The following specification claims priority from Indian Patent Application bearing Number 546/CHE/2009 dated Mar 11, 2009

FIELD OF THE INVENTION

The present invention provides novel polymorphic forms of Rilpivirine and processes for preparation of the same.

BACKGROUND OF THE INVENTION

Retroviruses are class of viruses which lower the immunity levels in mammals particularly Humans. Human Immuno deficiency Virus is one such retrovirus which causes AIDS. Short life cycle and high error rate causes the virus to mutate very rapidly, resulting in a high genetic variability of HIV. Antiretroviral drugs include Nucleoside reverse transcriptase inhibitors (NRTI's), Non- Nucleoside reverse transcriptase inhibitors (NNRTI's), HIV protease inhibitors, fusion inhibitors, maturation inhibitors. Compound 4-((4_((4.(( 1 E)-2-Cyanoethenyl)-2,6-dimethylphenyl)amino)-2-pyrimidinyl) amino)benzo-nitrile [TMC278], generically designated as Rilpivirine is shown below.

Rilpivirine is an investigational new drug developed by Tibotec, a biotechnology company in Belgium; for the treatment of HIV infection. It is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTIs). Rilpivirine prevents HIV from entering the nucleus of healthy CD4 cells. This prevents the cells from producing new virus and decreases the amount of virus in the body. Rilpivirine is being studied in combination with other HIV medicines in two groups of HIV-positive people: those starting HIV treatment for the first time and those in need of newer medicines to treatment HIV that has become resistant to older options.

us 7,125,879 specifically claims Rilpivirine. This patent discloses various processes for the preparation of Rilpivirine one of which involves condensation of 3-(4-amino-3,5-dimethylphenyl)-acrylonitrile either in free base or hydrochloride salt with 4-(4-chloropyrimidin-2-ylamino)benzonitrile using potassium carbonate.

US 2006/0111379 Al discloses Rilpivirine hydrochloride salt and its polymorphic form designated as Form A. This patent application also discloses solvates or pseudo polymorphic forms of Rilpivirine hydrochloride Form B, Form C and Form D respectively.

WO 2009/007441 designates crystalline Rilpivirine of US 7,125,879 as Polymorphic Form II. Rilpivirine polymorphic form II is characterized by PXRD peaks at about 8.5, 12.4, 12.9, 17.6, 21.0, 24.8, 25.8 and 27.9 ±0.2 0° and DSC thermogram showing melting at 243.2°C. This patent application claims another polymorphic form of Rilpivirine designated as Polymorphic Form I. The given morph is characterized by PXRD peaks at about 9.0, 11.3, 14.3, 17.1, 19.1, 24.2 and 27.6 ± 0.2 0° and DSC thermogram showing melting at 257.5°C. The polymorphs I and II also differ in their IR spectrum with typical absorption bands at about 3348, 3274, 2217, 2209, 1477 and 1334 cm"' for Form I and at about 3316, 223, 2215,1483,1325 cm"' for Form II.

OBJECT OF THE INVENTION

Principle object of the present invention is to provide crystalline Rilpivirine Form III and process for the preparation of the same.

Another principle object of the present invention is to provide crystalline Rilpivirine Form IV and process for the preparation of the same.

Yet another principle object of the present invention is to provide crystalline Rilpivirine Form V and process for the preparation of the same.

Still another principle object of the present invention is to provide substantially pure amorphous Rilpivirine and process for the preparation of the same.

Yet another object of the present invention is to provide improved processes for the preparation of Rilpivirine Form I and Form II.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a crystalline form of 4-((4-((4-((lE)-2-Cyanoethenyl)-2,6-dimethylphenyl)amino)-2-pyrimidinyl)amino)benzonitrile [Rilpivirine] designated as Form III, wherein the crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (29) of 6.61, 10.49, 13.22, 16.43, 16.98,18.28,19.61, 20.01,21.94,22.13,23.03, 24.20, 25.00°.

The present invention provides process for preparing crystalline Rilpivirine Form III comprising: a) suspending Rilpivirine in dimethyl sulfoxide (DMSO) to form slurry; b) heating the slurry to become clear solution; c) cooling the clear solution; and d) isolating Form III.

