This application claims priority to Indian patent application No. 2115/CHE/2009 filed on September 01, 2009, the contents of which are incorporated by reference in their entirety

FIELD OF THE INVENTION

The present invention relates to processes for the preparation of amorphous Elvitegravir ,crystalline Elvitegravir Form I, II & III.

BACKGROUND OF THE INVENTION

Elvitegravir is structurally represented by the compound of formula I and is indicated for the potential treatment of HIV infection.

Elvitegravir is first disclosed in US Patent No 7176220. Thasrsaid patent disclosed Elvitegravir, process for preparation, pharmaceutically acceptable salts, pharmaceutical composition containing them and their method of treatment. International Patent Applications WO 2005113508 and WO 2007148780 disclosed the process for the preparation of Elvitegravir analogs.

US 7635704 disclosed Elvitegravir Form I, Form II and Form III and processes for their preparation. Process for the preparation of Form I disclosed in this patent is by dissolving Elvitegravir in methanol followed by addition of water as an anti solvent. The processes for the preparation of Form II disclosed in the said patent include dissolution followed by isolation,or anti-solvents addition.

The process for the preparation of Form III includes dissolution of Form II in isobutyl acetate by heating followed by cooling the reaction mass thus precipitating the solid. The other process for making Form III include seeding with Form III obtained through above process. Another method for the preparation which includes dissolving Form II in 2-propanol followed by seeding with Form III.

OBJECT OF THE INVENTION

The main object of the present invention is to provide processes for the preparation of amorphous Elvitegravir and crystalline Elvitegravir Form I, 11 & III.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a process for the preparation of amorphous Elvitegravir comprising the steps of dissolving Elvitegravir in an organic solvent, adding to an anti-solvent and isolating amorphous form of Elvitegravir.

In another aspect, the present invention provides a process for preparation of amorphous Elvitegravir by forming a melt by heating the Elvitegravir followed by cooling the melt to form amorphous Elvitegravir.

Yet another aspect, the present invention provides a process for the preparation of amorphous Elvitegravir comprising the steps of dissolving Elvitegravir in an organic solvent, removing the solvent to obtain amorphous form of Elvitegravir.

Yet another aspect, the present invention provides a process for the preparation of crystalline Form I of Elvitegravir comprising the steps of dissolving Elvitegravir in an organic solvent, adding anti- solvent and isolating crystalline Form I of Elvitegravir.

Yet another aspect, the present invention provides a process for the preparation of crystalline Form II of Elvitegravir comprising the steps of dissolving Elvitegravir in an organic solvent, adding anti- solvent and isolating crystalline Form II of Elvitegravir.

Yet another aspect, the present invention provides a process for the preparation of crystalline Form III of Elvitegravir comprising the steps of dissolving Elvitegravir in an organic solvent, adding anti-solvent and isolating crystalline Form III of Elvitegravir.

Yet another aspect, the present invention provides a process for the preparation of crystalline Form III of Elvitegravir comprising the steps of dissolving Elvitegravir in an organic solvent, cooling the resultant solution and isolating crystalline Form III of Elvitegravir.

Yet another aspect, the present invention provides a process for the preparation of crystalline Form III of Elvitegravir comprising the steps of dissolving Elvitegravir in an organic solvent, followed by removing the solvent to obtain crystalline Form III of Elvitegravir.

Yet another aspect, the present invention provides a process for the preparation of crystalline Form III of Elvitegravir comprising the steps of dissolving Elvitegravir in an organic solvent, followed by agitation at ambient temperature for several days to obtain crystalline Form III of Elvitegravir.

Yet another aspect of the present invention also provides pharmaceutical compositions comprising crystalline of amorphous Elvitegravir and salt so prepared and an excipient/carrier, known in the art.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a representative X-ray diffraction pattern of amorphous form of Elvitegravir FIG. 2 is a representative X-ray diffraction pattern of crystalline Form I of Elvitegravir FIG. 3 is a representative X-ray diffraction pattern of crystalline Form 11 of Elvitegravir FIG. 4 is a representative X-ray diffraction pattern of crystalline Form III of Elvitegravir

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the processes for the amorphous Elvitegravir. The present invention also encompasses processes for the preparation of Elvitegravir Form I, Form II and Form III.

