Crystallization process of aripiprazole derivatives in extended release formulations for treatment of schizophrenia
Processes for providing depot injections of recrystallized aripiprazole lauroxil in which particles of the aripiprazole lauroxil have a surface area of about 0.50 to about 3.3 m 2 /g; and crystals of aripiprazole lauroxil produced by such processes.
1. A process for making a compound of Formula (A) in crystal form:
wherein R a is CH 2 OC(O)R 1 and wherein R 1 is a substituted or unsubstituted aliphatic moiety;
the process comprising the steps of:
(a) dissolving the compound of Formula (A) or a salt or solvate thereof in a first solvent to form a homogeneous drug solution;
(b) optionally combining the drug solution with a second solvent;
(c) cooling the solution; and
(d) further homogenizing the solution to induce formation of the compound of Formula (A) in crystal form.
2. The process of claim 1 , further comprising the steps of:
(e) stopping the homogenization, and re-dissolving the compound of Formula (A) in crystal form by heating the solution;
(f) cooling the solution; and
(g) further homogenizing the solution to induce formation of the compound of Formula (A) in crystal form.
3. The process of claim 1 , wherein the crystallized particles have a surface area of about 0.50 to about 3.3 m 2 /g.
4. The process of claim 1 , wherein the crystallized particles have a surface area of about 0.80 to about 1.1 m 2 /g.
5. The process of claim 1 , wherein the crystallized particles have a surface area of about 1.00 m 2 /g.
6. The process of claim 1 , wherein the Dv[50] of the crystallized particles is about 10 to about 30 microns.
7. The process of claim 1 , wherein the Dv[50] of the crystallized particles is about 10 to about 20 microns.
8. The process of claim 1 , wherein in step (a), the first solvent is isopropyl acetate.
9. The process of claim 1 , wherein in step (a), the first solvent is a mixture of isopropyl acetate and n-heptane.
10. The process of claim 1 , wherein in step (b), the second solvent is n-heptane.
11. The process of claim 1 , wherein in step (b), the temperature of the solution is in the range of about 55° C. to about 65° C.
12. The process of claim 1 , wherein in step (d), the temperature of the solution is within the range of about 31-38° C.
13. The process of claim 1 , wherein in step (d), the temperature of the solution is within the range of about 31-35° C.
14. The process of claim 1 , wherein in step (d), the temperature of the solution is about 34° C.
15. The process of claim 1 , wherein one or more of steps (a) through (c) is performed under agitation.
16. The process of claim 2 , wherein one or more of steps (a), (b), (c), (d), (e), (f), and (g) is performed under agitation.
17. The process of claim 1 , wherein the process further comprises the step of filtering the crystallized particles.
18. The process of claim 17 , wherein the process further comprises the step of rinsing the crystallized particles.
19. The process of claim 18 , wherein the process further comprises the step of drying the crystallized particles.
20. The process of claim 1 , wherein the compound of Formula (A) is selected from the group consisting of:
21. The process of claim 2 , wherein the compound of Formula (A) is selected from the group consisting of:
22. The process of claim 1 , wherein the solution of step (d) is further homogenized by a homogenizer.
23. The process of claim 20 , wherein the compound of Formula (A) is a compound of Formula (I):
24. The process of claim 21 , wherein the compound of Formula (A) is a compound of Formula (I):