DESC:FORM 2

THE PATENT ACT, 1970
(39 of 1970)

COMPLETE SPECIFICATION
(See section 10, rule 13)

“PROCESS FOR PREPARATION OF POLYMORPHIC FORM OF CABOTEGRAVIR SODIUM”

Laurus Labs Limited, an Indian company of DS-1, IKP Knowledge Park, Genome Valley, Turkapally, Shameerpet Mandal, Medchal-Malkajgiri district, Hyderabad-500 078, Telangana, INDIA

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

FIELD OF THE INVENTION

The present invention relates to a process for preparation of polymorphic form of cabotegravir sodium and pharmaceutical composition thereof.

BACKGROUND OF THE INVENTION

Cabotegravir is a class of polycyclic carbamoyl pyridone compounds and is chemically known as (3S,11aR)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d] pyrazine-8-carboxamide, and is approved as free acid and its sodium salt, it has the following structure:

Cabotegravir was approved as its free acid and its sodium salt and sold under the brand name Vocabria® (Cabotegravir Sodium (Tablet; Oral)) & Cabenuva® KIT (combination co-pack of Cabotegravir and Rilpivirine (Suspension, Extended Release; Intramuscular)) for treatment of human immunodeficiency virus type 1 (HIV-1) infection. Further, on December 20, 2021, U.S. FDA approved Cabotegravir free acid under the brand name Apretude® (Cabotegravir extended-release injectable suspension) for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1.

PCT application Number: 2006/116764 (“the ‘764 publication”) discloses a process for preparation of cabotegravir sodium from ethanol and 1.0 M sodium hydroxide.

PCT application Number (s): 2010/068253 (“the ‘253 publication”) and 2010/011814 (“the ‘814 publication”) discloses a process for preparation of cabotegravir sodium from a mixture of ethanol: water and 1N sodium hydroxide.

PCT application Number: 2015/177537 (“the ‘537 publication”) discloses a process for preparation of cabotegravir sodium from ethanol and 2 N sodium hydroxide.

PCT application Number: 2018/109786 (“the ‘786 publication”) discloses crystalline cabotegravir sodium Form N-I, Form N-II; and crystalline forms of cabotegravir potassium Form K-I, Form K-II, Form K-III and its processes.

PCT application Number: 2018/149608 (“the ‘608 publication”) discloses crystalline cabotegravir sodium Form A, Form B, Form C and its processes. According to this publication, cabotegravir sodium Form A was resulted according to the process disclosed under WO2006/116764 and WO2010/068253.

Cabotegravir or its pharmaceutically acceptable salts is one of the important approved carbamoylpyridone HIV integrase inhibitors drug available in the market for the treatment of (HIV)-1 infection.

The reported methods for preparation of crystalline cabotegravir sodium are not consistently producing single crystalline form instead producing mixture of one or more other crystalline forms. Hence there exists a need in the art to develop a process to produce crystalline form of cabotegravir sodium consistently without contamination of one or more of other polymorphs.

The present invention is to provide a process for preparation of crystalline form of cabotegravir sodium, specifically crystalline Form A which is reproducible, commercially feasible on large scale production with greater yield, higher purity and good stability.

SUMMARY OF THE INVENTION

The present invention encompasses a process for preparation of crystalline cabotegravir sodium Form A.

In accordance with one embodiment, the present invention provides a process for preparation of crystalline cabotegravir sodium Form A, comprising:
a) suspending or dissolving cabotegravir in an organic solvent,
b) adding sodium source to step a) reaction mass (or) adding step a) reaction mass to sodium source, and
c) isolating cabotegravir sodium Form A; wherein the organic solvent is selected from the group comprising of alcohols, ketones, sulfoxides, nitriles, ethers and the like or mixtures thereof.