In one embodiment, the present invention provides a process for the preparation of amorphous Elvitegravir comprising the steps of:

a) dissolving Elvitegravir in an organic solvent;
b) adding to an anti-solvent; and
c) isolating amorphous Elvitegravir.

According to the present invention, Elvitegravir is dissolved in an organic solvent such as N,N-dimethylformamide, dimethylsulfoxide, A/-methylpyrrolidone, acetic acid, formic acid, N,N-dimethylacetamide, 2-methoxyethanol. The resultant solution is added to an anti-solvent such as water, thus isolating amorphous form of Elvitegravir.

In another embodiment, the present invention provides a process for preparation of amorphous Elvitegravir comprising the steps of:

a) heating the Elvitegravir to higher temperature to form a melt;
b) cooling the melt; and
c) isolating the amorphous Elvitegravir.

According to the present invention, Elvitegravir is heated to 150-160°C to form a melt followed by cooling the obtained melt and isolating the amorphous Elvitegravir.

Yet another embodiment, the present invention provides a process for the preparation of amorphous Elvitegravir comprising the steps of:

a) dissolving Elvitegravir in an organic solvent; and
b) removing the solvent to obtain amorphous form of Elvitegravir.

According to the present invention, Elvitegravir is dissolved in an organic solvent such as acetone followed by removal of solvent using conventional techniques such as distillation, freeze drying, spray drying or agitated thin film drier (ATFD) and thus isolating amorphous form of Elvitegravir.

In further embodiment, the present invention provides an amorphous form of Elvitegravir, having an X-ray powder diffraction pattern as shown in Fig. 1.

Yet another embodiment, the present invention provides a process for the preparation of crystalline Form I of Elvitegravir comprising the steps of:

a) dissolving Elvitegravir in an organic solvent;
b) adding anti-solvent; and
c) isolating crystalline Form I of Elvitegravir.

According to the present invention, Elvitegravir is dissolved in an organic solvent such as nitromethane, dichloromethane. To the resultant solution, anti-solvent is added and thus isolating crystalline Form I of Elvitegravir. The anti-solvent is selected from isopropyl ether, diethylether or methyl t-butylether.
In yet another embodiment of the present invention, the crystalline Form I of Elvitegravir prepared according to the above method, have an X-ray powder diffraction pattern with peaks at 6.61, 14.46, 14.71, 15.28, 16.55, 21.23, 25.30, 25.72 and 26.14 ± 0.2 two theta, shown in Fig.2

In yet another embodiment, the present invention provides a process for the preparation of crystalline Form II of Elvitegravir comprising the steps of:

a) dissolving Elvitegravir in an organic solvent;
b) adding anti-solvent; and
c) isolating crystalline Form II of Elvitegravir.

According to the present invention, Elvitegravir is dissolved in an organic solvent such as acetone, acetic acid, 2-methoxyethanol, n-propanol, 1, 4-dioxane. To the resultant solution was added anti-solvent thus isolating crystalline Form II of Elvitegravir. The anti-solvent is selected from isopropyl ether, hexane, cyclohexane or heptane.

In yet another embodiment of the present invention, the crystalline Form II of Elvitegravir prepared according to the above method, have an X-ray powder diffraction pattern with peaks at 6.66, 9.21, 13.31, 14.82, 15.42, 16.70, 19.99, 21.05, 21.39, 25.42, 26.30 and 27.51 ± 0.2 two theta, shown in Fig.3

In yet another embodiment, the present invention provides a process for the preparation of crystalline Form III of Elvitegravir comprising the steps of:

a) dissolving Elvitegravir in an organic solvent;
b) adding anti-solvent; and
c) isolating crystalline Form III of Elvitegravir.

According to the present invention, Elvitegravir is dissolved in an organic solvent selected from acetone, ethylacetate or mixtures thereof. To the resultant solution an anti-solvent was added thus isolating crystalline Form III of Elvitegravir. The anti-solvent selected from isopropyl ether, hexane, cyclohexane or heptane.

In yet another embodiment, the present invention provides a process for the preparation of crystalline Form III of Elvitegravir comprising the steps of:

a) dissolving Elvitegravir in an organic solvent;
b) leaving the solution for crystallization; and
c) Isolating the Form III of Elvitegravir.

