DESC:Field of Invention
This invention relates to new solvates of HIV protease inhibitor and processes for preparation thereof.

Background of Invention
The Protease inhibitors are a class of antiviral drugs that are widely used to treat HIV/AIDS and hepatitis caused by hepatitis C virus. Protease inhibitors prevent viral replication by selectively binding to viral proteases (e.g. HIV-1 protease) and blocking proteolytic cleavage of protein precursors that are necessary for the production of infectious viral particles.

Darunavir is a new HIV protease inhibitor and approved by the FDA under the name Prezista. Prezista is administered in combination with a low-dose of ritonavir and other active anti-HIV drugs.

Figure - 1
Prezista is presented with darunavir ethanolate as a film coated tablets. Darunavir ethanolate (as described in Figure-1) is in white to off-white hygroscopic powder. It is chemically known as [(1S,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)-amino]-2-hydroxy-1 -(phenylmethyl)propyl] carbamic acid (3R,3aS,6aR)-hexahydrofuro-[2,3-b]furan-3-yl ester monoethanolate. It exists as a non-solvated amorphous form and solvated forms as well.
US Patent 7700645 discloses ethanolate, and other solvates of darunavir. This patent also discloses an amorphous form of darunavir. However, these solvates and amorphous form of darunavir are hygroscopic in nature and less stable for longer duration. US Patent 8518987 discloses hydrate of darunavir and process for preparation thereof.
Hence, it is need to prepare the solvate of darunavir, which would be less hygroscopic, more stable, cost-effective, and viable at plant scale.

Summary of Invention
This invention provides solvates of darunavir. These solvates of darunavir are less hygroscopic, stable, and viable at plant scale. These solvates are also helpful for achieving higher stablility and bioavailibility.

Brief description of the drawing
Figure - 2 – Powder X-ray diffraction pattern of darunavir glycerol solvate.

Detailed description
The present invention provides solvates of darunavir and processes for preparation thereof. Particularly, the present invention emphasizes on alcoholate of darunavir having 2 or more hydroxy groups such as glycerol, polyethylene glycol, and sorbitol solvates of darunavir.
This invention also describes process for preparation of glycerol, polyethylene glycol, and sorbitol solvates of darunavir. These solvates are highly stable at higher humid conditions.
These solvates are free of other solvates or pseudopolymorphic forms described in prior art.
These solvates of darunavir are analyzed, and characterized by different methods described in prior art.
The present invention also provides process for preparation of glycerol, polyethylene glycol, and sorbitol solvate of darunavir. Wherein, the darunavir is stirred in water, water miscible solvent, water immiscible solvent or mixture thereof at higher temperature. The organic layer is separated and concentrated under reduced pressure. The resulting mass is further heated in desired solvent for solvate for 12 to 15 hours in solvent and then filtered. The resulting solid dried at higher temperature.
The water miscible solvent/solvent used in the process of present invention may be methanol, ethanol, and isopropanol.
The water immiscible solvent/solvent used in the process of present invention may be chloroform, dichloromethane, hexane, heptane, and toluene, etc., but preferably the solvent used in dichloromethane and toluene.
The solvent used for solvate in the process of present invention may be glycerol, polyethylene glycol and sorbitol.
The present invention also provides process for preparation of glycerol, polyethylene glycol, and sorbitol solvate of darunavir. Wherein, the darunavir is stirred in solvents for solvate at higher temperature. The organic layer is separated and concentrated under reduced pressure.
Solvents used for process of present invention may be glycerol, polyethylene glycol and sorbitol etc., preferably glycerol.
The higher temperature used in the process of present invention and drying purpose may be 25 to 100°C. etc., preferably 50-55°C.
The present invention will now be further illustrated by reference to the following examples, which do not limit the scope of the invention any way.

Example 1-Process for preparation of darunavir glycerol solvate:
In a round bottom flask, 70 ml of dichloromethane and water was added followed by 10 gms of darunavir. This reaction mass was stirred for 15 to 20 minutes. After stirring, the reaction mass was settled and layers were separated. The organic layer was concentrated under reduced pressure, 1.86 gm (1.2 mol. eq.) glycerol and 100ml toluene was added and it was heated for 12 to 15 hours. The product was filtered and washed with 20 ml toluene and dried at 50 -55°C under reduced pressure. Yield: 9-9.8 gm. Melting point: 90.5 °C to 91.8 °C.
Example 2-Process for preparation of darunavir sorbitol solvate:
In a round bottom flask, 70 ml of dichloromethane and water was added followed by 10 gms of darunavir. This reaction mass was stirred for 15 to 20 minutes. After stirring, the reaction mass was settled and layers were separated. The organic layer was concentrated under reduced pressure, 3.99 gm (1.2 mol. eq.) glycerol and 100ml toluene was added and it was heated for 12 to 15 hours. The product was filtered and washed with 20 ml toluene and dried at 50 -55°C under reduced pressure. Yield: 9-10.5gm.
Example 3-Process for preparation of darunavir glycerol solvate:
In a round bottom flask, 10 gms of darunavir and 20 ml glycerol was added and was heated at 85-90°C for 5-8 hours. This reaction mass was cooled and the product was filtered. The product was washed with 5 ml glycerol and it was dried at 50 to 55°C under reduced pressure. Yield: 8-9 gm.
,CLAIMS:1) Darunavir glycerol solvate.
2) Darunavir sorbitol solvate.
3) A process for the preparation of darunavir glycerol solvate, which comprises:
a) treating darunavir solvate or free of solvate form of darunavir with glycerol, optionally in presence of a solvent or mixture of solvents; and b) isolating darunavir glycerol solvate.
4) The process according to claim 3, wherein darunavir is selected from darunavir ethanolate and darunavir amorphous.
5) The process according to claim 3, wherein solvent is selected from methanol, ethanol, isopropanol, chloroform, dichloromethane, hexane, heptane, and toluene or mixture thereof preferably dichloromethane and toluene.
6) A process for the preparation of darunavir sorbitol solvate, which comprises:
a) treating darunavir solvate or free of solvate form of darunavir with sorbitol, optionally in presence of a solvent or mixture of solvents; and b) isolating darunavir sorbitol solvate.
7) The process according to claim 6, wherein darunavir is selected from darunavir ethanolate and darunavir amorphous.
8) The process according to claim 6, wherein solvent is selected from methanol, ethanol, isopropanol, chloroform, dichloromethane, hexane, heptane, and toluene or mixture thereof preferably dichloromethane and toluene.