Method of Generating Amorphous Solid for Water-Insoluble Pharmaceuticals
The invention encompasses a method for making an amorphous solid of a water-insoluble pharmaceutical comprising: (1) dissolving the water-insoluble pharmaceutical in a water-miscible solvent, optionally with water, to make a solution; (2)(i) rapidly mixing the solution with an antisolvent, wherein the antisolvent is water, at low temperature to precipitate an amorphous solid of the water-insoluble pharmaceutical, or (ii) rapidly mixing the solution with an antisolvent, wherein the antisolvent is water, to precipitate an amorphous solid of the water-insoluble pharmaceutical and subsequently cooling to low temperature; and (3) isolating the amorphous solid of the water-insoluble pharmaceutical. In an embodiment of the invention, the rapid mixing is conducted using an impinging jet device.
1 . A method for making an amorphous solid of a water-insoluble pharmaceutical comprising:
(1) dissolving the water-insoluble pharmaceutical in a water-miscible solvent, optionally with water, to make a solution;
(2) (i) rapidly mixing the solution with an antisolvent, wherein the antisolvent is water, at low temperature to precipitate an amorphous solid of the water-insoluble pharmaceutical, or
(ii) rapidly mixing the solution with an antisolvent, wherein the antisolvent is water, to precipitate an amorphous solid of the water-insoluble pharmaceutical and subsequently cooling to low temperature; and
(3) isolating the amorphous solid of the water-insoluble pharmaceutical.
2 . The method according to claim 1 wherein the water-insoluble pharmaceutical is a compound of Formula I
3 . The method according to claim 1 wherein the solution is rapidly mixed using an impinging jet device, mixing-T, vortex mixer, or a high speed rotor-stator homogenizer.
4 . The method according to claim 3 wherein the solution is rapidly mixed using an impinging jet device.
5 . The method according to claim 1 wherein the low temperature is within 15 degrees above the freezing temperature of the water-miscible solvent and anti-solvent mixture.
6 . The method according to claim 1 wherein the water-miscible solvent is selected from the group consisting of methanol, ethanol, acetone, acetonitrile, acetic acid, 1,4-dioxane, tetrahydrofuran (THF), diethoxymethane (DEM), dimethylsulphoxide (DMSO), N-methyl-pyrrolidone (NMP), dimethylformamide (DMF), dimethylacetamide (DMA), glycerol, ethylene glycol, and polyethylene glycol.
7 . The method according to claim 1 wherein the water-miscible solvent is a high boiling point water miscible solvent.
8 . The method according to claim 7 wherein the high boiling point water miscible solvent is selected from the group consisting of: acetic acid, 1,4-dioxane, dimethyl sulfoxide (DMSO), N-methylpyrrolidinone (NMP), dimethylformamide (DMF), dimethylacetamide (DMA), glycerol, ethylene glycol and polyethylene glycol.
9 . The method according to claim 8 wherein the high boiling point water miscible solvent is dimethyl sulfoxide
10 . The method according to claim 1 wherein the water-miscible solvent is an explosive water miscible solvent.
11 . The method according to claim 10 wherein the explosive water miscible solvent is selected from the group consisting of: tetrahydrofuran (THF) and diethoxymethane (DEM).
12 . The method according to claim 1 wherein subsequently cooling to low temperature is done by adding the slurry resulting from the rapid mixing of the solution with the antisolvent to a reservoir of antisolvent at low-temperature.
13 . The method according to claim 12 wherein the reservoir is a jacketed crystallizer.
14 . The method according to claim 1 wherein at least one inactive pharmaceutical ingredient is added to step (1) or step (2) in order to stabilize the amorphous solid of the water-insoluble pharmaceutical or improve filtration or both.
15 . The method according to claim 1 wherein:
the water-insoluble pharmaceutical is a compound of Formula I
the solution is rapidly mixed using an impinging jet device.
16 . The method according to claim 15 wherein the solution is rapidly mixed with the antisolvent, wherein the antisolvent is water, to precipitate an amorphous solid of the water-insoluble pharmaceutical and subsequently cooled to low temperature.
17 . The method according to claim 16 wherein subsequently cooling to low temperature is done by adding the slurry resulting from the rapid mixing of the solution with the antisolvent to a reservoir of antisolvent at low-temperature.
18 . The method according to claim 17 wherein the reservoir is a jacketed crystallizer.
19 . The method according to claim 15 wherein the water miscible solvent is dimethyl sulfoxide.
20 . The method according to claim 15 wherein the water-miscible solvent is tetrahydrofuran.
21 . The method according to claim 1 wherein the water miscible solvent/antisolvent ratio during the rapid mixing of step (2) is in the range of 1/1 to 1/10.
22 . The method according to claim 21 wherein the water miscible solvent/antisolvent ratio is in the range of 1/2 to 1/5.