This application claims priority to Indian patent application No. 2548/CHE/2009 filed on Oct 22, 2009.

FIELD OF THE INVENTION

The present invention relates to process for the preparation of amorphous Darunavir.

BACKGROUND OF THE INVENTION

Darunavir, also known as PREZISTA or TMC114, 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.

Darunavir Ethanolate, has the chemical name: [(15,2/?)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1 -(phenylmethyl)propyl]-carbamic acid (3R,3aS,6aR)-hexahydro-furo[2,3-ft]furan-3-yl ester monoethanolate and has the following structural formula:

Darunavir and it's process are first disclosed in US 6248775, wherein Darunavir is
prepared by condensing 2R-hydroxy-3-[[(4-aminophenyl)sulfonyl](2-
methylpropyl)amino]-l 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 patent 7700645 disclosed the various solvates of Darunavir including ethanolate and method for their preparation as well as their use as a medicament. The same patent disclosed the amorphous Darunavir by Raman spectra.

The inventors of the present invention developed a process for the preparation of amorphous Darunavir, which is feasible at large scale.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a process for the preparation of amorphous Darunavir, comprising the steps of: a) suspending Darunavir in an organic solvent, b) heating the solution to get clear solution, c) adding water as an anti-solvent, d) cooling the reaction mass, and e) isolating amorphous Darunavir.

In another aspect, the present invention provides a process for the preparation of amorphous Darunavir, comprising the steps of: a) dissolving Darunavir in solvent, b) removing the solvent, and c) isolating amorphous Darunavir.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a representative X-ray diffraction pattern of amorphous Darunavir

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to process for the preparation of amorphous Darunavir.

In one embodiment, the present invention provides a process for the preparation of
amorphous Darunavir comprising the steps of:

a) suspending Darunavir in an organic solvent,

b) heating of step (a) to get clear solution,

c) adding water as an anti-solvent,

d) cooling the reaction mass, and

e) isolating amorphous Darunavir.

According to the present invention, Darunavir is suspended in an organic solvent then heated to 40-80°C to get a clear solution and added water as an anti-solvent. The resultant solution was cooled to an ambient temperature and thus isolating amorphous Darunavir.

The organic solvent for the suspension of Darunavir is selected from acetic acid, dimethyl solfoxide, methanol, ethanol, isopropyl alcohol, n-butanol or N, N-dimethylformamide.

In another embodiment, the present invention provides a process for preparation of amorphous Darunavir by comprising the steps of:

a) dissolving Darunavir in a solvent,

b) removing the solvent, and

c) isolating amorphous Darunavir.

According to the present invention, Darunavir is dissolved in a solvent, filtered through hyflow bed to remove the particles, removed the solvent by using conventional technique and thus isolating amorphous Darunavir.

The solvent used for the dissolution of Darunavir is selected from methanol, ethanol, isopropyl alcohol, n-butanol, methylene dichloride, acetonitrile, ethyl acetate, isopropyl acetate, methyl acetate, acetone or tetrahydrofuran.

The conventional technique is selected from distillation, evaporation, spray drying, freeze drying, agitated thin film dryer (ATFD) or lyophilization.

In another embodiment, the present invention provides a process for preparation of amorphous Darunavir by comprising the steps of:

a) dissolving Darunavir in a aqueous alcohol at reflux temperature,

b) removing the solvent, and

c) isolating amorphous Darunavir.

According to the present invention, Darunavir is dissolved in aqueous alcohol at 90-100°C, cooled the solution to ambient temperature, and removed the solvent by using conventional technique and thus isolating amorphous Darunavir.

The aqueous alcohol is selected from aqueous methanol, aqueous ethanol, aqueous isopropyl alcohol or aqueous n-butanol.

The conventional technique is selected from distillation, evaporation, spray drying, freeze drying, agitated thin film dryer (ATFD) or lyophilization.

In yet another embodiment, the present invention provides a process for preparation of
amorphous Darunavir by comprising the steps of:

a) dissolving Darunavir in water at reflux temperature,

b) removing the water, and

c) isolating amorphous Darunavir.

According to the present invention, Darunavir is dissolved in water at 90-100°C, cooled the solution and removed the water by using conventional technique and thus isolating amorphous Darunavir.

The conventional technique is selected from distillation, distillation, evaporation, spray drying, freeze drying, agitated thin film dryer (ATFD) or lyophilization and thus isolating amorphous Darunavir.

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 0/9 configuration and LynxEye detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 29 range of 2.9°-59.0°, 9.930° step size and 59 seconds step time.

