Related Application:

This application claims priority to our Indian patent application 202041040660 filed on September 19, 2020 the disclosure of which is incorporated herein by reference in its entirety.

Field of the Invention:

The present invention relates to a novel crystalline polymorph of Bictegravir sodium represented by the following structural formula- la and process for preparation thereof.

Formula- 1 a

Background of the Invention:

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]p yrazino[2,l-b][l,3]oxazepin-8- olate, commonly known as Bictegravir sodium is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI).

Bictegravir sodium is approved by USFDA on Feb 7, 2018 and sold under the brand name BIKTARVY.

BIKTARVY is a three-drug combination of Bictegravir sodium (BIC), a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI), Emtricitabine (FTC) and Tenofovir alafenamide (TAF), both HIV-1 nucleoside analog reverse transcriptase inhibitors (NRTIs), and is indicated as a complete regimen for the treatment of HIV- 1 infection in adults who have no antiretroviral treatment history. US9216996B2, US9732092B2 & US9708342B2 describes Bictegravir sodium, its analogs and process for preparation thereof.

US9708342B2 describes crystalline form -I of Bictegravir sodium and process for preparation thereof.

WO2019154634A1 describes crystalline form- II and 2,2,2-trifluoroethanol solvate form of Bictegravir sodium and process for preparation thereof.

WO2019207602 Al describes amorphous form, amorphous solid dispersion of Bictegravir sodium and processes for preparation thereof.

W02020003151A1 describes crystalline form HN-1 of Bictegravir sodium and process for preparation thereof.

WO2020161744A1 describes crystalline forms C2, C3, C4, C5, C6, C7, C8 and C9 of Bictegravir sodium and processes for preparation thereof.

Still, there is a significant need in the art to develop a novel polymorph of Bictegravir sodium which is suitable for the preparation of various pharmaceutical compositions.

The present inventors after significant efforts have surprisingly found a novel crystalline polymorph of Bictegravir sodium which is useful for the preparation of various pharmaceutical compositions.

Brief description of the invention:

The first embodiment of the present invention is to provide a novel crystalline polymorph of Bictegravir sodium, which is herein designated as form-N.

The second embodiment of the present invention is to provide a process for the preparation of crystalline form-N of Bictegravir sodium.

Brief Description of the Drawings:

Figure- 1: Illustrates the PXRD (powder X-Ray diffraction) pattern of crystalline form-N of Bictegravir sodium

Figure-2: Illustrates the PXRD pattern of (2R,5S,13aR)-8-(benzyloxy)-7,9-dioxo- 2,3,4,5,7,9,13,13a-octa hydro-2, 5-methanopyrido[ l',2':4, 5]pyrazino[2,l -b][l, 3]oxazepine-10- carboxylic acid obtained as per the process of example-2 Figure-3: Illustrates the PXRD pattern of (2R,5S,13aR)-8-(benzyloxy)-7,9-dioxo-N-(2,4,6- trifluoro benzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[T,2': 4,5]pyrazino[2,l- b][l,3] oxazepine-10-carboxamide obtained as per the process of example-3

Figure-4: Illustrates the PXRD pattern of lithium (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 obtained as per the process of example-4

Figure-5: Illustrates the PXRD pattern of Bictegravir sodium obtained as per the process of example-5.

Detailed description of the Invention:

The first embodiment of the present invention provides a novel crystalline polymorph of Bictegravir sodium, which is herein designated as crystalline form-N. The crystalline form-N of Bictegravir sodium of the present invention is characterized by its PXRD pattern having peak at 6.9 ± 0.2° of 2-theta. The crystalline form-N of Bictegravir sodium of the present invention is further characterized by its PXRD pattern having peaks at 10.3, 13.8, 17.2 and 20.7 ± 0.2° of 2-theta.

The crystalline form-N of Bictegravir sodium of the present invention is further characterized by its PXRD pattern as illustrated in figure- 1.

The second embodiment of the present invention provides a process for the preparation of crystalline form-N of Bictegravir sodium, comprising: a) providing a solution of sodium hydroxide in a first solvent, b) combining the solution of step-a) with a solution of Bictegravir of formula- 1 in a second solvent to obtain crystalline form-N of Bictegravir sodium.

