FIELD OF THE INVENTION
The present invention relates to a Crystalline polymorph of Sodium (2R35S313aR)-739-dioxo-10-((254,6-trifluorobenzyl) carbamoyl)-2,354,5,7,9513,13a-octahydro-235-Methanopyrido[r,2':435]pyrazino[23l-b][l33] oxazepin-8-olate of Formula-1.
BACK GROUND OF THE INVENTION
Sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,
13as-octahydro-2)5-Methanopyrido[r,2':455]pyrazino[2;l-b][l,3]oxazepin-8-olate is
known to be Bictegravir sodium, which has been approved as the combination drug in US as Bictegravir;Emtricitabine;Tenofoviralafenamide under the trade name of BIKTARVY® for treating HIV.
(2R,5Ss13aR)-7)9-dioxo-10-((2,4,6-trifluoroben2yl)carbamoyl)-2,3,4,5,7,9,13,l-3a-
octahydro-2,5-lvlethanopyrido[r,2':4,5]pyrazino[25l-b][l,3] oxazepin-8-olate as well as its pharmaceutically acceptable salts are first known in US 9,216,996 B2.(US3996).
US'996 has disclosed the following process for the preparation of (2R,5S,13aR)-739-dioxo-10-((2,4,6-trifluorobenzyl) carbamoyl)-2,334,5;7,9313313a- octahydro-2,5-Methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3] oxazepin-8-olate :

US'996 has disclosed pharmaceutically acceptable salts of (2R,5S,13aR)-739-dioxo-10-((2,4,6-trifluorobenzyl) carbamoyl)-2,3,4,5,7,9,13,13a- octahydro-2,5- Methanopyrido [l',2':4.5]pyrazino[2,l-b][l,3] oxazepin-8-olate, however there is no exemplification of sodium salt of (2R35S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl) carbamoyl)- 2,3,4,5, 7,9,13,13a- octahydro-2,5- Methanopyrido[r,2':4,5]pyrazino[2,l-b][l33] oxazepin-8-olate.
US 9,708,342 B2 discloses Sodium (2R35S313aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl) carbamoyl)-2,3s4,5,799,13,13a-octahydro-2,5-Methanopyrido[ 1 ',2':4,5]pyrazino[2,1 -b] [1,3] oxazepin-8-olate having X-ray powder diffraction peaks about 5.5, 16.1, 17.9, 19.5, 22.1, 22.5, 23.3, 28.5 ± 0.2° 29, which is designated as Form-I, and provided single PXRD figure.
US'342 has disclosed the following process for-the preparation of Sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4)6-trifluorobenzyl)carbamoyl)-2,3,4,5,7!9,13,13a-octahydro-2,5-Methanopyrido[r,2':4,5]pyrazino[2,l-b][l33] oxazepin-8-olate :'

European medical agency (EMA) stated that, "Only one polymorphic form was identified during development of Sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl) carbamoyl)-2:3,4,5,7,9,13,13a-octahydro-2,5-Methanopyrido[ 1 ',2':4,5]pyrazino[2,1 -b] [1,3] oxazepin-8-olate." (Ref: EMA/293559/2018-Scientific discussion).
US 9,682,084 B2 discloses the polymorphic forms of (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl) carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5- Methanopyrido[ 1 ',2':4,5] pyrazino[2,l-b] [1,3] oxazepin-8-olate free base designated as Crystalline Form I, Form II, Form III, Form IV, Form V, Form VI, Form VII and Form VIII and amorphous Form. Further this patent discloses the cocrystals (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl) carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5- Methanopyrido[l',2':4,5] pyrazino[2,l-b] [1,3] oxazepin-8-olate, including Oxalic acid, Fumaric acid and Citric acid.
US 9,682,084 B2 discloses the polymorphic forms of the (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3)4,5,7,9,13,13a-octahydro-2,5- Methanopyrido [l',2':4,5] pyrazino[2,l-b] [1,3] oxazepin-8-olate, potassium salt designated as Form-I, Form-II and Form-Ill.
During the development of the process the present inventors noticed that the Sodium (2R,5S,13aR)-7,9-dioxo-10-((23436-trifiuorobenzyl)carbamoyI)-2,3,4,5,7,9,13,13a-octahydro-2,5-Methanopyrido[r,2':4,5]pyrazino[2,l-b] [1,3] oxazepin-8-olate exhibits polymorphism and obtains new crystalline form,which is stable and PXRD 28 values as well as figure is different from the known crystalline form of US'342 .
OBJECTIVES OF THE INVENTION
The objective of the present invention, is to provide crystalline form of Sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,354,5,7,9,13,13a-
■ E (\j q;ctahydrqT2x5(Mjthano;B^ ^xazepin-^-ola^e/. ■ ■

