Process for preparing anhydrous Aripirazole type I

1. A process for preparing hygroscopic anhydrous aripiprazole having major peaks in an X-ray powder diffractogram substantially as shown in FIG. 1 comprising:

(A) dissolving aripiprazole, or an acid salt thereof, in a water miscible organic solvent, optionally containing up to 50% water (by volume), with heating to form a solution of aripiprazole, or a solution of an acid salt thereof;

(B) when the solution comprises a solution of an acid salt, adding a base to the solution in an amount sufficient to neutralize the acid salt;

(C) optionally contacting the solution with decolorizing carbon or diatomaceous earth;

(D) maintaining the temperature of the solution above about 70° C., and adding sufficient water to produce an aqueous organic solution containing at least 5% water (by volume);

(E) cooling the aqueous organic solution, as required, to a temperature of 25 to 78° C. and seeding the solution with hygroscopic anhydrous aripiprazole crystals having major peaks in an X-ray powder diffractogram substantially as shown in FIG. 1 ;

(F) agitating the aqueous organic solution at a temperature in the range of 25 to 78° C. to initiate crystallization and form a slurry containing aripiprazole crystals;

(G) cooling the aripiprazole slurry with agitation to a temperature in the range of 15 to 25° C., and maintaining the slurry in that temperature range for at least 2 hours to complete crystal formation;

(H) isolating the crystals by filtration and optionally washing the crystals with organic solvent; and

(I) drying the isolated crystals under a vacuum and at a temperature of not greater than 80° C. until the isolated crystals contain less than about 1.0% water by weight.

2. The process according to claim 1 , wherein the water miscible organic solvent optionally contains up to 30% water (by volume), the aqueous organic solution is cooled, as required, to a temperature of 45 to 78° C. in step (E) and the aqueous organic solution is agitated at a temperature in the range of 45 to 60° C. in step (F).

3. The process according to claim 2 , wherein the organic solvent comprises an alcoholic solvent selected from the group consisting of methanol, ethanol, isopropanol, n-butanol and pentanol.

4. The process according to claim 3 , wherein the alcoholic solvent comprises isopropanol.

5. The process according to claim 2 , wherein the aqueous organic solution contains about 5 to about 30 percent water (by volume).

6. The process according to claim 5 , wherein the aqueous organic solution contains about 15 to about 25 percent water (by volume).

7. The process according to claim 2 , wherein seeding is carried out at a temperature in the range of about 45 to 60° C.

8. The process according to claim 7 , wherein seeding comprises adding hygroscopic anhydrous aripiprazole crystals having major peaks in an X-ray powder diffractogram substantially as shown in FIG. 1 in an amount of about 0.05 to about 1.0 percent by weight of the original aripiprazole.

9. The process according to claim 8 , wherein seeding comprises adding the hygroscopic anhydrous aripiprazole crystals in an amount of about 0.1% by weight of the original aripiprazole.