DESC:FIELD OF THE INVENTION

The present invention is directed to process for preparation of Form II and Form III of Elvitegravir of formula-I. The present invention further relates to pharmaceutical compositions containing them, and method of treatment using the same.


BACKGROUND OF THE INVENTION

Elvitegravir is an HIV-1integrase strand transfer inhibitor (INSTI), developed by Gilead Science that is used to treat HIV-1 infection.

Elvitegravir, Tenofovir alafenamide, Emtricitabine and Cobicistat are approved in fixed dose combination tablet recently by the USFDA under brand name Genvoya for the treatment of treatment of HIV-1 infection.

Elvitegravir chemically known as 6-(3-chloro-2-fluorobenzyl)-1-[(2S)-1¬-hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxo-1,4-dihydroquinoline
-3-carboxylic acid. It has the following structural formula:

Elvitegravir and its pharmaceutically acceptable salts were first disclosed in US7176220 (Indian Family equivalent: IN245833). However, no information on solid state forms of Elvitegravir was given.

Drugs in pharmaceutical compositions can be prepared in a variety of different forms. Such drugs can be prepared so as to have a variety of different chemical forms including chemical derivatives or salts. Such drugs can also be prepared to have different physical forms. For example, the drugs may be amorphous or may have different crystalline polymorphs, perhaps existing in different solvation or hydration states. By varying the form of a drug, it is possible to vary the physical properties thereof. For example, crystalline polymorphs typically have different solubility from one another, such that a more thermodynamically stable polymorph is less soluble than a less thermodynamically stable polymorph. Pharmaceutical polymorphs can also differ in properties such as shelf-life, bioavailability, morphology, vapor pressure, density, color, and compressibility. Accordingly, variation of the solvation state of a drug is one of many ways in which to modulate the physical properties thereof.

US7635704 and US8981103 (Indian Family equivalent: IN4680/CHE/2006 and IN357/CHE/2010) discloses solid state forms Elvitegravir namely Form I, Form II and Form III and process for the preparation thereof.

WO2010137032 (Indian Family equivalent: IN1114/CHE/2009) discloses process for the preparation of Form II, Form III and amorphous form of Elvitegravir.

IN2115/CHE/2009 discloses process for the preparation of Form I, Form II, Form III and amorphous form of Elvitegravir.

CN103864682A discloses process for the preparation of Form III of Elvitegravir.

Prior art processes for preparation of Elvitegravir form II and form III do not possess desired repeatability and reproducibility of desired polymorphic purity. Hence there is a need to develop new robust process for preparation of Form II and Form III which produces desired polymorphic purity and can be used for commercial purposes.

Present invention provides novel process for the preparation of Form II and Form III of Elvitegravir. The process as disclosed herein is highly reproducible and is suitable for scale up production.

OBJECT OF THE INVENTION

In one aspect, the present invention relates to process for the preparation of crystalline Form II and Form III of Elvitegravir.

In one aspect, the present invention relates to process for the preparation of crystalline Form II of Elvitegravir comprising steps of:
i) dissolving Elvitegravir in one or more of suitable organic solvent(s) or water or mixture thereof;
ii) optionally heating the reaction mixture obtained in step (i);
iii) optionally, adding anti-solvent;
iv) isolating crystalline Form II of Elvitegravir by conventional techniques.

In one aspect, the present invention relates to process for the preparation of crystalline Form III of Elvitegravir comprising steps of:
i) dissolving Elvitegravir in one or more of suitable organic
solvent(s) or water or mixture thereof;
ii) optionally heating the reaction mixture obtained in step (i);
iii) optionally, adding anti-solvent;
iv) isolating crystalline Form III of Elvitegravir by conventional techniques.

In another aspect, the present invention provides pharmaceutical compositions comprising crystalline Form II or Form III of Elvitegravir alone or in combination with other drugs.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of crystalline Form II and Form III of Elvitegravir with improved polymorphic purity making it reliable for large scale production.