Yet another objective of the present invention is to provide a process for the preparation of Crystalline Sodium (2R,5S,13aR)-7;9-dioxo-10-((2,436-trifluorobenzyl) carbamoyl)-233)4s5)7,9,13,13a-octahydro-255-Methanopyrido[r.2':4,5]pyrazino[2,]-b][l,3] oxazepin-8-olate, which is consistent3reproducible, stable and industrially viable.
SUMMARY OF THE INVENTION
The present invention relates to a Crystalline form of Sodium (2R35S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl) carbamoyl)-2,3,4,5)7,9313313a-octahydro-2,5- Methanopyrido [T,2':4,5]pyrazino[2sl-b][l,3] oxazepin-8-olate having the X-ray powder diffraction pattern shown in Figure 1 and having 20 peak of 9.0±0.2° 20; DSC is as shown in Figure 2.
The present invention also relates to a process for the preparation of Sodium (2R35S,13aR)-739-dioxo-10-((23436-trifluorobenzyl) carbamoyl)- 2333435,7,9,13, 13a-octahydro-235-Methanopyrido[r,2':4,5] pyrazino [2,l-b][l,3] Oxazepin-8-olate crystalline HN-1 form, which comprises:
a) dissolving (2R35S,13aR)-739-dioxo-10-((23436-trifluorobenzyl)carbamoyl)-23334353739313313a-octahydro-235-Methanopyrido[r,2':435]pyrazino[2,l-b][l33] Oxazepin-8-olate, in an organic solvent, water and/or mixtures thereof;
b) optionally treatment with carbon;
c) preparing a source of sodium base ;
d) adding step(c) to step-(a) or step-(a) to step(c);
e) heating the obtained reaction mixture to 40-50°C;
f) cooling the obtained reaction mixture to room temperature; and
g) isolating Sodium (2R35S,13aR)-7,9-dioxo-10-((234,6-trifluorobenzyl) carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-Methanopyrido[rs2':4,5]pyrazino [2,l-b][l,3] oxazepin-8-olate in crystalline form.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1. is a a X-ray powder diffraction spectrum of crystalline Form HN-1 Sodium
(2R35S,13aR)-739-dioxo-10-((2,4,6-trifluorobenzyl) carbamoyl)-2,3,4,5,7,9,13,13a-
octahydro-2,5-Methanopyrido[ 1 ',2':4,5]pyrazino [2,1 -b][ 1,3] oxazepin-8-olate.

Figure 2. is a DSC of crystalline Form HN-1 Sodium (2R,5S,13aR)-7,9-dioxo-10-((234;6-Trifluorobenzyl)carbamoy])-2.3,4=53739313,13a-octahydro-2.5-Methanopyrido [1\2':4,5] pyrazino [2,l-b][l,3] oxazepin-8-olate.
Figure 3. is a DSC of Form-I of Sodium (2R,5S313aR)-7,9-dioxo-10-((2,4,6-Trifluorobenzyl)carbamoyl)-2)3s4,55759,13)13a-octahydro-2,5-Methanopyrido[r,2':4,5] pyrazino [2,l-b][l,3] oxazepin-8-olate.
POWDER X-RAY DIFFRACTION METHOD:
X-ray powder diffraction spectrum was measured on a broker axs D8 advance X-ray powder diffractometer having a copper-Ka radiation. Approximately 1 gm of sample was gently flattered on a sample holder and scanned from 2 lo 50 degrees two-theta, at 0.02 degrees two theta per step and a step time of 10.8 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA.
DIFFERENTIAL SCANNING CALORIMETRY:
Thermal properties of sodium (2R,5S313aR)-7,9-dioxo-10-((2)4)6-
trifluorobenzyl)carbamoyl)-253,4,5,759,13,13a-octahydro-2s5-methanopyrido[r,2':435] pyrazino[2,l-b][l,3]oxazepin-8-olate Form I and Form HN-1 were evaluated using a Differential Scanning calorimetry (DSC) instrument (TA. Q2000, TA Instruments) Approximately 5 to 10 mg of solid sample was placed in a standard aluminum pan vented with a pinhole for each experiment and heated at a rate of 10° C./min under a 50 mL/min nitrogen purge.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a Crystalline form of Sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl) carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-235- Methanopyrido [rs2':4,5]pyrazino[2)l-b][l53] oxazepin-8-olate having the X-ray powder diffraction pattern shown in Figure 1 and having 29 peak of 9.0±0.2° 20; DSC is as shown in Figure 2.
In another embodiment of the present invention, Sodium (2Rs5S,13aR)-7,9-dioxo-10-
E N (|(2,4^6pri%orobenzy])^ £ .- ^Methanopyrido
[r,2':4,5]pyrazino[2,l-b][l,3] oxazepin-8-olate HN-1 crystalline form with water content

