DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. IN 201941032384 filed on August 09, 2019.
FIELD OF THE INVENTION
The present invention relates to novel salts of bictegravir, polymorphic forms of bictegravir salts and a process for the preparation thereof.
BACKGROUND OF THE INVENTION
Bictegravir (formerly known as GS-9883) also referred to as bictegravir free acid is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor that was discovered by Gilead Sciences.
Bictegravir sodium is approved as part of a single tablet regimen in combination with tenofovir alafenamide (TAF) and emtricitabine (FTC) for the treatment of HIV-1 infection under the brand name of BIKTARVY®, marketed by Gilead Sciences. Bictegravir sodium is chemically known as (2R,5S,13aR)- 2,5-Methanopyrido[1’,2’:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide, 2,3,4,5,7,9, 13,13a-octahydro-8-hydroxy-7,9-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-, sodium salt (1:1), having the structure below:

Bictegravir is disclosed in U.S Patent No. 9,216,996, which is hereby incorporated by reference.
The inventors of the present disclosure have developed novel salts of bictegravir, crystalline forms of bictegravir salts and a process for the preparation.
OBJECT OF THE INVENTION
The main object of the present invention is to provide novel salts of bictegravir, which are crystalline in nature.
Another object of the present invention is to provide crystalline forms of bictegravir salts.
In another object, the present invention is to provide a process for the preparation of crystalline forms of bictegravir salts.
SUMMARY OF THE INVENTION
One aspect of the present invention is to provide novel salts of bictegravir of formula I and a process for the preparation thereof.

Formula I
wherein M represents lithium, cesium, magnesium, ammonium and oroate.
Another aspect of the present invention is to provide novel salts of bictegravir, which are crystalline in nature.
In another aspect, the present invention provides crystalline bictegravir potassium Form M1.
Yet another aspect of the present invention is to provide a process for the preparation of crystalline bictegravir potassium Form M1 comprising the steps of:
a) dissolving bictegravir in organic solvent at elevated temperature;
b) adding source of potassium;
c) cooling the reaction mass to 20-30 °C; and
d) isolating crystalline bictegravir potassium Form M1.
Another aspect, the present invention provides crystalline bictegravir lithium Form M1.
In another aspect, the present invention provides a process for the preparation of crystalline bictegravir lithium Form M1 comprising the steps of:
a) dissolving bictegravir in organic solvent at elevated temperature;
b) adding source of lithium;
c) cooling the reaction mass to 20-30 °C; and
d) isolating crystalline bictegravir lithium Form M1.
Yet another aspect of the present invention is to provide a process for the preparation of crystalline bictegravir cesium Form M1comprising the steps of:
a) dissolving bictegravir in organic solvent at elevated temperature;
b) adding source of cesium;
c) cooling the reaction mass to 20-30 °C; and
d) isolating crystalline bictegravir cesium Form M1.
In another aspect, the present invention is to provide a process for the preparation of crystalline bictegravir magnesium Form M1 comprising the steps of:
a) dissolving bictegravir in organic solvent at elevated temperature;
b) adding source of magnesium;
c) cooling the reaction mass to 20-30 °C; and
d) isolating crystalline bictegravir magnesium Form M1.
Another aspect of the present invention is to provide a process for the preparation of crystalline bictegravir ammonium Form M1comprising the steps of:
a) dissolving bictegravir in organic solvent at elevated temperature;
b) adding source of ammonium;
c) cooling the reaction mass to 20-30 °C; and
d) isolating crystalline bictegravir ammonium Form M1.
Yet another aspect of the present invention is to provide a process for the preparation of crystalline bictegravir orotate salt Form M1comprising the steps of:
a) dissolving bictegravir in organic solvent at elevated temperature;
b) adding orotic acid or a solution of orotic acid;
c) cooling the reaction mass to 20-30 °C; and
d) isolating crystalline bictegravir orotate Form M1.
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 bictegravir potassium Form M1;
Figure 2 is an X-ray powder diffractogram of crystalline bictegravir lithium Form M1;
Figure 3 is an X-ray powder diffractogram of crystalline bictegravir cesium Form M1.