In one embodiment, the present invention relates to process for the preparation of crystalline Form II of Elvitegravir comprising steps of:
i) dissolving Elvitegravir in one or more of suitable organic
solvent (s) or water or mixture thereof;
ii) optionally heating the reaction mixture obtained in step (i);
iii) optionally, adding anti-solvent;
iv) isolating crystalline Form II of Elvitegravir by conventional techniques.

In one embodiment, the present invention relates to process for the preparation of crystalline Form III of Elvitegravir comprising steps of:
i) dissolving Elvitegravir in one or more of suitable
solvent (s) or water or mixture thereof;
ii) optionally heating the reaction mixture obtained in step (i);
iii) optionally, adding anti-solvent;
iv) isolating crystalline Form III of Elvitegravir by conventional techniques.

In another embodiment, the present invention provides pharmaceutical compositions comprising crystalline Form II or Form III of Elvitegravir alone or in combination with other drugs.

Further the present invention provides a process of preparing a pharmaceutical composition comprising crystalline Form II or Form III of Elvitegravir alone or in combination with other drugs. Conveniently the following combinations of carrier or excipient and co- precipitation medium can be employed in a process according to the present invention.

Suitable premixing agents are pharmaceutically acceptable carrier or excipients include polymers/agents used in the process for manufacturing of the premix may be selected from group of cellulose derivatives but not limited to Croscarmellose Sodium, micro crystalline cellulose, hydroxyethylcellulose(HEC), hydroxypropylcellulose(HPC), hydroxypropyl methylcellulose (HPMC), hydroxymethylethylcellulose (HEMC), ethylcellulose (EC), methylcellulose (MC), cellulose esters, cellulose glycolate, hydroxypropyl methyl cellulose phthalate, polymethylacrylate (HPMCP), hypromellose, vinylpyrrolidone monomers but not limited to polyvinylpyrrolidone and polyol but not limited to mannitol. The said polymers/agents are used to facilitate the presence of Elvitegravir.

The term "conventional techniques" as used herein includes but not limited to distillation, distillation under reduced pressure or vacuum, evaporation, solvent-antisolvent, spray drying, lyophilization or freeze drying.
The term “suitable organic solvents” and “suitable anti-solvents” as used herein includes but not limited to polar protic and aprotic solvents as well as non-polar solvents selected from water, hydrocarbons, ketones, alcohols, ethers, esters, halogenated solvents, DMSO, DMF, pyridine, phenol, DMA, carbon disulphide, acetic acid, acetonitrile and mixtures thereof.

Hydrocarbons include but not limited to such as benzene, toluene, xylene, pentane, hexane, heptane, cyclo hexane and tetraline.

Ketones include but not limited to such as acetone, methyl ethyl ketone, cyclohexanone and methyl isobutyl ketone.

Alcohols include but not limited to such as methanol, ethanol, propanol, butanol, octanol, ethanediol, 1, 2-propane diol and S (+)-1, 2-propane diol.

Ethers include but not limited to such as diethyl ether, di isopropyl ether, di butyl ether, methyl tert-butyl ether, 1,4-dioxane, tetrahydrofuran and cyclo pentyl methyl ether.

Halogenated solvents include but not limited to such as chloroform, carbon tetrachloride, methylene chloride and 1, 2-dichloro ethane.

Esters include but not limited to such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and n-propyl acetate.

The starting material “Elvitegravir” used for preparation of crystalline Form II and Form III of present invention can be prepared by the process as disclosed, e.g., in US7176220 (Indian Family equivalent: IN245833) or any other process known to the person skilled in the art. The solid state form of starting material “Elvitegravir” used for preparation of crystalline Form II and Form III of present invention can be crystalline Form I or Form II or Form III or mixture thereof or an amorphous form.