In the first aspect of the second embodiment of the present invention, a solution of sodium hydroxide in a first solvent is prepared by combining sodium hydroxide with the first solvent at a temperature ranging from about 0°C to about 30°C and optionally heating the reaction mixture to a temperature ranging from about 30°C to about 60°C or reflux temperature based on the solvent used. In the second aspect of the second embodiment of the present invention, a solution of Bictegravir in a second solvent is provided by combining Bictegravir with the second solvent at a temperature ranging from about 0°C to about 30°C and optionally heating the reaction mixture to a temperature ranging from about 30°C to about 100°C or to about the reflux temperature based on the solvent used.

In the third aspect of the second embodiment of the present invention, the first solvent is methanol/water mixture and the second solvent is selected from chlorobenzene and dichlorobenzene.

In the above described process, after combining the solution of step-a) with a solution of Bictegravir in a second solvent, the resulting mixture can be stirred for about 15 min to about 3 hr at about 25-30°C.

In the fourth aspect of the second embodiment of the present invention, a solution of sodium hydroxide in a first solvent can be a solution of sodium hydroxide in methanol/water mixture.

In the fifth aspect of the second embodiment of the present invention, the sodium hydroxide solution in step(a) may be prepared by combining sodium hydroxide with a mixture of methanol and water.

In the sixth aspect of the second embodiment of the present invention, the sodium hydroxide solution in step(a) may be prepared by combining aqueous sodium hydroxide solution with methanol.

In the seventh aspect of the second embodiment of the present invention, the sodium hydroxide solution in step(a) may be prepared by combining a solution of sodium hydroxide in methanol with water.

In the eighth aspect of the second embodiment of the present invention, the sodium hydroxide solution in step(a) may be prepared for example by adding 10 gm of sodium hydroxide to 100 ml of aqueous methanol which contains 95 ml of water and 5 ml of methanol. From this solution, the required amount of sodium hydroxide solution can be taken for the preparation of crystalline form-N of compound of formula- 1 a of the present invention. For instance, 1.2 ml of said solution is used for 600 mg of Bictegravir in example-6 and 0.8 ml of said solution is used for 400 mg of Bictegravir in example-7. Bictegravir which is used as an input in the above described process has the following structural formula- 1 and it can be synthesized by any of the processes known in the art or it can be synthesized by the process of the present invention.

The crystalline form-N of Bictegravir sodium of formula- la of the present invention is useful as an input for preparing any of the known polymorphic forms of compound of formula- 1 a.

The novel crystalline form-N of compound of formula- la of the present invention is useful for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used where at least a portion of compound of formula- la is present in the composition in particular polymorphic form mentioned.

The third embodiment of the present invention provides the use of crystalline form-N of compound of formula- la of the present invention for the preparation of pharmaceutical formulations.

The fourth embodiment of the present invention provides a pharmaceutical composition comprising crystalline form-N of Bictegravir sodium of formula- la and one or more pharmaceutically acceptable excipients.

The “excipient” is selected from but not limited to polyvinylpyrrolidone (povidone or PVP), polyvinylpolypyrrolidone, polysorbate, copovidone, cross linked polyvinyl pyrrolidone (crospovidone), polyethylene glycol (macrogol or PEG), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethylethyl cellulose (CMEC), ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropyl methyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxyethyl methyl cellulose succinate (HEMCS), hydroxypropyl cellulose acetate succinate (HPCAS), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropyl methylcellulose acetate phthalate, microcrystalline cellulose (MCC), cross linked sodium carboxymethyl cellulose (croscarmellose sodium), cross linked calcium carboxymethyl cellulose, magnesium stearate, aluminium stearate, calcium stearate, magnesium carbonate, talc, iron oxide (red, yellow, black), stearic acid, dextrates, dextrin, dextrose, sucrose, glucose, xylitol, lactitol, sorbitol, mannitol, maltitol, maltose, raffinose, fructose, maltodextrin, anhydrous lactose, lactose monohydrate, starches such as maize starch or corn starch, sodium starch glycolate, sodium carboxymethyl starch, pregelatinized starch, gelatin, sodium dodecyl sulfate, edetate disodium, sodium phosphate, sodium lauryl sulfate, triacetin, sucralose, calcium phosphate, poly dextrose, a-, P-, y-cyclodex trins, sulfobutylether beta-cyclodextrin, sodium stearyl fumarate, fumaric acid, alginic acid, sodium alginate, propylene glycol alginate, citric acid, succinic acid, carbomer, docusate sodium, glyceryl behenate, glyceryl stearate, meglumine, arginine, polyethylene oxide, polyvinyl acetate phthalates and the like.