The present invention also provides alternate process for preparing crystalline Rilpivirine Form III comprising: a) dissolving Rilpivirine is dimethyl sulfoxide (DMSO) to obtain clear solution; b) cooling the solution to room temperature; c) subjecting the cooled mass to evaporation; and d) isolating Form III.

In another aspect, the present invention provides a crystalline form of Rilpivirine designated as Form IV, wherein the crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (29) of 5.98, 7.59, 9.33, 12.19,14.68,15.19, 17.97,18.57, 19.44, 20.52, 21.95,23.84,25.19°.

The present invention provides process for preparing crystalline Rilpivirine Form IV comprising:

a) suspending Rilpivirine in acetic acid to form slurry; b) heating the slurry to become clear solution; c) cooling the clear solution and adding this clear solution to anti-solvent;

and d) isolating Form IV.

The present invention also provides alternate process for preparing crystalline Rilpivirine Form IV comprising: a) dissolving Rilpivirine in acetic acid at 60-70°C; b) cooling the obtained solution to room temperature; c) subjected the cooled solution to evaporation; and d) isolating Form IV.

The present invention further provides alternate process for preparing crystalline Rilpivirine Form IV comprising: a) dissolving Rilpivirine in acetic acid at high temperatures; b) cooling the obtained clear solution; c) filtering the mass; and d) subjecting the filtered mass to spray-drying; and e) isolating Rilpivirine Form IV.
In yet another aspect, the present invention provides a crystalline form of Rilpivirine designated as Form V, wherein the crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (26) of 17.01, 18.01, 18.30, 19.56, 19.89, 20.62, 21.02, 21.50, 22.06, 23.38, 24.35,25.51,2733, 28.12, 32.04, 32.85, 34.18°.

The present invention provides process for preparing crystalline Rilpivirine Form V comprising: a) suspending Rilpivirine in formic acid to form slurry; b) heating the slurry to become clear solution; c) cooling the clear solution and adding this clear solution to anti-solvent; and d) isolating Form V.

The present invention also provides alternate process for preparing crystalline Rilpivirine Form V comprising: a) dissolving Rilpivirine in formic acid; b) cooling the solution to room temperature; c) subjecting the clear solution to evaporation; and d) isolating Form V.

In still another aspect, the present invention provides amorphous Rilpivirine. The present invention provides process for the preparation of Rilpivirine amorphous form comprising a) heating Rilpivirine to higher temperature; b) holding the mass to form a melt; and c) cooling the resulting melt to ambient temperature and d) isolating amorphous Rilpivirine.

In yet another aspect, the present invention provides improved processes for the preparation of Rilpivirine Form I and II using the polymorphic forms of Rilpivirine disclosed in the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel polymorphic forms of 4-((4-((4-((lE)-2- Cyanoethenyl)-2,6-dimethyIphenyl)amino)-2-pyrimidinyl)amino)benzonitrile [Rilpivirine] designated as Form III, Form IV, Form V and amorphous. The present invention also relates to processes for the preparation of the said polymorphic forms.

According to one embodiment, the present invention provides crystalline form of Rilpivirine, referred to herein as Form III as shown in Figure 1, characterized by X-ray powder diffraction pattern at about 6.61, 13.22, 16.43, 21.94, 22.13, 25.00° ± 0.2° two theta.

Crystalline Rilpivirine Form III is further characterized by PXRD peaks at about 6.61, 9.02, 10.49, 13.22, 14.88, 16.433, 16.98, 18.28, 19.60, 20.01, 21.94, 22.13, 22.51, 23.03, 24.20, 25.00, 28.19 and 32.14° ± 0.2° two theta; DSC as shown in Fig 5 with an endotherm at 112.55°C and TGA as shown in Fig 6 showing weight loss 28.29%

The present invention provides process for preparing crystalline Rilpivirine Form III comprising: a) suspending Rilpivirine in dimethyl sulfoxide to form slurry; b) heating the slurry to become clear solution; c) cooling the clear solution; and d) isolating Form III.

