The application claims priority to Indian patent application no 3106/CHE/2009 filed on Dec 16, 2009 the contents of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to a novel Darunavir N, N-dimethylformamide solvate and process for its preparation.

BACKGROUND OF THE INVENTION

Darunavir, also known as PREZISTA or TMC114, marketed in the form of Darunavir ethanolate, is a type of medicine called a protease inhibitor (PI) work by blocking protease and is particularly well suited for inhibiting HIV-1 and HIV-2 viruses. Virus-encoded proteases, which are essential for viral replication, are required for the processing of viral protein precursors. Interference with the processing of protein precursors inhibits the formation of infectious virions. Accordingly, inhibitors of viral proteases may be used to prevent or treat chronic and acute viral infections.

Darunavir Ethanolate, has the chemical name: [(lS,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-l-(phenylmethyl)propyl]-carbamic acid (3R,3aS,6aR)-hexahydro- furo[2,3-b]furan-3-yl ester monoethanolate and has the following structural formula:

Darunavir is first disclosed in US 6248775, wherein Darunavir is prepared by condensing 2R-hydroxy-3 - [ [(4-aminophenyl)sulfonyl] (2-methylpropyl)amino] -1 S(phenylmethyl)propylamine with hexahydro-furo[2,3-b]furan-3-ol in anhydrous acetonitrile in the presence of anhydrous pyridine and N,N'-disuccinimidyl carbonate at ambient temperature.

US 7700645 patent discloses Darunavir in amorphous form and solvates including ethanolate and method for their preparation as well as their use as a medicament.
There exist a need in the art for exploration of new polymorphic forms with improved bioavailability and pharmaceutical activity. The inventors of the present invention have developed a novel Darunavir solvate.

SUMMARY OF THE INVENTION

In the main aspect, the present invention provides a novel Darunavir N, N-dimethylformamide solvate characterized by PXRD.

The novel Darunavir N, JV-dimethylformamide solvate is further characterized by the DSC as shown in Figure 2, which shows no desolvation peak but a sharp endothermic peak at 74.43°C due to melting of the product. However, the TGA of novel crystalline form of Darunavir shows a weight loss ranging 4-6%, attributed to desolvation as shown in Figure 3 and the water content determined by the Karl-Fisher method is about 1.0 %.

In the another aspect, the present invention provides a process for the preparation of a novel Darunavir N, iV-dimethylformamide solvate comprising the steps of dissolving Darunavir in N, N-dimethylformamide and removing the solvent to obtain a novel Darunavir N, N-dimethylformamide solvate.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a representative X-ray diffraction pattern of a novel crystalline N, N-
dimethylformamide solvate of Darunavir. FIG. 2 is DSC of a novel Darunavir TV, JV-dimethylformamide solvate. FIG. 3 is TGA of a novel Darunavir N, A^-dimethylformamide solvate.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a novel Darunavir N, N-dimethylformamide solvate and process for preparation of the same.

The main embodiment of the present invention provides a novel Darunavir N, N-dimethylformamide solvate, characterized by Powder X-ray diffraction pattern as in Figure 1 comprising 20 peaks of 6.89, 8.87, 10.34, 11.02, 13.67, 14.37, 16.33, 16.80, 17.87, 18.62, 19.45, 19.90, 20.26, 20.80, 22,21 and 22.62 ± 0.2 degrees.

The novel Darunavir N, Af-dimethylformamide solvate is further characterized by the DSC as shown in Figure 2, which shows no desolvation peak but a sharp endothermic peak at 74.43°C due to melting of the product. However, the TGA of novel crystalline form of Darunavir shows a weight loss ranging 4-6%, attributed to desolvation as shown in Figure 3 and the water content determined by the Karl-Fisher method is about 1.0 %.

Yet another embodiment of the present invention provides a process for the preparation of a novel Darunavir N, N-dimethylformamide solvate comprising the steps of:

a) dissolving Darunavir in N, N-dimethylformamide at 60-80°C;
b) cooling to room temperature,
c) holding the solution to crystallize; and
d) isolating a Darunavir JV, JV-dimethylformamide solvate.

According to the present invention, solvent is removed by slow solvent evaporation, distillation under vacuum , spray drying or agitated thin film drier (ATFD) and thus isolating a Darunavir JV, JV-dimethylformamide solvate.

Yet another embodiment of the present invention provides a process for the preparation of a Darunavir JV, JV-dimethylformamide solvate comprising the steps of:

a) dissolving Darunavir in JV, JV-dimethylformamide;
b) removing the solvent;
c) adding an organic solvent; and
d) isolating a Darunavir JV, JV-dimethylformamide solvate.

According to the present invention, Darunavir is dissolved in JV, JV-dimethylformamide at ambient temperature, removed the solvent using conventional technique, and added an organic solvent and thus isolating a Darunavir JV, JV-dimethylformamide solvate.

The conventional technique to remove the solvent is selected from evaporation, distillation under vacuum, spray drying or agitated thin film drier (ATFD). The organic solvent in step c) is selected from n-hexane, cyclohexane, isopropyl ether, toluene or xylene.

Yet another embodiment of the present invention provides a process for the preparation of a Darunavir JV, JV-dimethylformamide solvate comprising the steps of:

a) dissolving Darunavir in JV, JV-dimethylformamide;
b) adding water as an anti-solvent; and
c) isolating a Darunavir N, N-dimethylformamide solvate.