DETAILED DESCRIPTION OF THE INVENTION
The present disclosure relates to bictegravir salts and its crystalline forms. The present disclosure also relates to process for the preparation of crystalline forms of bictegravir salts.
Within the context of the present disclosure, the term “elevated temperature” means the temperature above 35°C and it is depending on the organic solvent/bictegravir ratio.
The crystalline forms of bictegravir disclosed herein may be characterized by X-ray powder diffraction pattern (PXRD). Samples of each polymorph were analyzed on a BRUKER D-8 Discover powder diffractometer equipped with goniometer of ?/2? configuration and Lynx Eye detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 2? range 5 of 2.0°-50.0°, 0.030° step size and 0.4 seconds step time.
In one embodiment, the present invention relates to novel salts of bictegravir of formula I and a process for the preparation thereof.

Formula I
wherein M represents lithium, cesium, magnesium, ammonium and oroate.
In other embodiment, the present invention provides crystalline bictegravir potassium Form-M1 which has a powder X-ray diffraction pattern having significant peaks at 2? angles positions at about 6.38, 9.17, 15.63 and 19.24 ± 0.2°; and characterized by a PXRD pattern as shown in Figure 1.
In another embodiment, the present invention provides a process for the preparation of of crystalline bictegravir potassium Form M1 comprising the steps of:
a) dissolving bictegravir in organic solvent at elevated temperature;
b) adding source of potassium;
c) cooling the reaction mass to 20-30 °C; and
d) isolating crystalline bictegravir potassium Form M1.
According to the present invention, bictegravir is dissolved in an organic solvent at elevated temperature and added a potassium source. The reaction mass is cooled and stirred to produce a solid. The obtained solid may then filtered and dried to get crystalline bictegravir potassium Form M1.
Within the context of the present disclosure, bictegravir is dissolved in an organic solvent at elevated temperature, preferably of about 50-60 °C.
Within the context of this embodiment of the present invention, the organic solvent employed may include, alcoholic solvents such as methanol, ethanol, isopropanol or mixtures thereof. In particular useful embodiments of the present invention organic solvent is methanol.
Within the context of this embodiment of the present invention, potassium source employed may include, potassium hydroxide, potassium t-butoxide, potassium methoxide, potassium carbonate and the like mixtures thereof. The source of potassium can be added as a solution in suitable solvent or it may be added as a solid. In particular useful embodiments of the present invention potassium source is potassium hydroxide.
Another embodiment of the present invention provides crystalline bictegravir lithium Form M1, which has a powder X-ray diffraction pattern having significant peaks at 2? angles positions at about 6.33, 12.76, 17.43 and 19.57 ± 0.2°; and characterized by a PXRD pattern as shown in Figure 2.
In another embodiment, the present invention provides a process for the preparation of crystalline bictegravir lithium Form M1 comprising the steps of:
a) dissolving bictegravir in organic solvent at elevated temperature;
b) adding source of lithium;
c) cooling the reaction mass to 20-30 °C; and
d) isolating crystalline bictegravir lithium Form M1.
According to the present invention, bictegravir is dissolved in an organic solvent at elevated temperature and added a lithium source. The reaction mass is cooled and stirred to produce a solid. The obtained solid may then filtered and dried to get crystalline bictegravir lithium Form M1.
Within the context of the present disclosure, bictegravir is dissolved in an organic solvent at elevated temperature, preferably of about 55-65 °C.
Within the context of this embodiment of the present invention, the organic solvent employed may include, alcoholic solvents such as methanol, ethanol, isopropanol or mixtures thereof. In particular useful embodiments of the present invention organic solvent is methanol.
Within the context of this embodiment of the present invention, lithium source employed may include, lithium hydroxide, lithium carbonate, lithium methoxide and the like mixtures thereof. The source of lithium can be added as solution in suitable solvent or it may be added as a solid. In particular useful embodiments of the present invention lithium source is lithium hydroxide.