According to the present invention, Elvitegravir is dissolved in an organic solvent such as ethyl acetate or acetonitrile and resulting solution is left for 2-6 hrs under agitation at ambient temperature to obtain the crystalline form III of Elvitegravir.
In another embodiment, the present invention provides a process for the preparation of Form III of Elvitegravir comprising the steps of:

a) dissolving Elvitegravir in an organic solvent;
b) evaporating the solvent at 25-30°C; and
c) isolating the Form III of Elvitegravir.

According to the present invention, Elvitegravir is dissolved in an organic solvent such as ethyl acetate followed by aerial evaporation of the solvent at 25-30''C for several hours and thus isolating Form III of Elvitegravir.

In yet another embodiment of the present invention, the crystalline Form III of Elvitegravir prepared according to the above method, have an X-ray powder diffraction pattern with peaks at 8.55, 14.05, 15.68, 17.06, 17.25, 17.85, 19.52, 22.26, 24.19 and 25.74 ± 2 theta, shown in Fig. 4

In yet another embodiment, the invention is further directed to pharmaceutical composition comprising; (a) a therapeutically effective amount of crystalline or amorphous Elvitegravir or salt thereof of the present invention; and (b) at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient.

The term "pharmaceutical composition" as used herein refers to dosage form for oral administration in the form of tablets, capsules, pills, powders, granules, particles, pellets, beads, or mini-tablets. Preferred dosage forms are tablets or capsules.

The excipients included in the composition are those which are customary and known to a person skilled in the art. These include without any limitations, diluents, fillers, binders, disintegrants, surfactants, stabilizers, glidants, lubricants etc.

The tablets or capsules can be prepared by any conventional processes known to a person skilled in the art.

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the in any way.

Elvitegravir used in the present invention is selected from the group consisting of but not limited to crystalline and amorphous Elvitegravir.

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way.

EXPERIMENTAL SECTION

Powder X-ray Diffraction (PXRD)

The X-ray diffraction patterns of said polymorphs of the invention were measured on Bruker D8 Discover powder diffractometer equipped with goniometer of 6/6 configuration and LynxEye detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 29 range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.

Preparation of amorphous Elvitegravir

Example 1:
Elvitegravir (0.5 g) was dissolved in /V.AZ-dimethylformamide (3 mL) at 25-30°C. The solution was filtered to remove the undisclosed particulate material. The clear solution was then added to water (30 mL) and stirred for 1-3 hrs at 25-30°C. The solid obtained was filtered and identified as amorphous Elvitegravir.

Example 2:
Elvitegravir (0.5 g) was dissolved in dimethylsulfoxide (3 mL) at 25-30°C. The solution was filtered to remove the undissolved particulate material. The clear solution was then added to water (30 mL) and stirred for 1-3 hrs at 25-30°C. The solid obtained was filtered and identified as amorphous Elvitegravir.

Example 3:
Elvitegravir (0.5 g) was dissolved in A/-methylpyrrolidine (3 mL) at 25-30°C. The solution was filtered to remove the undissolved particulate material. The clear solution was then added to water (30 mL) and stirred for 1-3 hrs at 25-30°C. The solid obtained was filtered and identified as amorphous Elvitegravir.

Example 4:
Elvitegravir (0.5 g) was dissolved in acetic acid (3 mL) at 25-30°C. The solution was filtered to remove the undissolved particulate material. The clear solution was then added to water (30 mL) and stirred for 1-3 hrs at 25-30°C. The solid obtained was filtered and identified as amorphous Elvitegravir.

Example 5:
Elvitegravir (0.5 g) was dissolved in formic acid (3 mL) at 25-30°C. The solution was filtered to remove the undissolved particulate material. The clear solution was then added to water (30 mL) and stirred for 1-3 hrs at 25-30°C. The solid obtained was filtered and identified as amorphous Elvitegravir.

Example 6:
Elvitegravir (0.5 g) was dissolved in A/,A/-dimethylacetamide (3 mL) at 25-30°C. The solution was filtered to remove the undissolved particulate material. The clear solution was then added to water (30 mL) and stirred for 1-3 hrs at 25-30°C. The solid obtained was filtered and identified as amorphous Elvitegravir.