To characterize individual crystal forms of a particular compound, and/or to detect the presence of a particular form in a complex composition techniques known to those of skill in the art, such as that X-ray diffraction patterns, differential scanning calorimeter, thermograms, thermal gravimetric analyzers thermograms, melting point information, polarized light microscopy, hotstage microscopy, dynamic vapor sorption/desorption information, water content, IR spectra, NMR spectra and hygroscopicity profile to name a few are used.

The following examples are provided here to enable one skilled in the art to practice the invention and merely illustrate the process of this invention. However, it do not intended in any way to limit the scope of the present invention.

EXAMPLES

PREPARATION OF ELVITEGRAVIR FORM-II:

Example: 1
Ethyl acetate (120 ml) was charged to the crude Elvitegravir and heated to dissolve at 70-750C. N-hexane (75 ml) was added to reaction mass. The reaction mass was cooled to room temperature and stirred for 1 to 2 hours. The reaction mass was filtered and washed with Ethyl acetate: n-hexane (1:1) mixture. The product dried under vacuum at 450C for 12 hrs to get Elvitegravir form-II (37.0 g) (HPLC purity- 98.22 %)

Example: 2
Cyclohexane (90 ml) was charged to Elvitegravir (9.0 g). The reaction mass was stirred at room temperature for 3 to 4 hours. The reaction mass was filtered and washed with cyclohexane. Product was dried under vacuum at 450C for 12 hrs to get Elvitegravir form-II (8.3 g) (HPLC purity- 98.98 %)

Example: 3
Ethyl acetate (50 ml), water (2.0 ml) were charged to Elvitegravir (5.0 g) and the reaction mass was heated to reflux. The solvent was distilled out atmospherically till the remaining volume becomes approximately about 10 ml. N-hexane was added (7.5 ml) and the reaction mass was cooled to room temperature, stirred for 30 min and filtered. The product was dried under vacuum at 350C for 12 hrs to get Elvitegravir form-II (3.5 g). (HPLC purity- 99.22%).

Example: 4
Isopropyl alcohol (15 ml) was charged to Elvitegravir (3.0 g) and the reaction mass was heated to 65-700C for 30 min. The reaction mass was cooled to room temperature, stirred for 2 hours and filtered. The product was dried under vacuum at 450C for 12 hrs to get Elvitegravir form-II (2.4 g). (HPLC purity- 98.41%).

Example: 5
N-butyl acetate (15 ml) was charged to Elvitegravir (3.0 g) and the reaction mass was heated to 80-850C for 30 min. The reaction mass was cooled to room temperature, stirred for 2 hours and filtered. The product was dried under vacuum at 450C for 15 hrs to get Elvitegravir form-II (2.0 g). (HPLC purity- 98.24 %)

Example: 6
Methanol: water mixture (4:6) (30 ml) was charged to Elvitegravir (3.0 g) and the reaction mass heated to 60-650C for 30 min. The reaction mass was cooled to room temperature, stirred for 2 to 3 hours and filtered. The product dried under vacuum at 450C for 8 hrs to get Elvitegravir form-II (2.8g). (HPLC purity- 98.23 %)

Example: 7
Ethyl acetate (200 ml) was charged to Elvitegravir (100 g) and heated to dissolve at 70-750C. Cyclohexane (200 ml) was added to reaction mass and the reaction mass was cooled to room temperature and stirred for 1 to 3 hours. The reaction mass was filtered and washed with Ethyl acetate: cyclohexane (1:1) mixture. The product was dried under vacuum at 450C for 12 hrs to get Elvitegravir form-II (88.0 g) (HPLC purity- 95.72 %)

Example: 8
Ethyl acetate: cyclohexane mixture (1:2) (600 ml) was charged to Elvitegravir (100 g) and heated to 70-750C for 60 min. The reaction mass was cooled to room temperature and stirred for 2 to 3 hours. The reaction mass was filtered and washed with Ethyl acetate: cyclohexane (1:1) mixture. The product dried under vacuum at 450C for 8 hrs to get Elvitegravir form-II (94.6 g) (HPLC purity- 98.28 %)