According to the present invention, Rilpivirine is suspended in dimethyl sulfoxide and the suspension is heated to 45-80°C, preferably 60-70°C, to get clear solution. The clear solution is then cooled to 10-35°C, preferably 25-30°C. The obtained solid is filtered and dried to get crystalline Rilpivirine Form III.

The present invention also provides alternate process for preparing crystalline Rilpivirine Form III comprising: a) dissolving Rilpivirine is dimethyl sulfoxide (DMSO) to obtain clear solution; b) cooling the solution to room temperature; c) subjecting the cooled mass to evaporation; and d) isolating Form III.

According to the present invention, Rilpivirine is suspended in dimethyl sulfoxide and raised the temperature to 40-80°C preferably 60-70°C. Clear solution is obtained. Reaction mass is subjected to evaporation. Evaporation can be carried out in less time by taking Rilpivirine mass onto a Petri dish and left open. Or else for slow evaporation, Rilpivirine mass is transferred to a conical flask and small apertures are to be made to the parafilm such that solvent evaporates vey slowly from the flask. Finally the obtained solid is filtered and dried under vacuum. The obtained solid is subjected to characterization studies and identified to be Rilpivirine Form-III.

According to another embodiment, the present invention provides crystalline form of Rilpivirine, referred to herein as Form IV as shown in Figure 2, characterized by X-ray powder diffraction pattern at about 5.98, 7.59, 9.33, 12.19, 14.68, 15.19, 18.57, 25.19° ± 0.2° two theta.

Crystalline Rilpivirine Form IV is further characterized by PXRD peaks at about 5.98, 7.59, 9.33, 12.19, 14.68, 15.19, 17.18, 17.97, 18.57, 19.44, 20.52, 21.95, 22.50, 23.10, 23.49, 23.84, 25.19, 26.97, 32.53 and 33.58° ± 0.2° two theta, DSC as shown in Fig 7 with an endotherm at 160.38°C and 257.47°C and TGA as shown in Fig 8 showing weight loss 14.45%.

The present invention provides process for preparing crystalline Rilpivirine Form IV comprising: a) suspending Rilpivirine in acetic acid to form slurry; b) heating the slurry to become clear solution; c) cooling the clear solution and adding this clear solution to anti-solvent; and d) isolating Form IV.

According to the present invention, Rilpivirine is suspended in acetic acid. The suspension is heated to 50-80°C, preferably 60-70°C, to get clear solution. The resulting clear solution is cooled to room temperature. The obtained solution is added to anti-solvent at room temperature (25-30°C). The anti-solvent used is selected from isopropyl ether, diethyl ether, methyl t-butyl ether, water or mixtures thereof, preferably isopropyl ether. Resulting solution is stirred to enhance the rate of precipitation. The resulting solid is filtered and dried to obtain Form IV.

The present invention also provides alternate process for preparing crystalline Rilpivirine Form IV comprising: a) dissolving Rilpivirine in acetic acid at 60-70°C; b) cooling the obtained solution to room temperature; c) subjected the cooled solution to evaporation; and d) isolating Form IV.

According to the present invention, Rilpivirine is suspended in acetic acid and raised the temperature to 40-80°C preferably 60-70°C. Clear solution is obtained. Reaction mass is subjected to evaporation. Evaporation can be carried out in less time by taking Rilpivirine mass onto a Petri dish and left open. Finally the obtained solid is filtered and dried under vacuum. The obtained solid is subjected to characterization studies and identified to be Rilpivirine Form-IV.

The present invention further provides alternate process for preparing crystalline Rilpivirine Form IV comprising: a) dissolving Rilpivirine in acetic acid at high temperatures; b) cooling the obtained clear solution; c) filtering the mass; and d) subjecting the filtered mass to spray-drying; and e) isolating Rilpivirine Form IV.
According to the present invention, Rilpivirine is dissolved in acetic acid by subjecting the material to high temperatures such as 90-130°C preferably 100-110°C. The obtained clear solution is cooled and filtered to remove the particles if any. The clear solution is subjected to spray-drying in a spray dryer of the make (Model Buchi - 290). The obtained material is observed of Rilpivirine Form IV.