approximately ranging from 3 to 6 % w/w. This form is characterized by a DSC thermogram as reported in FIG. 2, with two exothermic peaks at -81 °C and- 383°C; and powder X-ray diffraction spectrum as illustrated in FIG. 1, wherein the most intense diffraction peaks fall at 6.4, 9.0, 12.0, 15.9,17.2,19.4,20.9,22.6, 23.2 and 25.7±0.2° in 29.
In another embodiment of the present invention, isolated crystalline form of Sodium (2Rs5S)13aR)-7,9-dioxo-10-((2s4,6-trifluorobenzyl)carbamoyl)-2,334353759,13,13a-octahydro-2,5- Methanopyrido [l',2':4,5]pyrazino[2,l-b][l,3] oxazepin-8-olate has water content in the range of 3-6% w/w by Karl Fischer method.
In another embodiment of the present invention, isolated crystalline form of Sodium (2R,5S, 13aR)-739-dioxo-l 0-((2,4,6-trifluorobenzy l)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5- Methanopyrido [r,2':435]pyrazino[2,l-b][l,3] oxazepin-8-olate has been designated as FormHN-1.
In another embodiment of the present invention, a process for the preparation crystalline
HN-1 form of Sodium (2R)5S)13aR)-7)9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-
2,3,4,5,7,9,13,13a-octahydro-2,5-Methanopyrido[l',2':4,5]pyrazino[2,l-b][l,3]oxazepin-
8-olate, which comprises dissolving (2R,5S513aR)-7s9-dioxo-10-((2,436-trifluorobenzyl)
carbamoyl)-2}354,5s7,9;13313a-octahydro-2,5-Methanopyrido[r52':435]pyrazino[2,l-b]
[l,3]oxazepin-8-olate in in an organic solvent, water or mixture thereof; optionally
treating with carbon; preparing a source of sodium base and added to the obtained
reaction mixture (or) reaction mixture added to a source of sodium base slowly followed
by heating the obtained reaction mixture to 40-50°C. Cooling the obtained reaction
mixture to room temperature and isolating crystalline HN-1 form of
Sodium(2R,5S,13aR)-7)9-dioxo-10-((2,4s6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-235-methanopyrido [l',2':4,5] pyrazino [2,l-b][l,3] oxazepin-8-olate.
In another embodiment of the present invention, a process for the preparation Sodium
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoy])-2,3,4,5,7,9,13,13a-
octahydro-2,5-methanopyrido[r,2':4)5]pyrazino[2,l-b][l,3]oxazepin-8-olate, which
comprises dissolving (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl) carbamoyl)-253,4,5,739,13,13a-octahydro-235-methanopyrido[r,2':435]pyrazino[2,l-b][l,3]oxazepin-8-olate in an organic solvent, water or mixture thereof; wherein the obtained reaction E M mixture treatedEwithCc^oft [an,d, remov&lgthe (ga|bon"2%ojig^ hj[fl§w. wherein organic solvent is selected from the groups comprising of halogenated solvents, alcohols, ketonic