Example: 9
Iso-Butyl acetate (15 ml) was charged to Elvitegravir (5.0 g) and the reaction mass was heated to 80-850C for 30 min. The reaction mass was cooled to room temperature, stirred for 3 hours and filtered. The product dried under vacuum at 450C for 8 hrs to get Elvitegravir form-II (3.9 g). (HPLC purity- 98.31%)

Example: 10
Iso-propyl acetate (20 ml) was charged to Elvitegravir (5.0g) and heated to dissolve at 70-750C. N-heptane (10 ml) was added to the reaction mass. The reaction mass was cooled to room temperature and stirred for 2 to 3 hours. The reaction mass was filtered and washed with iso-propyl acetate: n-heptane (1:1) mixture. The product was dried under vacuum at 450C for 15 hrs to get Elvitegravir form-II (3.2 g) (HPLC purity- 95.83 %)

Example: 11
Iso-propyl acetate (20 ml) was charged to Elvitegravir (5.0g) and heated to dissolve at 70-750C. Cyclohexane (10 ml) was added to the reaction mass. The reaction mass was cooled to room temperature and stirred for 2 to 3 hours, filtered and washed with iso-propyl acetate: cyclohexane (1:1) mixture. The product was dried under vacuum at 450C for 15 hrs to get Elvitegravir form-II (2.8 g) (HPLC purity- 97.29 %)

Example: 12
Iso-Propyl acetate (15 ml) was charged to Elvitegravir (3.0g) and heated to dissolve at 70-750C. The reaction mass was cooled to room temperature and stirred for 2 to 3 hours. The reaction mass was filtered and washed with iso-propyl acetate. The product was dried under vacuum at 450C for 17 hrs to get Elvitegravir form-II (1.2 g) (HPLC purity- 98.74 %)

Example: 13
Methyl acetate (6 ml) was charged to Elvitegravir (3.0g) and heated to dissolve at 50-550C. N-heptane (3 ml) was added to the reaction mass. The reaction mass was cooled to room temperature and stirred for 2 to 3 hours. The reaction mass was filtered and washed with methyl acetate: n-heptane (1:1) mixture. The product dried under vacuum at 450C for 12 hrs to get Elvitegravir form-II (2.0 g) (HPLC purity- 96.54 %)

PREPARATION OF ELVITEGRAVIR FORM-III:

Example: 1
Methyl ethyl ketone (12 ml) was charged Elvitegravir (Form-II) (3.0 g) and the reaction mass was heated to 80-850C for 30 min. N-heptane (12 ml) was added and maintained for 30 min. The reaction mass was cooled to room temperature, stirred for 2 to 3 hours and filtered. The product was dried under vacuum at 450C for 15 hrs to get Elvitegravir form-III (2.4 g). (HPLC purity- 98.46 %)

Example: 2
Methanol: water mixture (8:2) (30 ml) was charged to Elvitegravir (Form-II) (3.0 g). The reaction mass was heated to 60-650C for 30 min. The reaction mass was cooled to room temperature, stirred for 2 to 3 hours and filtered. The product was dried under vacuum at 450C for 8 hrs to get Elvitegravir form-III (2.6 g). (HPLC purity- 98.23 %)

Example: 3
Methanol (10 ml) was charged to Elvitegravir (Form-II) (3.0 g) and the reaction mass was heated to 60-650C for 30 min. The reaction mass was cooled to room temperature, stirred for 2 to 3 hours and filtered. The product was dried under vacuum at 450C for 15 hrs to get Elvitegravir form-III (2.3 g). (HPLC purity- 98.60 %)

Example: 4
Ethanol (10 ml) was charged to Elvitegravir (Form-II) (3.0 g) and the reaction mass was heated to 70-750C for 30 min. The reaction mass was cooled to room temperature, stirred for 2 to 3 hours and filtered. The product was dried under vacuum at 450C for 14 hrs to get Elvitegravir form-III (2.5 g). (HPLC purity- 98.35 %)