In accordance with another embodiment, the present invention provides a process for preparation of crystalline cabotegravir sodium Form A, comprising:
a) suspending or dissolving cabotegravir in an organic solvent,
b) adding sodium source to step a) reaction mass (or) adding step a) reaction mass to sodium source, and
c) isolating cabotegravir sodium Form A; wherein the organic solvent is selected from the group comprising alcohols include but are not limited to methanol, ethanol, butanol, isobutanol, tert-butanol, propanol, isopropanol, pentanol, glycerol and the like; ketones include, but are not limited to acetone, methylisobutylketone, methylethylketone and the like; sulfoxides include, but are not limited to dimethyl sulfoxide, diethyl sulfoxide and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; ethers include, but are not limited to tetrahydrofuran, methyl tertiary butyl ether and the like and mixture thereof.

In accordance with another embodiment, the present invention provides a process for preparation of crystalline cabotegravir sodium Form A, comprising:
a) suspending or dissolving cabotegravir in an organic solvent,
b) adding sodium source to step a) reaction mass (or) adding step a) reaction mass to sodium source, and
c) isolating cabotegravir sodium Form A; wherein the organic solvent is selected from trifluoroethanol, dimethyl sulfoxide, methanol, ethanol, n-butanol, n-pentanol, acetone, acetonitrile, tetrahydrofuran and mixture thereof.

In accordance with another embodiment, the present invention provides a process for preparation of crystalline cabotegravir sodium Form A, characterized by a powder X-ray diffraction (PXRD) pattern peaks having peaks selected from at about: 5.4, 9.5, 11.0, 12.7, 13.1, 14.0, 14.6, 15.4, 15.7, 16.1, 19.0, 21.5, 22.1, 23.2, 23.8, 24.4, 25.4, 26.2, 27.1, 28.0, 28.9, 29.9, 32.6 and 34.5 ±0.2° 2?.

In accordance with one embodiment, the present invention provides a process for preparation of crystalline cabotegravir sodium Form A, comprising:
a) suspending or dissolving cabotegravir in an organic solvent,
b) adding sodium source to step a) reaction mass (or) adding step a) reaction mass to sodium source, and
c) isolating cabotegravir sodium Form A; wherein the organic solvent is selected from the group comprising alcohols, ketones, sulfoxides, nitriles, ethers and the like or mixtures thereof; wherein the crystalline cabotegravir sodium Form A, characterized by: a powder X-ray diffraction (PXRD) pattern having at least one peak selected from: 5.4, 9.5, 11.0, 12.7, 13.1, 14.0, 14.6, 15.4, 15.7, 16.1, 19.0, 21.5, 22.1, 23.2, 23.8, 24.4, 25.4, 26.2, 27.1, 28.0, 28.9, 29.9, 32.6 and 34.5 ±0.2° 2? and does not have a peak at about 6.2 and/or 6.8±0.2° 2?.

In accordance with another embodiment, the present invention provides substantially pure crystalline cabotegravir sodium Form A, characterized by: a powder X-ray diffraction (PXRD) pattern having at least one peak selected from: 5.4, 9.5, 11.0, 12.7, 13.1, 14.0, 14.6, 15.4, 15.7, 16.1, 19.0, 21.5, 22.1, 23.2, 23.8, 24.4, 25.4, 26.2, 27.1, 28.0, 28.9, 29.9, 32.6 and 34.5 ±0.2° 2? and does not have a peak at about 6.2 and/or 6.8±0.2° 2?.

In accordance with another embodiment, the present invention provides at least about 95% by weight of the solid crystalline cabotegravir sodium is Form A of cabotegravir sodium.

In accordance with another embodiment, the present invention provides at least about 99% by weight of the solid crystalline cabotegravir sodium is Form A of cabotegravir sodium.

In accordance with another embodiment, the present invention provides a pharmaceutical composition comprising cabotegravir sodium Form A prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.

Figure 1 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline cabotegravir sodium Form A.

DETAILED DESCRIPTION OF THE INVENTION

The present invention involves a process for preparation of crystalline cabotegravir sodium Form A and its pharmaceutical composition comprising thereof.