Another embodiment of the present invention provides crystalline bictegravir cesium Form M1, which characterized by a PXRD pattern as shown in Figure 3.
Yet another embodiment of the present invention is to provide a process for the preparation of crystalline bictegravir cesium Form M1 comprising the steps of:
a) dissolving bictegravir in organic solvent at elevated temperature;
b) adding source of cesium;
c) cooling the reaction mass to 20-30 °C; and
d) isolating crystalline bictegravir cesium Form M1.
According to the present invention, bictegravir is dissolved in an organic solvent at elevated temperature and added a cesium source. The reaction mass is cooled and stirred to produce a solid. The obtained solid may then filtered and dried to get crystalline bictegravir cesium Form M1.
Within the context of the present disclosure, bictegravir is dissolved in an organic solvent at elevated temperature, preferably of about 55-65 °C.
Within the context of this embodiment of the present invention, the organic solvent employed may include, alcoholic solvents such as methanol, ethanol, isopropanol or mixtures thereof. In particular useful embodiments of the present invention organic solvent is methanol.
Within the context of this embodiment of the present invention, cesium source employed may include, cesium hydroxide, cesium carbonate and the like mixtures thereof. The source of cesium can be added as solution in suitable solvent or it may be added as a solid. In particular useful embodiments of the present invention cesium source is cesium hydroxide.
In another embodiment, the present invention is to provide a process for the preparation of crystalline bictegravir magnesium Form M1 comprising the steps of:
a) dissolving bictegravir in organic solvent at elevated temperature;
b) adding source of magnesium;
c) cooling the reaction mass to 20-30 °C; and
d) isolating crystalline bictegravir magnesium Form M1.
According to the present invention, bictegravir is dissolved in an organic solvent at elevated temperature and added a magnesium source. The reaction mass is cooled and stirred to produce a solid. The obtained solid may then filtered and dried to get crystalline bictegravir magnesium Form M1.
Within the context of the present disclosure, bictegravir is dissolved in an organic solvent at elevated temperature, preferably of about 45-55 °C.
Within the context of this embodiment of the present invention, the organic solvent employed may include, alcoholic solvents such as methanol, ethanol, isopropanol or mixtures thereof. In particular useful embodiments of the present invention organic solvent is methanol.
Within the context of this embodiment of the present invention, magnesium source employed may include, magnesium hydroxide, magnesium methoxide, magnesium t-butoxide, magnesium carbonate, magnesium chloride and the like mixtures thereof. The source of magnesium can be added as solution in suitable solvent or it may be added as a solid. In particular useful embodiments of the present invention magnesium source is magnesium chloride.
Another embodiment of the present invention is to provide a process for the preparation of crystalline bictegravir ammonium Form M1comprising the steps of:
a) dissolving bictegravir in organic solvent at elevated temperature;
b) adding source of ammonium;
c) cooling the reaction mass to 20-30 °C; and
d) isolating crystalline bictegravir ammonium Form M1.
According to the present invention, bictegravir is dissolved in an organic solvent at elevated temperature and added ammonium source. The reaction mass is cooled and stirred to produce a solid. The obtained solid may then filtered and dried to get crystalline bictegravir ammonium Form M1.
Within the context of the present disclosure, bictegravir is dissolved in an organic solvent at elevated temperature, preferably of about 55-65 °C.
Within the context of this embodiment of the present invention, the organic solvent employed may include, alcoholic solvents such as methanol, ethanol, isopropanol or mixtures thereof. In particular useful embodiments of the present invention organic solvent is methanol.
Within the context of this embodiment of the present invention, ammonium source employed may include, ammonium hydroxide.
Yet another embodiment of the present invention is to provide a process for the preparation of crystalline bictegravir orotate salt Form M1 comprising the steps of:
a) dissolving bictegravir in organic solvent at elevated temperature;
b) adding orotic acid or a solution of orotic acid;
c) cooling the reaction mass to 20-30 °C; and
d) isolating crystalline bictegravir orotate Form M1.