According to another embodiment, the present invention provides crystalUne form of Rilpivirine, referred to herein as Form V as shown in Figure 3, characterized by X-ray powder diffraction pattern at about 18.00, 18.30, 20.62, 21.50, 24.35, 28.12° ± 0.2° two theta.

Crystalline Rilpivirine Form V is further characterized by PXRD peaks at about 15.28, 15.69, 16.06, 17.01, 18.00, 18.30, 19.56, 19.89, 20.62, 21.02, 21.50, 22.06, 23.38, 24.35, 25.51, 26.44, 27.33, 28.12, 29.84, 32.04, 32.85, 34.18, 36.14, 36.82, 41.20, 43.49° ± 0.2° two theta, DSC as shown in Fig 9 with an endotherm at 146.97°C and 257.43°C and TGA as shown in Fig 10 showing weight loss of 5.184%.

The present invention provides process for preparing crystalline Rilpivirine Form V comprising: a) suspending Rilpivirine in formic acid to form slurry; b) heating the slurry to become clear solution; c) cooling the clear solution and adding this clear solution to anti-solvent; and d) isolating Form V.

According to the present invention, Rilpivirine is suspended in formic acid and heated to 50-80°C, preferably 60-70°C, to get clear solution. The resulting clear solution is cooled to room temperature, preferably 25-30°C. The clear solution obtained is then added to anti-solvent at 25-30°C. The anti-solvent used is selected from isopropyl ether, diethyl ether, methyl t-butyl ether, water or mixtures thereof, preferably isopropyl ether. Resulting solution is stirred to enhance the rate of precipitation. The resulting solid is filtered and dried to obtain Form V.

The present invention also provides alternate process for preparing crystalline Rilpivirine Form V comprising: a) dissolving Rilpivirine in formic acid; b) cooling the solution to room temperature; c) subjecting the clear solution to evaporation; and d) isolating Form V.

According to the present invention, Rilpivirine is suspended in formic acid and the raised the temperature to 40-80°C preferably 60-70°C. Clear solution is obtained. Reaction mass is subjected to evaporation. Rilpivirine mass is transferred to a conical flask and covered with thin parafilm and small apertures are to be made to the parafilm such that solvent evaporates vey slowly from the flask. Finally the obtained solid is filtered and dried under vacuum. The obtained solid is subjected to characterization studies and identified to be Rilpivirine Form-V.

According to yet another embodiment, the present invention provides amorphous Rilpivirine as shown in figure 4.

The present invention provides process for the preparation of Rilpivirine amorphous form comprising the steps of a) heating Rilpivirine to higher temperature; b) holding the mass to form a melt; and c) cooling the resulting melt to ambient temperature and d) isolating the amorphous Rilpivirine.

According to the present invention, Rilpivirine is directly heated to at about 260°C and the material is held at 260°C for about 5 min to form a melt. The melt is cooled to 25-30°C to get amorphous Rilpivirine.

In another embodiment, the present invention provides process for the preparation of Form I, comprising the steps of a) heating Rilpivirine Form III and b) isolating Rilpivirine Form I.

According to the present invention, Rilpivirine Form III is heated at about 60-65°C in static dryer under reduced pressure to isolate Form I.

In another embodiment, the present invention provides process for the preparation of Form I, comprising the steps of a) suspending Rilpivirine in a solvent to form slurry; b) heating the slurry to obtain clear solution; c) concentrating the clear solution to half of the volume; d) cooling the remaining mass and adding another solvent; and e) isolating Form I.

According to the present invention, Rilpivirine is suspended in solvent selected from aprotic solvents dimethylformamide, tetrahydrofuran, dimethylacetamide preferably tetrahydrofuran to form a slurry. The slurry is heated to high temperatures preferably reflux to clear the contents. The clear solution so obtained is subjected to distillation such that half of the volume of the clear solution is distilled out. The remaining mass is cooled to 0 to -50°C preferably -35 to -40°C. To the cooled mass, another solvent such as non-polar solvents selected from n-heptane, n-hexane preferably n-hexane is added at -35 to -40 °C and stirred for 30-40 min. The solid obtained is filtered and dried to yield Rilpivirine Form I.