The compound obtained by the process of the present invention is characterized by X-ray powder diffraction (XRPD) pattern. The X-Ray powder diffraction data reported herein is analyzed using PANalytical X’per3pro X-ray powder Diffractometer equipped with a theta coupled goniometer in transmission geometry, Cu-anode ([?] =1.54 Angstrom), X-ray source operated at 45kV, 40 mA. Two-theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range=3-45°2?; step size=0.01°; and Time per step=50 sec.

As used herein in this specification, unless otherwise specified, cabotegravir, which is used as a starting material is known in the art and can be prepared by the process disclosed in art, for example cabotegravir or its sodium may be synthesized as disclosed in the ‘764 publication. The starting cabotegravir may be in any form such as crude obtained directly from the reaction mass, crystalline, amorphous or other forms of cabotegravir, including various solvates and hydrates known in the art.

The crystalline cabotegravir sodium Form A prepared according to the discourse of the ‘764 or ‘253 publications fails to provide same crystalline form consistently instead resulted a mixture of cabotegravir sodium Form A with either Form B (or) Form C. Therefore, the reported methods for crystalline cabotegravir sodium Form A is not suitable on commercial scale manufacturing as it does not produce pure Form A at all times. Hence it is important to have a consistent process for preparation of pure crystalline cabotegravir sodium Form A in a reproducible manner.

In accordance with one embodiment, the present invention provides a process for preparation of crystalline cabotegravir sodium Form A, comprising:
a) suspending or dissolving cabotegravir in an organic solvent,
b) adding sodium source to step a) reaction mass (or) adding step a) reaction mass to sodium source, and
c) isolating cabotegravir sodium Form A; wherein the one or more solvents are selected from the group comprising alcohols, ketones, sulfoxides, nitriles, ethers and the like and mixtures thereof.

The aforementioned process of step a) involves suspending or dissolving cabotegravir in one or more solvents at about 25°C to reflux temperature; preferably at about 25°C to about 80°C. Then, the resultant reaction mass may be optionally cool to below 25°C.

The organic solvent used herein step a) include, but are not limited to alcohols, ketones, sulfoxides, nitriles, ethers and the like and mixtures thereof. The alcohols include but are not limited to methanol, ethanol, butanol, isobutanol, tert-butanol, propanol, isopropanol, pentanol, glycerol and the like; ketones include, but are not limited to acetone, methylisobutylketone, methylethylketone and the like; sulfoxides include, but are not limited to dimethyl sulfoxide, diethyl sulfoxide and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; ethers include, but are not limited to tetrahydrofuran, methyl tertiary butyl ether and the like and mixture thereof; preferably trifluoroethanol, dimethyl sulfoxide, methanol, ethanol, n-butanol, n-pentanol, acetone, acetonitrile, tetrahydrofuran and mixture thereof.

The step b) of the aforementioned process involves, adding sodium source to step a) reaction mass or adding step a) reaction mass to sodium source at below 30°C.

The sodium source used herein for preparing cabotegravir sodium Form A is used directly as a solid or as a solution i.e. pre-dissolving the sodium source either in water, in a suitable solvent or a mixture thereof. The sodium source used herein is selected from the group comprising sodium hydroxide, sodium formate, sodium acetate and sodium alkoxide such as sodium methoxide, sodium ethoxide, sodium butoxide, sodium pentoxide and the like and mixtures thereof; preferably sodium hydroxide, sodium methoxide.

The solvent used to pre-dissolve sodium source is may be the same as the solvent used in step a) or may be different one include, but are not limited to alcohols, ketones, sulfoxides, nitriles, ethers, esters, amides and the like and water and mixtures thereof. The alcohols include but are not limited to methanol, ethanol, butanol, isobutanol, tert-butanol, propanol, isopropanol, pentanol, glycerol and the like; ketones include, but are not limited to acetone, methylisobutylketone, methylethylketone and the like; sulfoxides include, but are not limited to dimethyl sulfoxide, diethyl sulfoxide and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; ethers include, but are not limited to tetrahydrofuran, methyl tertiary butyl ether and the like; esters include, but are not limited to methyl acetate, ethyl acetate, isopropyl acetate and the like; amides include, but are not limited to dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like and water and mixture thereof; preferably methanol, ethanol, water and mixture thereof; more preferably methanol, water and mixture thereof.