According to the present invention, bictegravir is dissolved in an organic solvent at elevated temperature and added orotic acid solution. The reaction mass is cooled and stirred to produce a solid. The obtained solid may then filtered and dried to get crystalline bictegravir orotate Form M1.
Within the context of the present disclosure, bictegravir is dissolved in an organic solvent at elevated temperature, preferably of about 45-55 °C.
Within the context of this embodiment of the present invention, the organic solvent employed may include, polar aprotic solvents such as acetone, dimethylformamide, dimethyl sulfoxide or mixtures thereof. In particular useful embodiments of the present invention organic solvent is acetone.
Within the context of this embodiment of the present invention, orotic acid can be added as solution in suitable solvent such as dimethyl sulfoxide.
According to the present invention, the input bictegravir is prepared by any prior-art process for example PCT publication No. WO2015196116A1 or by the scheme shown below:

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present application. While particular aspects of the present application have been illustrated and described, it would be apparent to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the disclosure. It is therefore intended to encompass all such changes and modifications that are within the scope of this disclosure.
Example 1: Preparation of crystalline bictegravir potassium Form M1
Bictegravir (5 g) dissolved in 50 mL methanol at 55±5°C and added potassium hydroxide solution (0.68 g of potassium hydroxide dissolved in 10 mL methanol) at 55±5°C. Stirred the reaction mass for 30 minutes. The reaction mass was cooled to 25±5 °C and maintained under stirring at 25±5 °C for 30 min. The product obtained was filtered, washed with methanol (10 mL) and dried under vacuum at 50 °C for 12 hours. The solid obtained was identified as crystalline bictegravir potassium salt.
Yield:4.5g
Example 2: Preparation of crystalline bictegravir lithium Form M1
Bictegravir (5 g) dissolved in 50 mL methanol at 62±3°C and added lithium hydroxide solution (0.5 g of lithium hydroxide dissolved in 10 mL methanol) at 62±3°C. Stirred the reaction mass for 30 minutes. The reaction mass was cooled to 25±5°C and maintained under stirring at 25±5 °C for one hour. The product obtained was filtered, washed with methanol (10 mL) and dried under vacuum at 50 °C for 12 hours. The solid obtained was identified as crystalline bictegravir lithium salt.
Yield: 4.6 g
Example 3: Preparation of crystalline bictegravir cesium Form M1
Bictegravir (5 g) dissolved in 50 mL methanol at 62±3°C and added cesium hydroxide hydrate solution (1.8 g of cesium hydroxide hydrate dissolved in 10 mL methanol) at 62±3°C. Stirred the reaction mass for 30 minutes. The reaction mass was cooled to 25±5°C and maintained under stirring at 25±5 °C for 2 hours. The product obtained was filtered, washed with methanol (10 mL) and dried under vacuum at 50 °C for 18 hours. The solid obtained was identified as crystalline bictegravir cesium salt.
Yield: 5.34 g
Example 4: Preparation of crystalline bictegravir magnesium Form M1
Bictegravir (5 g) dissolved in 100 mL methanol at 47±3°C and added magnesium chloride solution (1.06 g of magnesium chloride dissolved in 10 mL methanol) at 47±3°C. Stirred the reaction mass for 30 minutes. The reaction mass was cooled to 25±5 °C and maintained under stirring at 25±5 °C for 4 hours. The product obtained was filtered, washed with methanol (5 mL) and dried under vacuum at 50 °C for 16 hours. The solid obtained was identified as crystalline bictegravir magnesium salt.
Yield: 1.20 g
Example 5: Preparation of crystalline bictegravir ammonium Form M1
Bictegravir (5 g) dissolved in 100 mL methanol at 60±5°C and added ammonia hydroxide solution (28 %) at 60±5°C. Stirred the reaction mass for 30 minutes at 60±5°C. The reaction mass was cooled to 25±5 °C and maintained under stirring at 25±5 °C for 16 hours. The product obtained was filtered, washed with methanol (5mL) and dried under vacuum at 50°C for 16 hours. The solid obtained was identified as crystalline bictegravir ammonium salt.