Example: 5
Acetone (10 ml) was charged to Elvitegravir (Form-II) (3.0 g) and the reaction was mass stirred at 20-250C for 10 min. N-heptane (15 ml) was added and maintained for 2 hrs. The reaction mass was filtered. The product was dried under vacuum at 450C for 12 hrs to get Elvitegravir form-III (2.1 g). (HPLC purity- 98.95 %)

Example: 6
MIBK (9 ml) was charged to Elvitegravir (Form-II) (3.0 g) and the reaction mass was heated to 50-550C for 30 min. The reaction mass was cooled to room temperature, stirred for 2 to 3 hours and filtered. The product was dried under vacuum at 450C for 14 hrs to get Elvitegravir form-III (1.7 g). (HPLC purity- 99.07 %)

Example: 7
Acetone: water mixture (6:4) (18 ml) was charged to Elvitegravir (Form-II) (3.0 g) and the reaction mass was heated to 60-650C for 30 min. The reaction mass was cooled to room temperature, stirred for 2 to 3 hours and filtered. The product was dried under vacuum at 450C for 8 hrs. to get Elvitegravir form-III (2.25 g). (HPLC purity- 99.04 %)

Example: 8
N--Propyl acetate (9 ml) was charged to Elvitegravir (Form-II) (3.0 g) and the reaction mass was heated to 85-880C for 30 min. The reaction mass was cooled to room temperature, stirred for 2 hours and filtered. The product was dried under vacuum at 450C for 15 hrs to get Elvitegravir form-III (2.0 g). (HPLC purity- 98.55 %)

Example: 9
Ethyl acetate (135 ml) was charged to Elvitegravir (45 g) and the reaction mass was heated to 75-800C for 60 min. The reaction mass was cooled to room temperature, stirred for 2 hours and filtered. The product was dried under vacuum at 450C for 14 hrs to get Elvitegravir form-III (27.7 g). (HPLC purity- 98.58 %)

Dated this 04th October 2018


,CLAIMS:WE CLAIM:

1. A process for preparation of crystalline Form II of Elvitegravir comprising the steps of:
(i) reacting Elvitegravir in one or more solvent(s) selected from ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, isopropyl acetate, methyl acetate, water, methanol, n-hexane, n-heptane, cyclo hexane to form reaction mixture;
(ii) optionally heating the reaction mixture obtained in step (i);
(iii) optionally adding anti-solvent;
(iv) isolating crystalline Form II of Elvitegravir.
2. The process as claimed in step (ii) of claim 1 wherein heating of reaction mixture is carried out within the temperature range of 40-100oC or reflux temperature.
3. The process as claimed in step (iii) of claim 1 wherein anti-solvent is selected from ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, isopropyl acetate, methyl acetate, water, methanol, n-hexane, n-heptane and cyclo hexane.
4. A process for preparation of crystalline Form III of Elvitegravir comprising the steps of:
(i) reacting Elvitegravir in one or more solvent(s) selected from methyl ethyl ketone, methanol, ethanol, acetone, methyl isobutyl ketone, n-propyl acetate, water, n-hexane, n-heptane, cyclo hexane to form reaction mixture;
(ii) optionally heating the reaction mixture obtained in step (i);
(iii) optionally adding anti-solvent;
(iv) isolating crystalline Form III of Elvitegravir.
5. The process as claimed in step (ii) of claim 4 wherein the heating of reaction mixture is carried out within the temperature range of 40-100oC or reflux temperature.
6. The process as claimed in step (iii) of claim 4 wherein anti-solvent is selected from methyl ethyl ketone, methanol, ethanol, acetone, methyl isobutyl ketone, n-propyl acetate, water, n-hexane, n-heptane and cyclo hexane.

Dated this 04th October 2018