Then the precipitated cabotegravir sodium Form A can be recovered by any conventional techniques, for example decantation, filtration; preferably by filtration. The resultant product may be further dried at suitable temperatures.

In another embodiment, the process of the present invention produces pure crystalline cabotegravir sodium Form A without contamination of any polymorph and is stable during storage. This property is important and advantageous for the desire use of cabotegravir in pharmaceutical product formulation.

In accordance with another embodiment, the present invention provides a process for preparation of crystalline cabotegravir sodium Form A, characterized by a powder X-ray diffraction (PXRD) pattern peaks having peaks selected from at about: 5.4, 9.5, 11.0, 12.7, 13.1, 14.0, 14.6, 15.4, 15.7, 16.1, 19.0, 21.5, 22.1, 23.2, 23.8, 24.4, 25.4, 26.2, 27.1, 28.0, 28.9, 29.9, 32.6 and 34.5 ±0.2° 2?.

In accordance with another embodiment, the present invention provides substantially pure crystalline cabotegravir sodium Form A, characterized by: a powder X-ray diffraction (PXRD) pattern having at least one peak selected from: 5.4, 9.5, 11.0, 12.7, 13.1, 14.0, 14.6, 15.4, 15.7, 16.1, 19.0, 21.5, 22.1, 23.2, 23.8, 24.4, 25.4, 26.2, 27.1, 28.0, 28.9, 29.9, 32.6 and 34.5 ±0.2° 2? and does not have a peak at about 6.2 and/or 6.8±0.2° 2?.

In accordance with another embodiment, the present invention provides at least about 95% by weight of the solid crystalline cabotegravir sodium is Form A of cabotegravir sodium.

In accordance with another embodiment, the present invention provides at least about 99% by weight of the solid crystalline cabotegravir sodium is Form A of cabotegravir sodium.

In another embodiment, the present invention provides a pharmaceutical composition comprising cabotegravir sodium Form A prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.

EXAMPLES

The following non limiting examples illustrate specific embodiments of the present invention. They are not intended to be limiting the scope of the present invention in any way.

EXAMPLE-1:

Preparation of Cabotegravir Form A

Cabotegravir (2 gm) and 2,2,2-trifluoro ethanol (10 mL) were added in to a round bottom flask at 20-25°C and heated to 58-62°C and stirred for 20-30 min at same temperature. Reaction mass was cooled to 22°C to 26°C. Then the solution was added to a mixture of aqueous sodium hydroxide and methanol (0.21 gm NaOH was dissolved in 2.64 mL water and 32 mL methanol) at 22°C to 26°C over a period of 30 min. To the reaction mass methanol (32 mL) was added at 22°C to 26°C and allowed to stir for 1-2 hours at same temperature. Solid was filtered and washed with methanol (10 mL), suck dried the solid for 15 min and dried the wet material under vacuum at 50-55°C for about 15 hrs to obtain the title compound. Wt: 2.1 gm. The PXRD is set forth in Figure-1.
EXAMPLE-2:

Preparation of Cabotegravir Form A

Cabotegravir (2 gm) and 2,2,2-trifluoro ethanol (10 mL) were added in to a round bottom flask at 20-25°C and heated to 58-62°C and stirred for 20-30 min at same temperature. Reaction mass was cooled to 22°C to 26°C. Then the solution was added to a methanol solution of sodium methoxide (0.28 gm sodium methoxide was dissolved in 32 mL methanol) at 22°C to 26°C over a period of 30 min. To the reaction mass methanol (32 mL) was added at 22°C to 26°C and allowed to stirred for 1-2 hours at same temperature. Solid was filtered and washed with methanol (10 mL), suck dried the solid for 15 min and dried the wet material under vacuum at 58-62°C for about 15 hrs to obtain the title compound. Wt: 2.05 gm.