The fifth embodiment of the present invention provides a method of treating a patient in need thereof comprising administering to the said patient a therapeutically effective amount of crystalline form-N of Bictegravir sodium of formula- la of the present invention.

The crystalline form-N of compound of formula- la produced by the process of the present invention is having particle size distribution of D90 less than about 400 pm or less than about 300 pm or less than about 200 pm or less than about 100 pm or less than about 50 pm or any other suitable particle sizes.

The compound of formula- la produced by the process of the present invention can be further micronized or milled to get desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction includes but not limited to single or multi-stage micronization using cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills. Milling/micronization may be performed before drying or after drying of the product. P-XRD Method of Analysis:

The PXRD analysis of compounds of the present invention was carried out by using BRUKER/D8 ADVANCE diffractometer using CuKa radiation of wavelength 1.5406A ⁰ and at a continuous scan speed of 0.037min.

The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.

Examples:

Example-1: Purification of 5-ethyl 2-methyl 3-(benzyloxy)-l-(2,2-dimethoxyethyl)-4- oxo-1 ,4-dihy dropyridine-2,5 -dicarboxylate

A mixture of 5-ethyl 2-methyl 3-(benzyloxy)-l-(2,2-dimethoxyethyl)-4-oxo-l,4- dihydropyridine-2,5-dicarboxylate (100 gm), cyclohexane (400 ml) and ethyl acetate (100 ml) was heated to 60-65 °C and stirred for 2 hr at the same temperature. Cooled the mixture to 10- 15 °C and stirred for 4 hr at the same temperature. Water was added to the mixture at 10- 15 °C and stirred for 30 min at the same temperature. Filtered the solid, washed with cyclohexane and suck dried. Ethyl acetate (50 ml) and methyl tert. butyl ether (100 ml) were added to the obtained compound at 25-30°C. Cooled the mixture to -10°C to -5°C and stirred for 4 hr at the same temperature. Filtered the solid, washed with methyl tert.butyl ether and dried the material to get the title compound.

Yield: 57.1 gm.

Example-2: Preparation of (2R,5S,13aR)-8-(benzyloxy)-7,9-dioxo-2,3,4,5,7,9,13,13a-octa hydro-2, 5-methanopyrido[l',2':4,5]pyrazino[2,l-b][l,3]oxazepine-10-c arboxylic acid