In another embodiment, the present invention provides process for the preparation of Form II, comprising the steps of a) suspending Rilpivirine in a solvent to form slurry; and b) isolating Rilpivirine Form II.

According to the present invention, Rilpivirine used in above slurry method is selected from either Form III or Form IV or Form V. The solvent used is selected from methanol, ethanol, propanol, preferably methanol. The Rilpivirine slurry is maintained for 1-3 hours, preferably 1 hour, at 25-30°C. The isolated solid is dried to obtain Rilpivirine Form II.

In another embodiment, the present invention provides process for the preparation of Form II, comprising the steps of a) suspending Rilpivirine in a solvent to form a slurry; b) heating the slurry to complete dissolution; c) subjecting the clear solution to either fast or slow cooling; d) isolating Form II.

According to the present invention, Rilpivirine either amorphous of crystalline is suspended in a solvent selected from alcohols, chlorinated solvents, polar aprotic solvents, nitriles, nitro alkanes such as methanol, dichloromethane (DCM), dimethylformamide, dimethylacetamide, acetonitrile, 1,4-dioxane, nitro methane, dimethyl carbonate to form a slurry. Volume of the solvent employed for forming a suspension can be selected from 10-20 volumes preferably 15 volumes. The slurry is heated to high temperatures to clear the contents. The obtained clear solution is cooled either slowly or rapidly to room temperature (25-30°C). The obtained solid is filtered, dried to get Rilpivirine Form II.

In another embodiment, the present invention provides process for the preparation of Form II, comprising the steps of a) suspending Rilpivirine in a solvent or mixture of solvents to form slurry; b) heating the slurry to complete dissolution; c) adding anti solvent to the clear solution; and d) isolating Form II.

According to the present invention, Rilpivirine either amorphous or crystalline is suspended in a solvent selected from alcohol, polar aprotic solvents, ketone, chlorinated solvents, esters, such as methanol, dimethyl sulfoxide, dimethylformamide, acetone, 1,4- dioxane, chloroform, dichloro- methane, ethanol, tetrahydrofuran, ethylacetate to form a slurry. Volume of the solvent employed for forming the slurry is selected from 1 to 3 times of Rilpivirine preferably 1.5 times. The slurry is stirred for about 5-20 min preferably 10 min at room temperature and raised to higher temperatures such that clear solution is obtained. Anti solvent added to the clear solution. Anti solvent is selected from water, ethers, non-polar solvents such as isopropyl ether, n-heptane, n-hexane. The solid obtained is filtered and dried to yield Rilpivirine Form II.

In another embodiment, the present invention provides process for the preparation of admixture of Form I and Form II, comprising the steps of a) heating Rilpivirine Form IV or Form V and b) isolating Rilpivirine Form I and Form II mixture.

According to the present invention, Rilpivirine is heated at about 60-65°C in a vacuum oven for overnight to isolate admixture of Rilpivirine Form I and Form II.

In another embodiment, the present invention provides a pharmaceutical composition that includes a therapeutically effective amount of pure Rilpivirine or its salts prepared according to the processes of the present invention and one or more pharmaceutically acceptable carriers, excipients or diluents.

Accordingly, the pharmaceutical composition comprising pure Rilpivirine or their pharmaceutically acceptable salts along with one or more pharmaceutically acceptable carriers of this invention may further be formulated as: solid oral dosage forms such as, hut not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions, and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. The compositions may be prepared by direct blending, dry granulation, or wet granulation or by extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Compositions of the present invention may further comprise one or more pharmaceutically acceptable excipients.

Instrumentation:

Powder X-ray Diffraction (PXRD)

The said polymorphs of the present invention are characterized by their X-ray powder diffraction pattern. Thus, the X-ray diffraction patterns of said polymorphs of the invention were measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of 9/G configuration and X'Celerator detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 20 range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.