solvents, ethers, esters, hydrocarbons, nitriles, dimethylformamide, dimethylsulfoxide, and dimethylacetamide at room temperature; wherein the halogenated solvents are selected from the group comprising of dichloromethane (MDC), ethylene dichloride (EDC), chloroform and the like; alcohols are selected from the group comprising of methanol, ethanol, isopropanol, 1-butanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 2,3 pentanol, 2-methyl-2-butanol, 2-methyl- 1-butanol, 3-methyl-2-butanol, and the like; ketonic solvents are selected from the group comprising of acetone, methylethyl ketone, methyl isobutyl ketone and the like; ethers are selected from the group comprising of tetrahydrofuran (THF), 2-methyltetrahydrofuran (MeTHF), diethyl ether, isopropyl ether, methyl isobutylether, methyl t-Bu ether (MTBE), dioxane and the like; esters are selected from the group comprising of ethyl acetate, isopropyl acetate and the like; hydrocarbons are selected from the group comprising of toluene, heptane, hexane, cyclohexane xylene and the like; nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile, acrylonitrile.
In another embodiment of the present invention, source of sodium base is prepared by dissolving sodium base in water; wherein sodium base is selected from the group comprising of Sodium hydroxide, sodium alkoxide, sodium-2-ethylhexanoate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium lactate, sodium dihydrogen phosphate; wherein sodium base is added to the obtained reaction mixture (or) reaction mixture is added to a source of sodium base slowly over a period of 1 hour at room temperature.
In another embodiment of the present invention, heating the obtained reaction mixture for 1 hour, wherein heating temperature is 40-60°C, preferably 45°± 5°C and there after cooled 25-30°C.
In another embodiment throughout the invention, the mixture of solvents means two or more solvents and room temperature is considered as 25-30°C.
The another embodiment of the present invention the isolation of crystalline Sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-Methanopyrido[l',2':4,5]pyrazino [2,l-b][l,3] oxazepin-8-olate is carried out by way of cooling, anti solvent technique, evaporation of solvent and filtration

In another embodiment throughout the invention, (2R,5S,13aR)-7,9-dioxo-10-((254J6-trifluorobenzyl) carbamoy1)-2,3,4,5,7,9,13,13a-octahydro-2,5- Methanopyrido[r,2':4s5] pyrazino[2,I-b][],3]oxazepin-8-olate is either crystalline or amorphous.
The present inventors have also studied the stability of crystalline Form KN-1 at 40°C and 75% RH for 6 months and found that the product complies with the initial results and found to be stable.
The stability of sample was tested by storing the samples at 40°C/75% relative humidity (RH) and 25°C/60% RH for 6 months. The stability of samples was tested by PXRD, HPLC and water content was measured by Karl Fischer method.
Data collected during these tests at 25°C/60% RH and 40°C/75% RH are as shown
The stability test revealed no changed in PXRD pattern and also in water content. There is no significant decrease in purity after storage, indicating that crystalline Form HN-1 of Sodium(2R,5S,13aR)-7,9-dioxo-10-((2)4,6-trifluorobenzyl)carbamoyl)-2s354)5s7)9,13,13a-octahydro-2,5- Methanopyrido [r,2':4,5]pyrazino[23l-b][l53] oxazepin-8-olate, (Form HN-1) is physically and chemically stable at 25°C/60% RH and 40°C/75%RH conditions.
The invention of the present application will be explained in more detail with reference to
the following examples, which should not be construed as limiting the scope of the
: NI OFFICE C H E NNAI '26/06/2019 16=47 invention in any manner.

