Pseudopolymorphic forms of a HIV protease inhibitor
New pseudopolymorphic forms of (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl (1S,2R)-3-[[(4-aminophenyl) sulfonyl] isobutyl) amino]-1-benzyl-2-hydroxypropylcarbamate and processes for producing them are disclosed.
1. A process comprising
combining (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl (1 S,2R)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-1-benzyl-2-hydroxypropylcarbamate with an organic solvent, water, or a mixture of water and a water miscible organic solvent, and
inducing crystallization to form (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl (1 S,2R)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-1-benzyl-2-hydroxypropylcarbamate pseudopolymorph Form B (hydrate): and
subjecting the pseudopolymorph to a temperature of about 40° C. and a relative humidity of about 75%, to convert the pseudopolymorph to amorphous (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl (1 S,2R)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-1-benzyl-2-hydroxypropylcarbamate.
2. The process of claim 1 , wherein the pseudopolymorph is prepared starting from the isopropanolate solvate of (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl (1 S,2R)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-1-benzyl-2-hydroxypropylcarbamate.
3. The process of claim 1 , comprising combining (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl (1 S,2R)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-1-benzyl-2-hydroxypropylcarbamate with a C1-C4 alcohol, water, or a mixture of a C1-C4 alcohol and water.
4. The process of claim 1 , wherein the ratio of compound to water in the pseudopolymorph ranges between 5:1 and 1:5.
5. The process of claim 1 , wherein the ratio of compound to water in the pseudopolymorph ranges between about 0.2:1 and about 3:1.
6. The process of claim 1 , wherein the ratio of compound to water in the pseudopolymorph ranges between about 1:1 and about 2:1.
7. The process of claim 1 , wherein the ratio of compound to water in the pseudopolymorph is about 1:1.