Differential Scanning Calorimetry (DSQ)

The DSC measurements were carried out on Mettler Toledo 822 star and TA QIOOO of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 50ml/min. Standard aluminum crucibles covered by lids with three pin holes were used.

Thermo gravimetric Analysis (TGA)

TGA was recorded on out using the instrument Mettler Toledo TGA/SDTA 851^ and TGA Q5000 of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 25ml/min.

The following non-limiting examples illustrate specific embodiments of the present invention. They are, not intended to be limiting the scope of present invention in any way.

Example 1

Process for the preparation of Rilpivirine Form III

Rilpivirine (2.5 g) was suspended in DMSO (10 ml) at room temperature. The slurry was heated to 60-70°C to get the clear solution. The solution was then cooled to room temperature and stirred for 60 min at 25-30°C. The solid obtained was filtered and dried for 2 hrs under vacuum at 25-30°C. The product obtained is identified as a crystalline Rilpivirine Form III.

Example 2

Process for the preparation of Rilpivirine Form III

Rilpivirine (200mg) was dissolved in DMSO (20ml) at 60-70°C. The solution was cooled to 25-30 °C and transferred to a conical flask. The conical flask was covered with a parafilm with small apertures on it for slow solvent evaporation. The solid material obtained was filtered and suck dried under vacuum. The solid material was isolated and identified as Rilpivirine Form III.

Example 3

Process for the preparation of Rilpivirine Form III

Rilpivirine (200mg) was dissolved in DMSO (20ml) at 60-70°C. The solution was cooled to 25-30 ° C and transferred to a petri dish for fast solvent evaporation. The solid material isolated was identified as Rilpivirine Form III.

Example 4

Process for the preparation of Rilpivirine Form IV

Rilpivirine (1 g) was suspended in acetic acid (5 ml) at room temperature. The slurry was heated at 60-70°C to get the clear solution. The resuhing solution was cooled to room temperature and added slowly to isopropyl ether (100 ml) at 25-30°C. The solution was stirred for 30 min at 25-30°C. The precipitated solid was filtered and suction dried. The solid obtained is identified as crystalline Rilpivirine Form IV.

Example 5

Process for the preparation of Rilpivirine Form IV

Rilpivirine (200mg) was dissolved in acetic acid (20ml) at 100-110°C. The solution was cooled to 25-30 ° C and filtered to remove particulate matter. The clear solution is subjected to spray drying in a spray-dryer of the make (Model Buchi - 290). The solid material obtained after isolated was identified as Rilpivirine Form IV.

Example 6

Process for the preparation of Rilpivirine Form V

Rilpivirine (1 g) was suspended in formic acid (5 ml) at room temperature. The slurry was heated at 60-70°C to get the clear solution. The resulting solution was cooled to room temperature and added to isopropyl ether (100 ml) at 25-30°C. The solution was stirred for 30 min at 25-30°C. The precipitated solid was filtered and dried. The solid obtained is identified as crystalline Rilpivirine Form V.

Example 7

Process for the preparation of Rilpivirine Form V

Rilpivirine (l00mg) was dissolved in formic acid (2ml) at 60-70°C. The solution was cooled to 25-30° C and transferred to a conical flask. The conical flask is covered with a parafilm with small apertures on it for slow solvent evaporation. The solid material obtained was filtered and suck dried under vacuum. The solid material was isolated and identified as Rilpivirine Form V.

Example 8

Preparation of amorphous Rilpivirine

Rilpivirine (Ig) was heated to about 260°C and held for about 5 minutes until a melt is formed. The resulting melt was cooled to ambient temperature. The solid obtained was identified as substantially pure amorphous Rilpivirine.

Example 9

Preparation of Rilpivirine Form I

Rilpivirine Form III (0.5g) obtained as described above (example 1) was kept in a static dryer and heated at 60°C under vacuum for 12-14 hrs. The product obtained was identified as crystalline Rilpivirine Form I.