A pre-cooled aqueous sulfuric acid solution (13.3 ml of sulfuric acid in 7.7 ml of water at 0-5°C) was slowly added to a mixture of 5-ethyl 2-methyl 3-(benzyloxy)-l-(2,2- dimethoxyethyl)-4-oxo-l,4-dihydropyridine-2,5-dicarboxylate (70 gm) and formic acid (210 ml) at 25-30°C and stirred the reaction mixture for 7 hr at the same temperature. Cooled the reaction mixture to 0-5 °C and aqueous sodium chloride solution was slowly added drop wise to it. Raised the temperature of the reaction mixture to 25-30°C and stirred for 15 min at the same temperature. Dichloromethane was added to the reaction mixture and stirred for 15 min. Both the organic and aqueous layers were separated and extracted the aqueous layer with dichloromethane. Combined the organic layers and washed with water. (lR,3S)-3- aminocyclopentanol hydrochloride (24.8 gm) followed by potassium acetate (29.48 gm) were added to the organic layer 25-30°C under nitrogen atmosphere and stirred the reaction mixture for 24 hr at the same temperature. Water was added to the reaction mixture at 25- 30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer with dichloromethane. Combined the organic layers and washed with water. Distilled off the solvent from the organic layer and co-distilled with methanol. Methanol (168 ml) was added to the obtained compound at 25-30°C and stirred the mixture for 4 hr at the same temperature. Filtered the mixture and washed with aqueous methanol. Cooled the filtrate to 5-10°C, aqueous sodium hydroxide solution (8.01 gm of sodium hydroxide in 154 ml of water) was slowly added to it. Raised the temperature of the reaction mixture to 25-30°C and stirred for 3 hr at the same temperature. Dichloromethane was slowly added to the reaction mixture. Slowly acidified the reaction mixture by using aqueous acetic acid solution at 5-10°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated and washed the organic layer with water. Distilled off the solvent completely from the organic layer under reduced pressure. Methyl tert.butyl ether (175 ml) was added to the obtained compound at 25-30°C and stirred for 90 min at the same temperature. Filtered the compound and washed with methyl tert-butyl ether. Dimethylsulfoxide (105 ml) was added to the obtained compound at 25-30°C. Heated the mixture to 60-65°C and stirred for 1 hr at the same temperature. Filtered the mixture and washed with dimethyl sulfoxide. Tertiary butyl amine (12.81 gm) was added to the filtrate at 25-30°C and stirred for 6 hr at the same temperature. Cooled the reaction mixture to 20-25°C and stirred for 90 min at the same temperature. Filtered the compound and washed with methyl tert.butyl ether. Dichloromethane (350 ml) and water (210 ml) were added to the obtained compound at 25-30°C and stirred for 10 min at the same temperature. Cooled the reaction mixture to 5-10°C and slowly acidified it by using aqueous acetic acid solution. Raised the temperature of the reaction mixture to 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer with dichloromethane. Combined the organic layers and washed with water. Distilled off the solvent from the organic layer under reduced pressure. Methyl tert.butyl ether (210 ml) was added to the obtained compound at 25-30°C and stirred the mixture for 3 hr at the same temperature. Filtered the solid, washed with methyl tert.butyl ether and dried to get the title compound. The PXRD pattern of the obtained compound is shown in figure-2.

Yield: 20 gm. Example-3: Preparation of (2R,5S,13aR)-8-(benzyloxy)-7,9-dioxo-N-(2,4,6-trifluoro benzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[l',2' :4,5]pyrazino[2,l-b][l,3] oxazepine-10-carboxamide

Carbonyldiimidazole (51.08 gm) was added to a mixture of (2R,5S,13aR)-8- (benzyloxy)-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-metha nopyrido[l',2':4,5]pyrazino [2,l-b][l,3]oxazepine-10-carboxylic acid (50 gm) and dichloromethane (500 ml) at 25-30°C and stirred the reaction mixture for 4 hr at the same temperature. Cooled the reaction mixture to -40°C to -35°C, a solution of 2,4,6-trifhiorobenzylamine (37.06 gm) in dichloromethane (100 ml) was slowly added to it and stirred the reaction mixture for 45 min at the same temperature. Water was added to the reaction mixture at -40°C to -35°C. Raised the temperature of the reaction mixture to 25-30°C, water was added to it and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and washed the organic layer with aqueous ammonia solution followed by with water. Distilled off the solvent from the organic layer under reduced pressure and co-distilled with methanol. Methanol (350 ml) was added to the obtained compound at 25-30°C. Heated the mixture to 60-65°C and stirred for 90 min at the same temperature. Cooled the mixture to 25-30°C and stirred for 3 hr at the same temperature. Filtered the compound and washed with methanol. Dimethylsulfoxide (225 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 90-95°C and stirred for 1 hr at the same temperature. Cooled the mixture to 25-30°C and stirred for 4 hr at the same temperature. Filtered the compound, washed with methanol and suck dried. Dimethylsulfoxide (200 ml) was added to the obtained compound at 25-30°C. Heated the mixture to 90-95°C and stirred for 1 hr at the same temperature. Cooled the mixture to 25-30°C and stirred for 4 hr at the same temperature. Filtered the compound, washed with methanol and suck dried. Dimethylsulfoxide (175 ml) was added to the obtained compound at 25-30°C. Heated the mixture to 90-95°C and stirred for 1 hr at the same temperature. Cooled the mixture to 25-30°C and stirred for 4 hr at the same temperature. Filtered the solid, washed with methanol and dried to get the title compound. The PXRD pattern of the obtained compound is shown in figure-3.

