This application claims priority to Indian patent application 3871 /CHE/2010 filed on Dec 20, 2010 the contents which are incorporated by reference in their entity.

FIELD OF THE INVENTION:

The present invention provides novel crystalline polymorphic form E of 4-((4-((4-((lE)-2-Cyanoethenyl)-2,6-dimethylphenyl)amino)-2-pyrimidinyl) amino) benzonitrile hydrochloride of formula (I) and process for the 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 of 4-((4-((4-(( 1 E)-2-Cyanoethenyl)-2,6-dimethylphenyl)amino)-2-
pyrimidinyl) amino) benzonitrile hydrochloride (Rilpivirine hydrochloride ) is shown in formula (I).

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.

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, 19.2, 24.2 and 27.6 ± 0.2 0° and DSC thermogram showing melting at 257.5°C. Stability data indicates Polymorphic Form I to be more stable.

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.

Polymorphism is the property of some molecules and molecular complexes to assume more than one crystalline form in the solid state. A single molecule may give rise to a variety of polymorphs having distinct physical properties.

One of the most important physical properties of a polymorphic pharmaceutical compound is the solubility of each of its forms in aqueous solution, particularly the solubility in gastric juices of a patient. Further, the discovery of new crystalline polymorphic forms of a drug enlarges the repertoire in ease of processing the form into pharmaceutical dosages, such as the tendency of a powdered or granulated form to flow and the surface properties that determine whether crystals of the form will adhere to each other when compacted into a tablet.

OBJECT AND SUMMARY OF THE INVENTION:

The main object of the present invention is to provide a novel crystalline polymorphic form E of 4-((4-((4-((lE)-2-Cyanoethenyl)-2, 6-dimethylphenyl) amino)-2-pyrimidinyl) amino) benzonitrile hydrochloride of formula (I) and process for the preparation of the same.

In one aspect, present invention provides novel crystalline polymorphic form E of Rilpivirine hydrochloride characterized by a powder X-ray diffraction pattern having peaks at about 8.1, 23.7, and 17.5 ± 0.29°.

In another aspect, present invention provides process for the preparation of crystalline polymorphic form E of Rilpivirine hydrochloride comprising the steps of:
a) dissolving Rilpivirine base in an organic solvent;
b) partially removing the solvent;
c) adding Hydrochloric acid to the solution; and
d) isolating Rilpivirine hydrochloride polymorphic form E.

BRIEF DESCRIPTION OF THE FIGURES:

FIGURE 1 shows the X-Ray diffractogram of polymorphic form E of Rilpivirne hydrochloride

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to novel crystalline polymorphic form E of 4-((4-((4-((lE)-2-Cyanoethenyl)-2,6-dimethylphenyl)amino)-2-pyrimidinyl) amino) benzonitrile hydrochloride of formula (I) . The present invention also relates to process for the preparation of the same.

In one embodiment, present invention provides crystalline polymorphic form E of Rilpivirne hydrochloride.

In one embodiment of the present invention, crystalline polymorphic form E of Rilpivirine hydrochloride is characterized by a powder X-ray diffraction pattern having peaks at about 8.1, 23.7, and 17.5 ± 0.20°.

In another embodiment of the present invention, crystalline polymorphic form E of Rilpivirine hydrochloride is further characterized by a powder X-ray diffraction pattern having peaks at about 8.1, 15.5, 16.2, 17.5, 18.8, 21.1, 22.5, 23.7, and 26.4 ± 0.29°.

In yet another embodiment of the present invention, crystalline polymorphic form E of Rilpivirine hydrochloride is further characterized by powder X-ray diffraction pattern substantially as depicted in FIGURE 1.

Another embodiment of the present invention provides, process for the preparation of crystalline polymorphic form E of Rilpivirine hydrochloride comprising the steps of:
a) dissolving Rilpivirine base in an organic solvent;
b) partially removing the solvent;
c) adding Hydrochloric acid to the solution; and
d) isolating Rilpivirine hydrochloride polymorphic form E.

In one embodiment of the present invention, Rilpirvirine base is dissolved in an organic solvent, where in the organic solvent is selected from polar aprotic solvents such as acetone, ethyl acetate, dimethyl sulfoxide, acetonitrile, 1,4-dioxane and dimethyl formamide. Preferably acetone.

In another embodiment of the present invention, the solvent is removed by a volume of 45-55 percent from its initial volume; preferably 30-35 perecnt.

In another embodiment of the present invention, hydrochloric acid is added to the reaction mixture and cooled to 45-35 °C; preferably 35- 25°C; more preferably 30-10 °C; to isolate Rilpivirine hydrochloride polymorphic form E.