EXAMPLE-3:

Preparation of Cabotegravir Form A

Cabotegravir (0.5 gm) and 2,2,2-trifluoro ethanol (2.5 mL) were added in to a round bottom flask at 20-25°C and heated to 58-62°C and stirred for 20-30 min at same temperature. Reaction mass was cooled to 22°C to 26°C. To the solution methanol solution of sodium hydroxide (0.52 gm sodium hydroxide was dissolved in 2.5 mL methanol) was added at 22°C to 26°C over a period of 15 min. To the reaction mass methanol (5 mL) was added at 22°C to 26°C and allowed to stirred for 1.5 hour at same temperature. Solid was filtered and washed with methanol (1 mL), suck dried the solid for 15 min and dried the wet material under vacuum at 58-62°C for about 15 hrs to obtain the title compound. Wt: 0.49 gm.

EXAMPLE-4:

Preparation of Cabotegravir Form A

Cabotegravir (2 gm) and dimethyl sulfoxide (36 mL) were added in to a round bottom flask at 20-25°C and heated to 73-77°C and stirred for 20-30 min at same temperature. Reaction mass was cooled to 22°C to 26°C. Then the solution was added to a mixture of aqueous sodium hydroxide and methanol (0.19 gm NaOH was dissolved in 2.48 mL water and 60 mL methanol) at 22°C to 26°C over a period of 20 min and allowed to stirred for 2 hours at same temperature. Solid was filtered and washed with methanol (10 mL), suck dried the solid for 15 min and dried the wet material under vacuum at 58-62°C for about 15 hrs to obtain the title compound. Wt: 2.04 gm.

EXAMPLE-5:

Preparation of Cabotegravir Form A

Cabotegravir (2 gm) and dimethyl sulfoxide (36 mL) were added in to a round bottom flask at 20-25°C and heated to 73-77°C and stirred for 20-30 min at same temperature. Reaction mass was cooled to 22°C to 26°C. Then the solution was added to aqueous sodium hydroxide (0.19 gm NaOH was dissolved in 2.48 mL water) at 22°C to 26°C over a period of 15 min and allowed to stirred for 2 hours at same temperature. Solid was filtered and washed with methanol (10 mL), suck dried the solid for 15 min and dried the wet material under vacuum at 58-62°C for about 15 hrs to obtain the title compound. Wt: 2.12 gm.

EXAMPLE-6:

Preparation of Cabotegravir Form A

Cabotegravir (2 gm) and dimethyl sulfoxide (36 mL) were added in to a round bottom flask at 20-25°C and heated to 73-77°C and stirred for 20-30 min at same temperature. Reaction mass was cooled to 22°C to 26°C. Then the solution was added to methanol solution of sodium methoxide (0.28 gm sodium methoxide was dissolved in 60 mL methanol) at 22°C to 26°C over a period of 15 min and allowed to stirred for 2 hours at same temperature. Solid was filtered and suck dried the solid for 15 min and dried the wet material under vacuum at 58-62°C for about 15 hrs to obtain the title compound. Wt: 2.09 gm.

EXAMPLE-7:

Preparation of Cabotegravir Form A

Cabotegravir (0.3 gm) and methanol (3 mL) were added in to a round bottom flask at 22-26°C. To the reaction mass methanolic solution of sodium hydroxide (0.32 gm sodium hydroxide was dissolved in 0.6 mL methanol) was added at 22°C to 26°C over a period of 5 min. To the reaction mass methanol (2.1 mL) was added at 22°C to 26°C and allowed to stirred for 8 hours at same temperature. Solid was filtered, washed with methanol (0.6 mL) and suck dried the solid for 15 min and dried the wet material under vacuum at 58-62°C for about 14 hrs to obtain the title compound. Wt: 0.25 gm.

