. Assembled the Micronizer parts such that no leakage from the parts of the Micronizer
3. Ensured the leakage of Micronizer with 11 kg/cm2 grinding pressure and 6 kg/cm2 feeding pressure
4. Noted the cycle-1 weight of Aripiprazole monohydrate and noted the value
5. Kept 4 grams of initial material for reference
6. Feeding pressure and Grinding pressure set to 6 kg/cm2 and 11 kg/cm2 respectively
7. Charged the material manually through feed hopper in certain interval of time
8. After completion of charging all parts of Micronizer disassembled and collected the material
9. Noted weight of the collected material.
10. Sieved the collected material through 30 mesh.
11. Noted the weight of oversize and undersize and loss in weight during sieving is observed.
12. Final undersize material stored in glass bottle at 25-30 °C and submitted for complete analysis.

Particle size data Aripiprazole Monohydrate (After Micronization):
S.No D10 D50 D90
1 0.954 2.272 4.281
2 0.936 2.558 5.601
3 0.828 2.633 9.55

,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 60-85 °C;
c) filter the reaction mass and wash with ethanol;
d) cool the reaction mass to 5-25 °C;
e) filter the reaction mass and wash with acetone;
f) isolating conventional Aripiprazole monohydrate;
g) micronize the compound obtained in Step f) in micronizer;
j) collect material & sieve through 10-180 mesh.

2. The process according to claim 1, wherein the micronization of step g) is carried out in Midas Micronizer having parameters,
a) grinding pressure of about 4 kg/cm2 to about 14 kg/cm2;
b) feeding pressure of about 2 kg/cm2 to about 10 kg/cm2;
c) micronizing fluid medium is Air or Nitrogen;
d) feed rate RPM is about 1 to 100.

3. The process according to claim 1, wherein the Micronized Aripiprazole monohydrate having a mean particle size of D90 greater than about 3 microns.

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

which comprises:
micronizing the crystalline material of conventional Aripiprazole monohydrate in micronizer at,
a) grinding pressure of about 4 kg/cm2 to about 14 kg/cm2;
b) feeding pressure of about 2 kg/cm2 to about 10 kg/cm2;
c) micronizing fluid medium is Air or Nitrogen ;
d) feed rate RPM is about 1 to 100;
d) collect the micronized Aripiprazole monohydrate material & sieve the material through the 10-180 mesh.