Preparation of amorphous Darunavir

Example 1:

Darunavir (9.2 g) was dissolved in acetic acid (1 mL) at 59°C. To the clear solution, water (19 mL) was added and stirred for 1-3 hrs at 25-39°C. The solid obtained was filtered, suck-dried and identified as amorphous Darunavir.

Example 2:

Darunavir (0.2 g) was dissolved in methanol (4 mL) at 50°C. To the clear solution, water (30 mL) was added and stirred for 18 hrs at 25-30°C. The solid obtained was filtered, suck-dried and identified as amorphous Darunavir.

Example 3:

Darunavir (0.2 g) was dissolved in dimethylsulfoxide (2 mL) at 50°C. To the clear solution, water (29 mL) was added and stirred for 18 hrs at 25-39°C. The solid obtained was filtered, suck-dried and identified as amorphous Darunavir.

Example 4:

Darunavir (1 g) was dissolved in water (85 mL) at 99-199°C followed by cooling to 25-30°C. The resulting solution was then transferred to another flask and subjected to freeze drying. The solid obtained was identified as amorphous Darunavir.

Example 5:

Darunavir (1 g) was dissolved in 30% methanol-water (v/v 65 mL) at 90-100°C followed by cooling to 25-30°C. The resulting clear solution was then subjected to freeze drying. The solid obtained was identified as amorphous Darunavir.

Example 6:

Darunavir (5g) was dissolved in methanol (50ml) at 25-30°C. The solution was filtered through hyflow bed to remove the undissolved particulate. The resulting solution was then subjected to spray drying to give amorphous Darunavir.

Example 7:

Darunavir (2 g) was dissolved in methanol (50 ml) at 25-30°C and stirred for 10 minutes. The resulting clear solution was then distilled out completely under vacuum at 40-50°C. The solid obtained was isolated and identified as amorphous Darunavir.

Example 8:

Darunavir (0.2g) was dissolved in acetonitrile (5 ml) at 25-30°C and stirred for 10 minutes. The resulting clear solution was then distilled out completely under vacuum at 40-50°C. The solid obtained was isolated and identified as amorphous Darunavir.

Example 9:

Darunavir (0.2 g) was dissolved in ethyl acetate (5 ml) at 25-30°C and stirred for 10 minutes. The resulting clear solution was then distilled out completely under vacuum at 40-50°C. The solid obtained was isolated and identified as amorphous Darunavir.

Example 10:

Darunavir (0.2 g) was dissolved in dichloromethane (5 ml) at 25-30°C and stirred for 10 minutes. The resulting clear solution was then distilled out completely under vacuum at 40-50°C. The solid obtained was isolated and identified as amorphous Darunavir.

Example 11: Physical stability of amorphous Darunavir

The physical stability of amorphous Darunavir was monitored by subjecting approximately 1.0 g of the sample to different stress conditions; a) Drying, b) exposure to Relative Humidity (RH) and c) Slurry conversion. The samples were tested by PXRD after 12 hrs. There is no discernible change in form observed under these conditions. The results are shown in the following Table 1.

We claim:

1. A process for the preparation of amorphous Darunavir comprising the steps:

a) suspending Darunavir in an organic solvent,

b) heating of step (a) to get clear solution,

c) adding water as an anti-solvent,

d) cooling the reaction mass, and

e) isolating amorphous Darunavir.

2. The process according to the claim 1, wherein said solvent used is selected from acetic acid, dimethyl sulfoxide, methanol, ethanol, isopropyl alcohol, n-butanol, TV, N-dimethylformamide.

3. A process for the preparation of amorphous Darunavir comprising the steps:

a) dissolving Darunavir in a solvent;

b) removing the solvent; and

c) Isolating amorphous Darunavir.

4. The process according to the claim 3, wherein said solvent is selected from methanol, ethanol, isopropyl alcohol, n-butanol, methylene dichloride, acetonitrile, ethyl acetate, isopropyl acetate, methyl acetate, acetone or tetrahydrofuran.

5. A process for the preparation of amorphous Darunavir comprising the steps:

a) dissolving Darunavir in a aqueous alcohol at reflux temperature;

b) removing the solvent; and

c) Isolating amorphous Darunavir.

6. The process according to the claim 5, wherein said alcohol is selected from aqueous methanol, aqueous ethanol, aqueous isopropyl alcohol or aqueous n-butanol.

7. A process for the preparation of amorphous Darunavir comprising the steps of:

a) dissolving Darunavir in water at reflux temperature,

b) removing the solvent; and

c) Isolating amorphous Darunavir.

8. The process according to the claim 3, claim 5, and claim 7, wherein said removal of solvent is carried by using conventional technique selected from distillation, evaporation, spray drying, freeze drying, agitated thin film dryer (ATFD) or lyophilization.