Yield: 1.40 g
Example 6: Preparation of crystalline bictegravir orotate Form M1
Bictegravir (5 g) dissolved in 50 mL acetone at 48±2°C and added Orotic acid solution (2 g of orotic acid dissolved in DMSO 14 mL) at 50±5°C. Stirred the reaction mass for 30 minutes at 48±2°C. The reaction mass was cooled to 25±5°C and added water (50 mL) to the reaction mass. Stirred for 12 hours. The product obtained was filtered, washed with acetone (10 mL) and dried under vacuum at 50°C for 12 hours. The solid obtained was identified as crystalline bictegravir orotate salt.
Yield: 4.0 g
Example 7: Preparation of crystalline bictegravir succinate salt:
Bictegravir (2 g) dissolved in 20 mL methanol at 62±3°C and added succinic acid solution (0.5 g of succinic acid dissolved in 5 mL methanol) at 62±3°C. Stirred the reaction mass for 15 minutes. The reaction mass was cooled to 25±5°C and maintained under stirring at 25±5 °C for 60 minutes. The product obtained was filtered, washed with methanol (5 mL) and dried at 50 °C for 3 hours. The solid obtained was identified as bictegravir succinic acid salt.
Yield: 0.9 g
Example 8: Preparation of crystalline bictegravir cinnamate salt:
Bictegravir (2 g) dissolved in 20 mL methanol at 62±3°C and added cinnamic acid solution (0.65 g of cinnamic acid dissolved in 5 ml methanol) at 62±3°C. Stirred the reaction mass for 15 minutes. The reaction mass was cooled to 25±5°C and maintained under stirring at 25±5 °C for 60 min. The product obtained was filtered, washed with methanol (5 mL) and dried at 45 °C for 3 hours. The solid obtained was identified as bictegravir cinnamic acid salt.
Yield: 0.7 g
Example 9: Preparation of crystalline bictegravir tartarate salt:
Bictegravir (2 g) dissolved in 20 ml methanol at 62±3°C and added D-(-) tartaric acid solution (0.67 g of D-(-) tartaric acid dissolved in 5 ml methanol) at 62±3°C. Stirred the reaction mass for 15 minutes. The reaction mass was cooled to 25±5°C and maintained under stirring at 25±5 °C for 60 min. The product obtained was filtered, washed with methanol (5 mL) and dried under vacuum at 45 °C for 3 hours. The solid obtained was identified as bictegravir tartarate acid salt.
Yield: 0.9 g
Example 10: Preparation of crystalline bictegravir maleate salt:
Bictegravir (2 g) dissolved in 20 mL ethanol at 62±3°C and added maleic acid (0.51 g) at 62±3°C. Stirred the reaction mass for 15 minutes. The reaction mass was cooled to 25±5°C and maintained under stirring at 25±5 °C for 30 minutes, further cool the reaction mass to 10±3°C and maintain for 60 minutes. The product obtained was filtered, washed with ethanol (5 mL) and dried under vacuum at 45 °C for 3 hours. The solid obtained was identified as bictegravir maleic acid salt.
Yield: 0.9 g
Example 11: Preparation of crystalline bictegravir camphor sulfonic acid salt:
Bictegravir (2 g) dissolved in 20 mL ethanol at 62±3°C and added D-(+)-10- camphor sulfonic acid (1.1 g) at 62±3°C. Stirred the reaction mass for 15 minutes. The reaction mass was cooled to 25±5°C and maintained under stirring at 25±5 °C for 30 min, further cool the reaction mass to 10±3°C and maintain for 60 minutes. The product obtained was filtered, washed with ethanol (5 mL) and dried under vacuum at 45 °C for 18 hours. The solid obtained was identified as Bictegravir camphor sulfonic acid salt.