Example 10

Preparation of Rilpivirine Form I

Rilpivirine (Ig) is suspended in THF (10 ml) at 25-30°C. The slurry was then heated to reflux to obtain the clear solution. Half of the solvent (~5 ml) was distilled out under vacuum at 50°C. The remaining mass was then cooled to -35 to -40°C and hexane (60 ml) was added to it and stirred for 30-40 min at same temperature. The solid obtained was filtered and suck dried for 15-30 min at 25-30°C.

Example 11

Preparation of Rilpivirine Form II

Rilpivirine (0.5g) is suspended in indicated solvents at the indicated volumes at 25-30°C and stirred for 1-3 hours. The product obtained was identified as crystalline Rilpivirine Form II. The results obtained are displayed in the following table.

Example 12

Preparation of Rilpivirine Form II by Crystallization

Rilpivirine (0.5g) was suspended in indicated solvents at the indicated volumes at 25-30°C and stir for 10 minutes. The resulting slurry was then heated for complete dissolution and allowed for slow or fast crystallization at room temperature. The results obtained are displayed in the following table

Example 13

Preparation of Rilpivirine Form II

Rilpivirine (0.5 g) was suspended in indicated solvents at the indicated volumes at 25-30°C and stirred for 10 minutes. The resulting slurry was then heated for complete dissolution followed by addition of an antisolvent. The results obtained are displayed in the following table.

Example 14

Preparation of admixture of Rilpivirine Form I and Form II from Form IV by heating Rilpivirine Form IV (0.5g) obtained as described above (examples 3) was kept in a static dryer and heated at about 40-60°C under vacuum. The resulting solid was identified as Rilpivirine Form I and II mixture.

Example 15

Preparation of admixture of Rilpivirine Form I and Form II from Form V by heating Rilpivirine Form V (0.5g) obtained as described above (example 3) was kept in a static dryer and heated at about 40-60°C under vacuum. The resulting solid was identified as Rilpivirine Form I and II mixture.

We Claim:

1. A process for the preparation of Rilpivirine Form I, which comprising the steps of: a) drying Rilpivirine Form III; and b) isolating Rilpivirine Form I.

2. A process for the preparation of Rilpivirine Form I, which comprising the steps of: a) dissolving Rilpivirine in a solvent; b) partially concentrating the solution; c) cooling the reaction mass, adding n-hexane; and d) isolating Rilpivirine Form I.

3. A process for the preparation of Rilpivirine Form II, which comprising the steps of: a) suspending Rilpivirine in methanol to form a slurry; and b) isolating Rilpivirine Form II.

4. A process for the preparation of Rilpivirine Form II, which comprising the steps of: a) dissolving Rilpivirine in a solvent; b) cooling the clear solution; and c) isolating Form II.

5. The process according to claim 4; wherein the solvent employed for slurrying is selected from methanol, dimethyl formamide, dimethyl acetamide, acetonitrile, 1,4-dixoane, dichloromethane and nitro methane.

6. A process for the preparation of Rilpivirine Form II, which comprising the steps of: a) dissolving Rilpivirine in a solvent or mixture of solvents to form clear solution; b) adding anti solvent to the clear solution; and c) isolating Form II.

7. The process according to claim 6; wherein the solvent is selected from methanol, dimethyl sulfoxide, diemthylformamide, dimethyl acetamide, 1,4-dioxane, acetone, chloroform, dichloromethane, ethanol, methanol, tetrahydrofuran, ethyl acetate or mixture thereof and anti solvent is selected from n-heptane, n-hexane, water, isopropyl ether, acetonitrile, nitro methane, or mixtures thereof.

8. A process for the preparation of admixture of Rilpivirine Form I and Form II, which comprising the steps of: a) drying Rilpivirine Form IV or Form V; and b) isolating admixture of Rilpivirine Form I and Form II.

9. A process for the preparation of amorphous Rilpivirine, which comprising the steps of: a) heating Rilpivirine to 260°C to form a mek; and b) isolating amorphous Rilpivirine.

10. Amorphous Rilpivirine prepared as per process according to claim 9.

11. A pharmaceutical formulation comprising Rilpivirine, wherein Rilpivirine used for formulation is selected from Rilpivirine polymorphic forms Form I, II, admixture of Form I and II and amorphous prepared as per any of the preceding claims.