DESC:FIELD OF THE INVENTION
The present invention relates to amorphous form of dolutegravir and processes for its preparation.

BACKGROUND OF THE INVENTION
Dolutegravir is an integrase inhibitor. It is used against HIV infections as a single drug or fixed-dose combination with abacavir sulphate and lamivudine under the trade names Tivicay® and Triumeq® respectively. These commercial products contain dolutegravir as its sodium salt. It was first approved by the US FDA on Aug 12, 2013. It is chemically known as (4R,12aS)-9-{[(2,4-difluorophenyl)methyl]carbamoyl}-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazin-7-olate (I) having following chemical structure.

(I)
Dolutegravir is described in in the PCT application WO 2006/116764.

BRIEF DESCRIPTION OF THE FIGURE
Figure 1 – PXRD diffractogram of amorphous form of dolutegravir

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to amorphous form of dolutegravir and processes for its preparation.

In one embodiment, the present invention provides amorphous form of dolutegravir.

The amorphous form of dolutegravir of the present invention can be characterized by PXRD pattern as depicted in Figure 1.

In another embodiment, the present invention provides a process for the preparation of amorphous form of dolutegravir comprising dissolving dolutegravir in a suitable solvent, removing the solvent and isolating the amorphous form of dolutegravir.

‘Dissolving dolutegravir in a suitable solvent’ includes the reaction mixture obtained in the synthesis of dolutegravir. For example, the filtrate obtained after the debenzylation reaction of (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-4-methyl-6,8-dioxo-7-(phenylmethoxy)-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazin-9-carboxamide of formula II with palladium carbon.

(II)
Solvent used in the present invention may be selected form the alcohol, ether, ester, dimethyl sulfoxide, dimethyl formamide and mixtures thereof.

Alcohol solvent may be selected from methanol, ethanol, and isopropanol.

Ether may be selected from tetrahydrofuran (THF), dioxane.

Solvent used in the present invention may be preferably mixture of THF and methanol. Quantity of solvent may be 5 to 50 volumes with respect to quantity of dilutegavir. The ratio of THF and methanol may be 10:1 to 2:1.

Solvent may be removed by concentrating under reduced pressure, spray drying, and freeze drying.

The X-ray powder diffraction spectrum (XRPD) was recorded at room temperature using PANalytical X’Pert PRO diffractogram with Cu Ka radiation (? = 1.54060 Å), running at 45 kV and 40 mA.

The present invention is described in the following examples, however it should be noted that the scope of present invention is not limited by the examples.

Example 1
Preparation of amorphous form of dolutegravir
Dolutegravir (5 g) was dissolved in mixture of THF (80 ml) and methanol (20 ml). The mixture was concentrated under reduced pressure on rotary evaporator to obtain amorphous form of dolutegravir. Yield: 4.7 g.

Example 2
Preparation of amorphous form of dolutegravir
(4R,12aS)-N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-4-methyl-6,8-dioxo-7-(phenylmethoxy)-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazin-9-carboxamide (II) (10 g) was added to mixture of THF (90 ml) and methanol (20 ml). Then 10 % palladium carbon (1 g) was added and the mixture was stirred under hydrogen atmosphere for two hours. The catalyst was filtered and washed with THF (20 ml). The filtrate was concentrated under reduced pressure to obtain amorphous form of dolutegravir. Yield: 6.5 g.
,CLAIMS:1. A process for the preparation of amorphous form of dolutegravir comprising dissolving dolutegravir in a suitable solvent, removing the solvent and isolating the amorphous form of dolutegravir.

2. The process as claimed in claim 1 wherein the solvent is selected from alcohol, ether, ester, dimethyl sulfoxide, dimethyl formamide and mixtures thereof.

3. The process as claimed in claim 2 wherein alcohol solvent is selected from methanol, ethanol, and isopropanol.

4. The process as claimed in claim 2 wherein ether is selected from tetrahydrofuran (THF), dioxane.

5. The process as claimed in claim 2 wherein the solvent is mixture of THF and methanol.

6. The process as claimed in claim 1 wherein the quantity of solvent is 5 to 50 volumes with respect to quantity of dolutegavir.

7. The process as claimed in claim 5 wherein the ratio of THF and methanol is 10:1 to 2:1.

8. The process as claimed in claim 1 wherein the solvent is removed by concentrating under reduced pressure, spray drying, and freeze drying.

9. An amorphous form of dolutegravir obtained according to the process of claim 1.

10. An amorphous form of dolutegravir having PXRD pattern as depicted in Figure 1 obtained according to the process of claim 1.