CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. 6001 /CHE/2013 filed on date December 20, 2013.

BACKGROUND OF THE INVENTION FIELD OF THE DISCLOSURE

The present disclosure relates to novel crystalline dolutegravir sodium Form-Mi, which is an N-methyl-2-pyrrolidone (NMP) solvate.

DESCRD7TION OF THE RELATED ART

Dolutegravir (DTG, GSKl 349572) is an integrase inhibitor being developed for the treatment of human immunodeficiency virus (HIV)-l infection.

TIVICAY® tablets contain dolutegravir sodium, which is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI). Dolutegravir sodium is chemically known as sodium (4R, 12aS)-9-((2,4-difluorobenzyl)carbamoyl)-4- methyl-6, 8-dioxo-3 ,4, 6, 8, 12, 12a-hexahydro-2H- pyrido [l ',2' :4,5] pyrazino[2, 1- b] [l,3]oxazin-7-olate, having the structure below:

Formula-I PCT Publication No. WO2006116764A1 (which is hereby incorporated by reference) discloses a crystalline form of dolutegravir sodium characterized by the following X- ray powder diffraction pattern having peaks at 6.4°±0.2°, 9.2°±0.2°, 13.8°±0.2°, 19.2°±0.2° and 21.8°±0.2° degrees 2Θ.

PCT Publication No. WO2013038407A1 (which is hereby incorporated by reference) discloses amorphous dolutegravir sodium characterized by the following characteristic peaks in infrared absorption spectrum at about 662±4, 766±4, 851±4, 886±4, 959±4, 1025±4, 1055±4, 1090±4, 1133±4, 1206±4, 1233±4, 1248±4, 1279±4, 1318±4, 1356±4, 2325±4 and 2348±4 cm ^"1 .

The present disclosure provides a novel crystalline form of dolutegravir sodium. SUMMARY OF THE DISCLOSURE

One aspect of the present disclosure provides crystalline dolutegravir sodium Form- Ml, which is an N-methyl-2-pyrrolidone (NMP) solvate, and may also be characterized by powdered X-ray diffraction pattern as shown in Figure 1.

In one embodiment, the present disclosure provides a process for the preparation of crystalline dolutegravir sodium Form-Ml that may be prepared by the following steps:

a) dissolving dolutegravir sodium in NMP at elevated temperature to form a solution;

b) cooling the solution to 25-35 °C;

c) optionally seeding with crystalline dolutegravir sodium Form-Ml ; and d) isolating crystalline dolutegravir sodium Form-Ml . Another embodiment of the present disclosure provides a process for the preparation of crystalline dolutegravir sodium Form-Mi that includes the steps of:

a) dissolving dolutegravir in NMP at ambient temperature to form a solution; b) optionally seeding with crystalline dolutegravir sodium Form-Mi ;

c) adding a sodium cation source to the solution; and

d) isolating crystalline dolutegravir sodium Form-Mi .

BRIEF DESCRIPTION OF THE FIGURES

Further aspects of the present disclosure together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of embodiments of the disclosure, which are shown in the accompanying drawing figures wherein:

Figure 1 is an X-ray powder diffractogram of crystalline dolutegravir sodium Form- Mi . DETAILED DESCRIPTION OF THE DISCLOSURE

It is to be understood that the description of the present invention has been simplified to illustrate elements that are relevant for a clear understanding of the invention, while eliminating, for purposes of clarity, other elements that may be well known.

The present invention encompasses novel crystalline form of dolutegravir sodium Form-Mi , which is an N-methyl-2-pyrrolidone solvate.

The polymorphs of the present invention may be characterized by X-ray powder diffraction pattern. Thus, the X-ray diffraction patterns of the polymorphs of the disclosure were measured on BRUKER D-8 Discover powder diffractometer equipped with goniometer of Θ/2Θ configuration and Lynx Eye detector. The Cu- anode X-ray tube was operated at 40 kV and 30 mA. The experiments were conducted over the 2Θ range of 2.0°-50.0°, 0.030° step size and 0.4 seconds step time.