Yield: 0.8 g
Example 12: Preparation of crystalline bictegravir malic acid salt:
Bictegravir (2 g) dissolved in 20 mL ethanol at 62±3°C and added L-malic acid (0.6 g) at 62±3°C. Stirred the reaction mass for 15 minutes at 62±3°C. The reaction mass was cooled to 25±5°C and maintained under stirring at 25±5 °C for 30 min, further cool the reaction mass to 10±3°C and maintain for 60 minutes. The product obtained was filtered, washed with ethanol (5 mL) and dried under vacuum at 45 °C for 18 hours. The solid obtained was identified as bictegravir malic acid salt.
Yield: 0.7g
Example 13: Preparation of crystalline bictegravir mandelic acid salt:
Bictegravir (2 g) dissolved in 20 mL ethanol at 62±3°C and added S-(+)-mandelic acid (0.7 g) at 62±3°C. Stirred the reaction mass for 15 minutes at 62±3°C. The reaction mass was cooled to 25±5°C and maintained under stirring at 25±5 °C for 18 hours. The product obtained was filtered, washed with ethanol (5 mL) and dried under vacuum at 45 °C for 18 hours. The solid obtained was identified as bictegravir mandelic acid salt.
Yield: 1.0g
Example 14: Preparation of amorphous bictegravir sodium from crystalline bictegravir sodium salt:
Bictegravir Sodium (5 g) was dissolved in a mixture of isopropyl alcohol (350 mL) and water (350 mL) at 80±2°C. The resulting clear solution was filtered to remove any undissolved particulates and subjected to spray-drying in a laboratory spray-dryer (Model: Buchi B-290) with feed rate of solution 15 mL/min and inlet temperature at 90°C with 100% aspiration to yield Bictegravir Sodium amorphous form.
Yield: 3 g.
,CLAIMS:1. A crystalline bictegravir potassium Form M1, which has a powder X-ray diffraction pattern having significant peaks at 2? angles positions at about 6.38, 9.17, 15.63 and 19.24 ± 0.2°; and characterized by a PXRD pattern as shown in Figure 1.
2. A process for the preparation of crystalline bictegravir potassium Form M1 comprising the steps of:
a) dissolving bictegravir in organic solvent at elevated temperature;
b) adding source of potassium;
c) cooling the reaction mass to 20-30 °C; and
d) isolating crystalline bictegravir potassium Form M1.
3. The process as claimed in claim 2, wherein the organic solvent is selected from alcoholic solvents such as methanol, ethanol, isopropanol or mixtures thereof; and potassium source is selected from potassium hydroxide, potassium t-butoxide, potassium methoxide, potassium carbonate and the like mixtures thereof.
4. A crystalline bictegravir lithium Form M1, which has a powder X-ray diffraction pattern having significant peaks at 2? angles positions at about 6.33, 12.76, 17.43 and 19.57 ± 0.2°; and characterized by a PXRD pattern as shown in Figure 2.
5. A process for the preparation of crystalline bictegravir lithium Form M1 comprising the steps of:
a) dissolving bictegravir in organic solvent at elevated temperature;
b) adding source of lithium;
c) cooling the reaction mass to 20-30 °C; and
d) isolating crystalline bictegravir lithium Form M1.
6. The process as claimed in claim 5, wherein the organic solvent is selected from alcoholic solvents such as methanol, ethanol, isopropanol or mixtures thereof; and lithium source is selected from lithium hydroxide, lithium carbonate, lithium methoxide and the like mixtures thereof.
7. A crystalline bictegravir cesium Form M1 which characterized by a PXRD pattern as shown in Figure 3.
8. A process for the preparation of crystalline bictegravir cesium Form M1 comprising the steps of:
a) dissolving bictegravir in organic solvent at elevated temperature;
b) adding source of lithium;
c) cooling the reaction mass to 20-30 °C; and
d) isolating crystalline bictegravir lithium Form M1.
9. The process as claimed in claim 8, wherein the organic solvent is selected from alcoholic solvents such as methanol, ethanol, isopropanol or mixtures thereof; and cesium source is selected from cesium hydroxide, cesium carbonate and the like mixtures thereof.
10. The process as claimed in above claims, wherein elevated temperature is 50-65°C.