Yield: 41.0 gm. Example-4: Preparation of lithium (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

Lithium chloride (9.82 gm) was added to a mixture of (2R,5S,13aR)-8-(benzyloxy)- 7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octah ydro-2,5-methanopyrido [r,2':4,5]pyrazino[2,l-b][l,3]oxazepine-10-carboxamide (25 gm), tetrahydrofuran (125 ml) and isopropyl alcohol (50 ml) at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 15 hr at the same temperature. Cooled the reaction mixture to 25-30°C, water was slowly added to it and stirred for 3 hr at the same temperature. Filtered the solid and washed with isopropyl alcohol. Dichloromethane (125 ml) and water (125 ml) were added to the obtained compound at 25-30°C and cooled the reaction mixture to 5-10°C. Acidified the reaction mixture by using aqueous acetic acid solution at 5 -KFC and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer with dichloromethane. Combined the organic layers and washed with aqueous sodium bicarbonate solution followed by with water. Distilled off the solvent from the organic layer and methanol (125 ml) was added to the obtained compound at 25-30°C. Heated the mixture to 60-65°C, mono ethylene glycol (7.5 ml) was added to it and stirred for 1 hr at the same temperature. Cooled the mixture to 25-30°C and stirred for 2 hr at the same temperature. Filtered the compound and washed with methanol. Methanol (125 ml) was added to the obtained compound at 25-30°C. Aqueous lithium hydroxide solution (2.13 gm of lithium hydroxide hydrate in 125 ml of water) was slowly added to the reaction mixture at 25-30°C and stirred for 4 hr at the same temperature. Filtered the solid, washed with methanol and dried the material to get the title compound.

The PXRD pattern of the obtained compound is shown in figure-4. Yield: 12.75 gm.

Example-5: Preparation of Bictegravir sodium

A mixture of lithium (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]pyr azino[2,l-b] [l,3]oxazepin-8- olate (94 gm), dichloromethane (470 ml) and water (470 ml) was cooled to 5-10°C. Aqueous acetic acid solution was added to the reaction mixture at 5-10°C and stirred for 20 min at the same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer with dichloromethane. Combined the organic layers and washed with aqueous sodium bicarbonate solution followed by with water. Distilled off the solvent from the organic layer and co-distilled with chlorobenzene. To the obtained Bictegravir compound of formula- 1, chlorobenzene (940 ml) was added at 25-30°C and stirred the mixture for 15 min at the same temperature. Heated the mixture to 60-65°C and stirred for 2 hr at the same temperature. Filtered the solution to make it particle free and washed with chlorobenzene. A solution of sodium hydroxide (9.08 gm) in methanol (9.4 ml) and water (188 ml) was slowly added to the filtrate at 25-30°C and stirred the reaction mixture for 3 hr at the same temperature. Filtered the solid, washed with chlorobenzene and dried to get the title compound. The PXRD pattern of the obtained compound is shown in figure-5.

Yield: 86 gm.

Example-6: Preparation of crystalline form-N of Bictegravir sodium

Added 10 gm of sodium hydroxide to a mixture of 95 ml of water and 5 ml of methanol and stirred for dissolution of sodium hydroxide. About 1.2 ml of the resulting solution is taken and added to a solution of Bictegravir compound of formula- 1 (600 mg) in dichlorobenzene (10 ml) at 25-30°C and the mixture was stirred for 2 hr at the same temperature. Filtered the precipitated solid and dried to get the title compound.

The PXRD pattern of the obtained compound is shown in figure- 1. Yield: 400 mg.

Example-7: Preparation of crystalline form-N of Bictegravir sodium

0.8 ml of the sodium hydroxide solution prepared according to example-6 above was added to a solution of Bictegravir compound of formula- 1 (400 mg) in chlorobenzene (10 ml) at 25-30°C and stirred the mixture for 2 hr and 30 min at the same temperature. Filtered the precipitated solid and dried to get the title compound.

The PXRD pattern of the obtained compound is similar to figure- 1.

Yield: 300 mg.