In one embodiment, the present disclosure provides crystalline dolutegravir sodium Form-Ml, characterized by powder X-ray diffraction pattern having 2Θ angle positions at about 5.88, 17.57, 20.55, 21.38 and 24.77 ± 0.2° degrees 2Θ.

According to the present disclosure, crystalline dolutegravir sodium Form-Ml is further characterized by powder X-ray diffraction pattern having 2Θ angle positions at about 6.37, 7.76, 9.54, 11.81, 12.24, 13.01, 14.55, 14.85, 15.20, 15.62, 16.10, 16.84, 17.97, 18.61, 19.07, 19.36, 19.73, 20.12, 22.23, 22.64, 22.95, 23.32, 24.09, 25.26, 25.81, 26.21, 26.67, 27.11, 27.69, 28.41, 29.65, 30.67, 31.21, 31.90, 32.55, 33.12, 34.09, 35.01, 35.44 and 36.06 ±0.2° degrees 2Θ.

In another embodiment, the present invention relates to a process for the preparation crystalline dolutegravir sodium Form-Ml including the general steps of:

a) dissolving dolutegravir sodium in NMP at elevated temperature to create a solution;

b) cooling the solution to 25-35 °C;

c) optionally seeding with crystalline dolutegravir sodium Form-Ml ; and d) isolating crystalline dolutegravir sodium Form-Ml. According to the present invention, dolutegravir sodium is dissolved in NMP at an elevated temperature and filtered the solution. The solution is then optionally seeding with crystalline dolutegravir sodium Form-Ml. The solution is then stirred, filtered, and washed with NMP before isolating the crystalline solid of dolutegravir sodium Form-Ml . If seeding is not performed, the solution may be stirred for a longer period of time to allow crystals of dolutegravir sodium Form-Ml to form slowly on their own. In one embodiment of the present invention, dolutegravir sodium is dissolved in NMP at an elevated temperature, which may range from about 70 to about 85 °C. The solution is then filtered, for example, through a Hyflo bed or through membrane filters. The filtered solution is stirred at a temperature of about 20-35 °C for about 12- 15 hours. The stir time may be reduced to 3-4 hours, if the solution is seeded with about 0.1 to 1.0% w/v crystalline dolutegravir sodium Form-Mi. The solution is then filtered (for example, through a Hyflo bed or membrane filter), washed with NMP, and the final crystalline dolutegravir sodium Form-Mi is isolated. In an additional embodiment, the present invention relates to a process for the preparation crystalline dolutegravir sodium Form-Mi, including the general steps of: a) dissolving dolutegravir in NMP at ambient temperature to create a solution; b) optionally seeding with crystalline dolutegravir sodium Form-Mi ;

c) adding a sodium cation source to the solution; and

d) isolating crystalline dolutegravir sodium Form-Mi .

In one embodiment of the present invention, dolutegravir sodium is dissolved in NMP at ambient temperatures. The solution may then be optionally seeded with an N- methyl-2-pyrrolidone solvate of dolutegravir sodium. A source of sodium cations may then be added to the solution. The solution is then stirred and filtered. The solid is then washed with NMP to isolate crystalline dolutegravir sodium Form-Mi. The final crystalline solid may further be dried under vacuum.

Within the context of the present disclosure, dolutegravir sodium is dissolved in NMP at a temperature of about 20-35 °C. The solution is then optionally seeded with crystalline dolutegravir sodium and a sodium cation source is added. The solution is further stirred at about 20-35 °C for about 3-4 hours, during which Form M-l crystals grow slowly. The solution is then filtered. The resultant solid is washed with NMP to obtain the crystalline dolutegravir sodium Form-Mi. The final crystalline solid may optionally further be dried under vacuum at about 80 °C for about 12-15 hours.

Within the context of the present disclosure, sodium cation source is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, and an alcoholic sodium hydroxide solution, such as methanolic sodium hydroxide.