EXAMPLE-8:

Preparation of Cabotegravir Form A

Cabotegravir (0.3 gm) and ethanol (3 mL) were added in to a round bottom flask at 22-26°C. To the reaction mass methanolic solution of sodium hydroxide (0.32 gm sodium hydroxide was dissolved in 0.6 mL methanol) was added at 22°C to 26°C over a period of 5 min. To the reaction mass ethanol (3 mL) was added at 22°C to 26°C and allowed to stirred for 8 hours at same temperature. Solid was filtered, washed with ethanol (1 mL) and suck dried the solid for 15 min and dried the wet material under vacuum at 58-62°C for about 14 hrs to obtain the title compound. Wt: 0.26 gm.

EXAMPLE-9:

Preparation of Cabotegravir Form A

Cabotegravir (0.3 gm) and n-butanol (3 mL) were added in to a round bottom flask at 22-26°C. To the reaction mass methanolic solution of sodium hydroxide (0.32 gm sodium hydroxide was dissolved in 0.6 mL methanol) was added at 22°C to 26°C over a period of 5 min. To the reaction mass n-butanol (5.4 mL) was added at 22°C to 26°C and allowed to stirred for 8 hours at same temperature. Solid was filtered, washed with n-butanol (0.9 mL) and suck dried the solid for 15 min and dried the wet material under vacuum at 58-62°C for about 14 hrs to obtain the title compound. Wt: 0.24 gm.

EXAMPLE-10:

Preparation of Cabotegravir Form A

Cabotegravir (0.3 gm) and n-pentanol (3 mL) were added in to a round bottom flask at 22-26°C. To the reaction mass methanolic solution of sodium hydroxide (0.32 gm sodium hydroxide was dissolved in 0.6 mL methanol) was added at 22°C to 26°C over a period of 5 min. To the reaction mass n-pentanol (4.2 mL) was added at 22°C to 26°C and allowed to stirred for 8 hours at same temperature. Solid was filtered, washed with n-pentanol (1 mL) and suck dried the solid for 15 min and dried the wet material under vacuum at 58-62°C for about 14 hrs to obtain the title compound. Wt: 0.28 gm.

EXAMPLE-11:

Preparation of Cabotegravir Form A

Cabotegravir (0.3 gm) and acetone (3 mL) were added in to a round bottom flask at 22-26°C. To the reaction mass methanolic solution of sodium hydroxide (0.32 gm sodium hydroxide was dissolved in 0.6 mL methanol) was added at 22°C to 26°C over a period of 5 min. To the reaction mass acetone (4.2 mL) was added at 22°C to 26°C and allowed to stir for 8 hours at same temperature. Solid was filtered, washed with acetone (0.6 mL) and suck dried the solid for 15 min and dried the wet material under vacuum at 58-62°C for about 14 hrs to obtain the title compound. Wt: 0.27 gm.

EXAMPLE-12:

Preparation of Cabotegravir Form A

Cabotegravir (0.3 gm) and acetonitrile (3 mL) were added in to a round bottom flask at 22-26°C. To the reaction mass was added a methanolic solution of sodium hydroxide (0.32 gm sodium hydroxide was dissolved in 0.6 mL methanol) at 22°C to 26°C over a period of 5 min. To the reaction mass was added acetonitrile (4.2 mL) at 22°C to 26°C and allowed to stir for 8 hours at same temperature. Solid was filtered, washed with acetonitrile (0.6 mL) and suck dried the solid for 15 min and dried the wet material under vacuum at 58-62°C for about 14 hrs to obtain the title compound. Wt: 0.2 gm.

EXAMPLE-13:

Preparation of Cabotegravir Form A

Cabotegravir (0.3 gm) and tetrahydrofuran (3 mL) were added in to a round bottom flask at 22-26°C. To the reaction mass was added a methanolic solution of sodium hydroxide (0.32 gm sodium hydroxide was dissolved in 0.6 mL methanol) at 22°C to 26°C over a period of 5 min. To the reaction mass was added tetrahydrofuran (4.2 mL) at 22°C to 26°C and allowed to stir for 8 hours at same temperature. Solid was filtered, washed with tetrahydrofuran (0.6 mL) and suck dried the solid for 15 min and dried the wet material under vacuum at 58-62°C for about 14 hrs to obtain the title compound. Wt: 0.25 gm.