Example 7:
Elvitegravir (0.5 g) was dissolved in 2-methoxyethanol (3 mL) at 25-30°C. The solution was filtered to remove the undissolved particulate material. The clear solution was then added to water (30 mL) and stirred for 1-3 hrs at 25-30°C. The solid obtained was filtered and identified as amorphous Elvitegravir.

Example 8:
Elvitegravir (0.5 g) was heated to 150-160°C for about 5-10 minutes to form a melt. The resulting melt was then slowly cooled to 25-30°C. The obtained solid was identified as amorphous Elvitegravir.

Example 9:
Elvitegravir (0.5 g) was dissolved in acetone (15 mL) at 25-30°C and stirred for 10 minutes. Tiie clear solution was then distilled out completely under vacuum at 40-5G°C. The solid obtained was isolated and identified as amorphous Elvitegravir.

Preparation of Elvitegravir Form I

Example 10:
Elvitegravir (0.5 g) was dissolved in nitromethane (2 mL) at 25-30°C. To the clear solution, Isopropyl ether (IPE) (20 mL) was added and stirred for 3-5 hrs at 25-30°C. The solid obtained was filtered and identified as crystalline Elvitegravir Form I.

Example 11:
Elvitegravir (0.5 g) was dissolved in dichloromethane (2 mL) at 25-30°C. To the clear solution, IPE (10 mL) was added and stirred for 3-5 hrs at 25-30°C. The solid obtained was filtered and identified as crystalline Elvitegravir Form I.

Preparation of Elvitegravir Form II

Example 12:
Elvitegravir (1 g) was dissolved in acetone (4 mL) at 25-30°C. To the clear solution, IPE (40 mL) was added and stirred for 18 hrs at 25-30°C. The solid obtained was filtered and identified as crystalline Elvitegravir Form II.

Example 13:
Elvitegravir (0.5 g) was dissolved in acetic acid (2 mL) at 25-30°C. To the clear solution, IPE (50 mL) was added and for 5 hrs at 25-30°C. The solid obtained was filtered and identified as crystalline Elvitegravir Form II.

Example 14:
Elvitegravir (0.5 g) was dissolved in 2-methoxyethanol (2 mL) at 25-30°C. To the clear solution, IPE (30 mL) was added and stirred for 18 hrs at 25-30°C. The solid obtained was filtered and identified as crystalline Elvitegravir Form II.

Example 15:
Elvitegravir (0.5 g) was dissolved in 1, 4-dioxane (4 mL) at 60-70°C. To the clear solution, IPE (20 mL) was added and stirred for 18 hrs at 25-30°C. The solid obtained was filtered and identified as crystalline Elvitegravir Form II.

Example 16:
Elvitegravir (0.5 g) was dissolved in 1, 4-dioxane (3 mL) at 60-70°C. To the clear solution, n-heptane (20 mL) was added and stirred for 18 hrs at 25-30°C. The solid obtained was filtered and identified as crystalline Elvitegravir Form II.

Example 17:
Amorphous Elvitegravir (0.5 g) was dissolved in n-propanol (4 mL) at 60-70°C. To the clear solution, IPE (20 mL) was added and stirred for 18 hrs at 25-30°C. The solid obtained was filtered and identified as crystalline Elvitegravir Form II.

Preparation of Elvitegravir Form III

Example 18:
Amorphous Elvitegravir (2 g) was dissolved in acetone (8 mL) at 25-30°C. To the clear solution, IPE (50 mL) was added and stirred for 3 hrs at 25-30°C. The solid obtained was filtered and identified as crystalline Elvitegravir Form III.

Example 19:
Elvitegravir (0.5 g) was dissolved in ethyl acetate (2 mL) at 25-30°C. The clear solution was agitated for 3-5 hrs at 25-30°C. The solid obtained was filtered and dried at 25-30°C. The product obtained was identified as crystalline Elvitegravir Form III.

Example 20:
Elvitegravir (0.5 g) was dissolved in acetonitrile (2 mL) at 25-30°C. The clear solution was agitated for 3-5 hrs at 25-30°C. The solid obtained was filtered and dried at 25-30°C. The product obtained was identified as crystalline Elvitegravir Form III.