Examples:
Example-1 Preparation of crystalline Sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-
trifIuorobenzyl)carbamoyl)-2,3»4,5,7,9,13,13a-octahydro-2,5-Methanopyrido
[l',2':4,51pyrazino|2,l-b][l,31oxazepin-8-olate:
Dissolving (2R;5S,13aR)-7;9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13, 13a-octahydro-2,5-Methanopyrido[r,2':4,5]pyrazino [2,l-b][l,3] oxazepin-8-olate(100 gm) in a mixture of MDC and Methanol (350 ml: 650ml) at room temperature. Carbon (2 gm) has been added to the reaction mixture and stirred for 10-15 minutes. The carbon has been removed through hyflow. Washing hyflow bed with mixture of MDC and Methanol (50 ml : 100ml). To the obtained filtrate aq NaOH (10 gm NaOH in 50 ml water) was added slowly for 30-45 minutes at room temperature and the reaction mixture heated to 40-45°C and stirred 1 hour. Thereafter reaction mixture cooled to room temperature and stirred for 1 hour. The obtained solid was filtered and washed with Methanol (50ml) followed by drying at 45-50°C to yield crystalline Sodium (2R,5S,13aR)- 759-dioxo-10-^^^-trifluorobenzy^carbamoyO^^^jSJ^jnjna-octahydro^^- Methanopyrido [ 1 ',2':4,5]pyrazino[2,1 -b] [1,3]oxazepin-8-olate. Yield: lOOgm; Purity by HPLC ( by chromatography): 99.82%.
Example-2: Preparation of crystalline Sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3i4,5,7,9,13,13a-octahydro-2,5-Methanopyrido [l',2':4,5] pyrazino[2,l-b][l,3]oxazepin-8-olate:
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)- 2,3,4,5,7,9,13,
13a-octahydro-2,5-Methanopyrido[l ',2':4,5]pyrazino[2,1 -b][ 1,3]oxazepin-8-olate( 1 Ogm)
was dissolved in a mixture of MDC and Methanol (35 ml: 65ml) at room temperature.
Carbon (0.2 gm) was added to the reaction mixture and stirred for 10-15 minutes. The
carbon removed through hyflow. To the obtained filtrate aq Na2COj (2.4 gm Na2CC>3 in 5
ml water) was added slowly at room temperature and the reaction mixture heated to 40-
45°C and stirred 1 hour. Thereafter reaction mixture cooled to room temperature and
stirred for 1 hour. The obtained solid was filtered and washed with Methanol (50ml)
followed by drying at 45-50°C to afford the title compound in -95% yield as depicted in
Figl.
Purity by HPLC ( by chromatography):99.78%

Examplc-3: Preparation of crystalline Sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-
trifluorobcnzy^carbamoyO^^^jS^^^S^Sa-octahydro-ljS-Mcthanopyrido
[1 ',2':4,5] pyrazino[2,l-bl[l,3|oxazepin-8-o1ate:
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbanioyl)-2,3,4,5,7,9,13, 13a-octahydro-2,5-Methanopyrido[r,2':4,5]pyrazino[23l-b][l,3]oxazepin-8-olate(10gm) was dissolved in a mixture of MDC and Isopropyl alcohol(IPA)(35 ml: 65ml) at room temperature. Carbon (0.2 gm) was added to the reaction mixture and stirred for 10-15 minutes. The carbon removed through hyflow. To the obtained filtrate aq NaOH (1 gm NaOH in 5 ml water) was added slowly at room temperature and the reaction mixture heated to 40-45°C and stirred 1 hour. Thereafter reaction mixture cooled to room temperature and stirred for 1 hour. The obtained solid was filtered and washed with IPA followed by drying at 45-50°C to afford the title compound in -95% yield as depicted in Figl. Purity by HPLC ( by chromatography):99.7%
Example-4: Preparation of crystalline Sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-Methanopyrido [l',2':4,5] pyrazino[2,l-b][l,3]oxazepin-8-o!ate:
(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13, 13a-octahydro-2,5-Methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate(10gm) was dissolved in a mixture of MDC and Acetone (35 ml: 65ml) at room temperature. Carbon (0.2 gm) was added to the reaction mixture and stirred for 10-15 minutes. The carbon removed through hyflow. To the obtained filtrate aq NaOH (1 gm NaOH in 5 ml water) was added slowly at room temperature and the reaction mixture heated to 40-45°C and stirred 1 hour. Thereafter reaction mixture cooled to room temperature and stirred for 1 hour. The obtained solid was filtered and washed with acetone followed by drying at 45-50°C to afford the title compound in -95% yield as depicted in Fig 1. Purity by HPLC ( by chromatography):99.81%
Example-5: Preparation of crystalline Sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-Methanopyrido
[l',2':4,5] pyrazino[2,l-b]|l,3|oxazepin-8-olatc:

13a-octahydro-2,5-Methanopyrido[r:2':4,5]pyrazino[2:l-b][l33]oxazepin-8-olate(10gm) was dissolved in a mixture of MDC and Methanol(35 ml: 65ml) at room temperature. Carbon (0.2 gm) was added to the reaction mixture and stirred for 10-15 minutes. The carbon removed through hyflow. Charged aq NaOH (1 gm NaOH in 5 ml water) in an another RB flask and added above filtrate slowly at room temperature and the reaction mixture heated to 40-45°C and stirred 1 hour. Thereafter reaction mixture cooled to room temperature and stirred for 1 hour. The obtained solid was filtered and washed with methanol followed by drying at 45-50°C to afford the title compound in -95% yield as depicted in Fig 1. Purity by HPLC ( by chromatography):99.69%