EXAMPLE-14:

Stability of Cabotegravir sodium Form A

a) Stability in aq medium (water)
Cabotegravir sodium Form A (200 mg) was suspended in water (2 mL) and stirred the mixture at room temperature for 1 hour, then heated to 50°C for 2 hours. A portion of the suspension was filtered at end of the each slurry step processed at room temperature and at 50°C to examine the stability of Form A. At both these conditions no change in polymorph nature indicating that Form A is stable in water even at 50°C.

b) Stability of Cabotegravir sodium Form A under humid air:

Cabotegravir sodium Form A (200 mg) was placed at 85% RH at room temperature for 24 hours. Wt: 199.9 mg. PXRD: Form A.
c) Stability of Cabotegravir sodium Form A under heating:

Cabotegravir sodium Form A (201.1 mg) was dried at 90±2°C in air tray dryer for 8 hours. Wt: 164.4 mg. PXRD: Form A.

All the above conditions Form A was retained and no change in polymorphic nature.

It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be constructed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.
,CLAIMS:We claim:

1. A process for preparation of crystalline cabotegravir sodium Form A, comprising:
a) suspending or dissolving cabotegravir in an organic solvent,
b) adding sodium source to step a) reaction mass (or) adding step a) reaction mass to sodium source, and
c) isolating cabotegravir sodium Form A; wherein the organic solvent is selected from the group comprising alcohols, ketones, sulfoxides, nitriles, ethers and the like or mixtures thereof.

2. The process as claimed in claim 1, wherein the organic solvent is selected from the group comprising methanol, ethanol, butanol, isobutanol, tert-butanol, propanol, isopropanol, pentanol, glycerol, acetone, methylisobutylketone, methylethylketone, dimethyl sulfoxide, diethyl sulfoxide, acetonitrile, propionitrile, tetrahydrofuran, methyl tertiary butyl ether and mixture thereof.

3. The process as claimed in claim 2, wherein the organic solvent is trifluoroethanol, dimethyl sulfoxide, methanol, ethanol, n-butanol, n-pentanol, acetone, acetonitrile, tetrahydrofuran and mixture thereof.

4. The process as claimed in claim 1, wherein the sodium source is selected from the group comprising sodium hydroxide, sodium formate, sodium acetate, sodium methoxide, sodium ethoxide, sodium butoxide, sodium pentoxide and mixtures thereof.

5. The process as claimed in claim 4, wherein the sodium source is sodium hydroxide or sodium methoxide.

6. The process as claimed in claim 1, wherein the step b) is carried out at temperature of below 30°C.

7. Crystalline cabotegravir sodium Form A prepared according to claim 1 to 6 is characterized by a powder X-ray diffraction (PXRD) pattern having at least one peak selected from: 5.4, 9.5, 11.0, 12.7, 13.1, 14.0, 14.6, 15.4, 15.7, 16.1, 19.0, 21.5, 22.1, 23.2, 23.8, 24.4, 25.4, 26.2, 27.1, 28.0, 28.9, 29.9, 32.6 and 34.5 ±0.2° 2? and does not have a peak at about 6.2 and/or 6.8±0.2° 2?.

8. Crystalline cabotegravir sodium Form A characterized by a powder X-ray diffraction (PXRD) pattern having at least one peak selected from: 5.4, 9.5, 11.0, 12.7, 13.1, 14.0, 14.6, 15.4, 15.7, 16.1, 19.0, 21.5, 22.1, 23.2, 23.8, 24.4, 25.4, 26.2, 27.1, 28.0, 28.9, 29.9, 32.6 and 34.5 ±0.2° 2? and does not have a peak at about 6.2 and/or 6.8±0.2° 2?.

9. The compound as claimed in claim 8, wherein the crystalline cabotegravir sodium having at least about 95% by weight of crystalline cabotegravir sodium Form A.

10. A composition comprising crystalline cabotegravir sodium Form A as prepared according to claim 1-9 and at least one pharmaceutically acceptable excipient.