Example 21:
Elvitegravir (0.5 g) was dissolved in etiiyl acetate (20rnL) at SO-SCC to obtain a clear solution. The resulting clear solution was allowed for fast evaporation on watch glass. The solid obtained was identified as crystalline Elvitegravir Form III.

Example 22:
The physical stability of Elvitegravir amorphous form was monitored by subjecting approximately 1.0 g of the sample to different stress conditions; a) Drying, b) exposure to Relative Humidity (RH) and c) Slurry conversion. The samples were tested by PXRD after 18 hrs. There is no discernible change in form observed under these conditions. The results are shown in the following Table 1.

Table 1

Example 14: Preparation of Elvitegravir dosage form
Elvitegravir (crystalline or amorphous) prepared according to the invention is incorporated into suitable pharmaceutical dosage form. Not limited by any example, various dosage forms can be prepared using Elvitegravir according to the invention. The tablet dosage form comprising elvitegravir is prepared as disclosed below:

Unit composition

Brief Manufacturing Process:
1. Sift Elvitegravir, lactose monohydrate, microcrystalline cellulose and dibasic calcium phosphate separately through suitable sieve.
2. Dissolve hypromeilose in purified water.
3. Load the materials of step 1 into rapid mixer granulator and granulate using the solution of step 2.
4. Dry the granulate of step 3 and mill through suitable screen.
5. Sift the remaining quantity of microcrystalline cellulose, sodium stearyl fumarate and magnesium stearate separately through suitable sieve.
6. Load the granules of step 4 and materials of step 5 into a blender and blend for suitable period of time.
7. Compress the blend of step 6 using appropriate tooling.
8. Coat the tablet with the commercially available Opadry® till the required weight build up.

Claims
1. A process for the preparation of amorphous Elvitegravir comprising the steps of:

a) dissolving Elvitegravir in an organic solvent such as A/./V-dimethylformamide, dimethylsulfoxide, A/-methylpyrrolidone, acetic acid, formic acid, N,N-dimethylacetamide or 2-methoxyethanol,

b) solution of step (a) adding to water, and

c) isolating amorphous Elvitegravir.

2. A process for the preparation of amorphous Elvitegravir comprising the steps of:

a) heating the Elvitegravir to 150-160°C to form a melt,
b) cooling the melt, and
c) isolating the amorphous Elvitegravir.

3. A process for the preparation of amorphous Elvitegravir comprising the steps of:

a) dissolving Elvitegravir in acetone, and
b) removing the solvent using conventional techniques such as distillation, freeze drying, spray drying or agitated thin film drier (ATFD) to obtain amorphous form of Elvitegravir.

4. A process for the preparation of crystalline Form I of Elvitegravir comprising the steps of:

a) dissolving Elvitegravir in nitromethane or dichoromethane,
b) adding anti-solvent, and
c) isolating crystalline Form I of Elvitegravir

5. A process for the preparation of crystalline Form II of Elvitegravir comprising the steps of:

a) dissolving Elvitegravir in an organic solvent such as acetone, acetic acid, 2-methoxyethanol, n-propanol or 1, 4-dioxane,
b) adding anti-solvent, and
c) isolating crystalline Form II of Elvitegravir.

6. A process for the preparation of crystalline Form III of Elvitegravir comprising the steps of:

a) dissolving Elvitegravir in acetone or ethyl acetate,
b) adding anti-solvent, and
c) isolating crystalline Form III of Elvitegravir.

7. The process according to claims 6, 7, and 9, wiierein said anti-solvent is selected from isopropyl ether, hexane, cyclohexane, diethylether, methyl t-butylether or heptane.

8. A process for the preparation of crystalline Form III of Elvitegravir comprising the steps of:

a) dissolving Elvitegravir in ethyl acetate or acetonitrile,
b) leaving the solution for crystallization,
c) Isolating the Form III of Elvitegravir.

9. A process for the preparation of crystalline Form III of Elvitegravir comprising the steps of:

a) dissolving Elvitegravir in ethyl acetate,
b) aerial evaporation of the solvent at 25-30°C
c) isolating the Form III of Elvitegravir.

10. A pharmaceutical composition comprising: (a) a therapeutically effective amount of amorphous or crystalline Elvitegravir; and (b) at least one pharmaceutically acceptable carrier.