According to the present invention, Rilpivirine base is dissolved in polar aprotic solvents such as acetone, ethyl acetate, dimethyl sulfoxide, acetonitrile, 1,4-dioxane and dimemthyl formamide, preferably acetone, at reflux temperature. The solvent is removed by 45-55 percent from its initial volume; preferably 30-35 perecnt. To the reaction mixture is added hydrochloric acid and cooled to 45-35 °C; preferably 35- 25°C; more preferably 30-10 °C and isolated the obtained solid through filtration followed by washing. The obtained solid was dried to give Rilpivirine hydrochloride polymorphic form E.

Instrumentation:

Powder X-ray Diffraction fPXRD)
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 9/9 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.

The following non-limiting example illustrate specific embodiments of the present invention. The example is not intended to be limiting the scope of present invention in any way.

Example 1:

To the 100 g of Rilpivirine was added 3000 ml of acetone and heated to reflux for 30 mins. The reaction mass was cooled and added 5 g of ceca carbon and again heated to reflux, followed by cooling to 59-53 °C. The reaction mass was filtered over hyflo bed and washed with acetone. From the obtained filtrate 1000 ml of acetone was distilled off under atmospherically and cooled to 58-45 °C and was added 2000 ml of dilute hydrochloric acid solution. The reaction mass was further cooled to 30-10 °C and filtered.

The resulting solid was washed with acetone and dried to give crystalline Polymorphic form E of Rilpivirine hydrochloride.

Example 2:

10 g of Rilpivirine base and 300 mL of acetone were added and heated to reflux. The reaction mass was maintained to get clear solution and the obtained clear solution was treated with 1.0 g of activated carbon; filtered over hyflo bed; and washed with 10 mL of acetone. The acetone layers were combined and distilled off acetone to retain 200 mL in reaction mass. The reaction mass was cooled to 45 °C and was slowly added 3 mL of Hydrochloric acid. The reaction mass was further cooled to 10 °C; maintained for 1 hour and filtered. The obtained solid was washed with 10 mL of acetone and dried under vacuum at 45 °C to yield 8 g polymorphic form E of Rilpivirine Hydrochloride as off-white powder.

Example 3:

5 g (13.66mmol) of Rilpivirine and 35 mL of 1,4-dioxane were added and heated to reflux. The reaction mass was maintained to get clear solution and the obtained clear solution was treated with 0.25g of activated carbon; filtered over hyflo bed and washed with 5 mL of 1,4-dioxane. The temperature of the reaction mass cooled to 72 °C and was slowly added 40 mL of dilute Hydrochloric acid. The temperature of the reaction mass is further cooled to 27 °C and maintained for 1 hour. The reaction mass was filtered and washed with 25 mL of purified water. The obtained solid was dried under vacuum at 50 °c to yield 4.7 g of polymorphic form E of Rilpivirine hydrochloride as pale yellow to off-white powder.

Example 4:

5 g of Rilpivirine and 150 mL of acetone were added; heated to reflux; and maintained to get clear solution. The obtained clears solution was treated with 250 g of activated carbon; filtered over hyflo bed and washed with 10 mL of acetone. The acetone layers were combined and the acetone was distilled off to retain 100 mL in reaction mass. The reaction mass was cooled to 45-50 °C and was slowly added of isopropanolic hydrochloric acid (2.5 mL of HC1 diluted with 85 mL of IPA). The reaction mass was further cooled to 27 °C; maintained for 1 hour; filtered and washed with 10 mL of isopropanol. The obtained solid was dried under vacuum at 45 °C to yield 4.9 g of polymorphic form E of Rilpivirne hydrochloride as off-white powder.

We Claim:

1. A crystalline polymorphic form E of Rilpivirine hydrochloride characterized by having X-ray diffraction peaks at about 8.1, 23.7, and 17.5 ± 0.28°.

2. The crystalline form according to claim 1, wherein the crystalline form is further characterized by an X-ray powder diffraction with peaks at about 8.1, 15.5, 16.2, 17.5, 18.8, 21.1, 22.5, 23.7, and 26.4 ± 0.29°.

3. The crystalline form according to claim 1, wherein the crystalline form is characterized by PXRD as depicted in Figure 1.

4. A process for preparing crystalline form E of Rilpivirine hydrochloride comprising:

a) dissolving Rilpivirine base in an organic solvent;
b) partially removing the solvent;
c) adding Hydrochloric acid to the solution; and
d) isolating Rilpivirine hydrochloride polymorphic form E.

5. The process according to claim 4, wherein the organic solvent used for dissolving Rilpivirine base is selected from polar aprotic solvents.

6. The process according to claim 5, wherein the polar aprotic solvent is selected from acetone, ethyl acetate, dimethyl sulfoxide, acetonitrile and dimethyl formamide.

7. The process according to claim 4, wherein the solution of step-c) is cooled to isolate Rilpivirine hydrochloride form E.

8. The process according to claim 7, wherein the solution is cooled to 45-35 °C.

9. The process according to claim 8, wherein the solution is cooled 30-10 °C.

10. The process of claim 7, wherein the cooled solution is filtered to isolate Rilpivirine hydrochloride polymorphic form E.