With all of the reactions disclosed above, one of skill in the art will recognize that the reaction conditions (e.g., reaction time or temperature) may be adjusted to achieve appropriate yield without undertaking undue experimentation and without departing from the scope of the present disclosure. The crystalline dolutegravir sodium Form-Mi of the present invention may be incorporated into a pharmaceutical formulation for the treatment of HIV in human patients. The pharmaceutical formulation may be an oral dosage form and in some embodiments a tablet. The tablet may include such excipients as D-mannitol, microcrystalline cellulose, povidone K29/32, sodium starch glycolate, and sodium stearyl fumarate. The tablet may be coated in a film that may contain the inactive ingredients iron oxide yellow, macrogol/PEG, polyvinyl alcohol-part hydrolyzed, talc, and titanium dioxide. The crystalline dolutegravir sodium Form-Mi may be administered in conjunction with other active pharmaceutical ingredients, including efavirenz, fosamprenavir, ritonavir, tipranavir, and rifampin.

In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules, compositions and Formulations according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.

Example 1: Preparation of crystalline dolutegravir sodium Form-Ml (NMP solvate).

Dolutegravir sodium (3 g) was dissolved in N-methyl 2-pyrrolidone (300 mL) at 75- 80 °C. The clear solution was filtered through a Hyflo bed and washed with N- methyl-2-pyrrolidone (15 mL) at 25-30 °C. The clear solution was stirred at 25-30 °C for 12-15 hours. The product obtained was filtered, washed with N-methyl-2- pyrrolidone (15 mL) at 25-30 °C and dried under vacuum at 80 °C for 12-15 hours. The resulting solid was identified as crystalline dolutegravir sodium Form-Ml, through the following analytical methods:

Yield: 80-85% (2.4 g)

PXRD: Crystalline

Purity by HPLC: 98.8 %

NMP content by GC: 13%

Example 2: Preparation of crystalline dolutegravir sodium Form-Ml (NMP solvate).

Dolutegravir sodium (1 g) was dissolved in N-methyl-2-pyrrolidone (100 mL) at 75- 80°C. The clear solution was filtered through a Hyflo bed and washed with N-methyl 2-pyrrolidone (5 mL) at 25-30 °C. The clear solution was seeded with N-methyl-2- pyrrolidone solvate of dolutegravir sodium Form-Ml (10 mg) and stirred at 25-30°C for 3-4 hours. The product obtained was filtered, washed with N-methyl-2- pyrrolidone (5 mL) at 25-30 °C and dried under vacuum at 80 °C for 12-15 hours. The resulting solid was identified as crystalline dolutegravir sodium Form-Ml, through the following analytical methods:

Yield: 80-85% (0.8 g) PXRD: Crystalline

Purity by HPLC: 99.03 %

NMP content by GC: 13% Example 3: Preparation of crystalline dolutegravir sodium Form-Ml (NMP solvate).

Dolutegravir (200 mg) was dissolved in N-methyl-2-pyrrolidone (6 mL) at 25-30 °C. The clear solution was seeded with N-methyl-2-pyrrolidone solvate of dolutegravir sodium Form-Ml (2 mg) and then 0.25 N methanolic sodium hydroxide solution (2 mL) was added and stirred at 25-30 °C for 3-4 hours. The product obtained was filtered and washed with N-methyl-2-pyrrolidone (5 mL) and dried under vacuum at 80 °C for 12-15 hours. The resulting solid was identified as crystalline dolutegravir sodium Form-Ml, through the following analytical methods:

Yield: 75% (160 mg)

PXRD: Crystalline

Purity by HPLC: 99.66%

Although the invention has been described in terms of particular embodiments in an application, one of ordinary skill in the art, in light of the teachings herein, can generate additional embodiments and modifications without departing from the spirit of, or exceeding the scope of, the claimed invention. Accordingly, it is understood that the descriptions herein are proffered only to facilitate comprehension of the invention and should not be construed to limit the scope thereof.