According to the present invention, Darunavir is dissolved in N, N-dimethylformamide at ambient temperature, added water as an anti-solvent and thus isolating a Darunavir N, N-dimethylformamide solvate.

The novel Darunavir N, Ar-dimethylformamide solvate was used to prepare amorphous and various anhydrous forms of Darunavir.

Darunavir used in the present invention is selected from the group consisting of but not limited to crystalline or amorphous Darunavir.

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way.

EXPERIMENTAL SECTION

Powder X-ray Diffraction (PXRD)
The X-ray diffraction patterns of said polymorphs of the invention were measured on Bruker D8 Discover powder diffractometer equipped with goniometer of 9/0 configuration and Lynx Eye detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 26 range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.

Diffrential Scanning Calorimetry (DSC)
The DSC measurements were carried out on TA Q1000 of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-200°C purging with nitrogen at a flow rate of 50mL/min. Standard aluminum crucibles covered by lids with three pin holes were used.

Thermo gravimetric Analysis (TGA)
TGA was recorded on out using the instrument TA Q5000 of TA instruments. The experiments were performed at a heating rate of 10.0°C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 25 mL/min.

Preparation of novel Darunavir N, N-dimethylformamide solvate

Example -1
Darunavir (0.2 g) was dissolved in N, N-dimethylformamide (DMF, 2 mL) at 60°C. The clear solution was kept at room temperature and closed with a parafilm with small apertures on it. The crystals obtained were characterized as novel crystalline N, 7V-dimethylformamide solvate of Darunavir by Powder X-ray diffraction analysis.

Example 2:
Darunavir (300 mg) was dissolved in N, JV-dimethylformamide (2 mL) at 25-30°C. The clear solution was then subjected to distillation to remove the solvent completely under vacuum at 70°C. The resultant compound was suspended in isopropyl ether (5 mL) at 25 to 30°C and stirred for 18 h. The separated solid was filtered, washed with isopropyl ether (5 mL) and dried at ambient temperature. The product obtained was identified a Darunavir N, Af-dimethylformamide solvate.

Example 3:
Darunavir (4 g) was dissolved in N, JV-dimethylformamide (4 mL) and stirred for 18 h at 25-30°C. To the clear solution, water (4 mL) was added drop-wise for 15 minutes at 25-30°C and stirred for 1h at 25-30°C. The solid obtained was filtered, washed with water and dried at ambient temperature. The product obtained was identified a Darunavir N, JV-dimethylformamide solvate.

Example 4: Physical stability of a Darunavir JV, JV-dimethylformamide solvate
The physical stability of novel crystalline JV, JV-dimethylformamide solvate of Darunavir was monitored by subjecting approximately 1.0 g of the sample for drying. The samples were tested by PXRD after 1, 3 and 12 h. The novel form is stable to heat. It is also stable on slurry wash with non-polar solvent like isopropyl ether but converts to ethanolate on slurry wash with ethanol. The results are shown in the following Table 1.

Table 1

We claim:

1. A process for the preparation a Darunavir N, N-dimethylformamide solvate
comprising the steps of:

e) dissolving Darunavir in N, N-dimethylformamide at 60-80°C;
f) cooling to room temperature,
g) holding the solution to crystallize; and
h) isolating a Darunavir N, N-dimethylformamide solvate.

2. A process for the preparation of a Darunavir N, N-dimethylformamide solvate
comprising the steps of:

a) dissolving Darunavir in N, N-dimethylformamide;
b) removing the solvent;
c) adding an organic solvent; and
d) isolating a Darunavir N, N-dimethylformamide solvate.

3. The process according to the claim 1 and claim 2, wherein the said solvent is removed by evaporation, distillation under vacuum, spray drying or agitated thin film drier (ATFD).

4. The process according to the claim 2, wherein the said organic solvent in step c) is selected from n-hexane, cyclohexane, isopropyl ether, toluene or xylene.
5. A process for the preparation of a Darunavir N, N-dimethylformamide solvate comprising the steps of:

a) dissolving Darunavir in N, N-dimethylformamide;
b) adding water as an anti-solvent; and
c) isolating a Darunavir N, N-dimethylformamide solvate

6. The process according to claims 1, 2 and 5, Darunavir N, jV-dimethylformamide solvate is characterized by an X-ray diffraction pattern having three or more peaks at 20 values selected from 6.89, 8.87, 10.34, 11.02, 13.67, 14.37, 16.33, 16.80, 17.87, 18.62, 19.45, 19.90, 20.26, 20.80, 22,21 and 22.62 ± 0.2 degrees as shown in Fig 1.

7. The process according to claims 1, 2 and 5, Darunavir N, N-dimethylformamide solvate is characterized by a DSC scan of having an endotherm at 74.43°C as shown in Fig 2.

8. The process according to claims 1, 2 and 5, Darunavir N, N-dimethylformamide solvate is characterized by a TGA of having solvent loss ranging from 4-6% as shown in Fig 3.

9. The process according to claim 1, 2 and 5, wherein the said novel Darunavir N,N-dimethylformamide solvate is used to prepare amorphous and various anhydrous forms of Darunavir.