The present invention relates to novel polymorphic form of efavirenz. The novel polymorphic form is designated as Form a of efavirenz. The invention further relates to the process for the preparation and pharmaceutical compositions useful in the treatment of HIV-1 infection of Form tt of efavirenz.
(4S)-6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; commonly known as efavirenz of Formula I is an HIV-1 specific, non-nucleoside, reverse transcriptase inhibitor. Efavirenz is indicated in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection.
(FORMULA REMOVED)
US Patent No. 5,519,021 and its equivalent PCT Patent Applications WO 94/03440, WO 95/20389 describe synthesis of efavirenz. In addition Tetrahedron Letters 36, 937-940 (1995); US Patent No. 5,698,741 and its equivalent PCT Patent Application WO 9637457 also provide various processes for preparation of efavirenz. Further the process for preparation of efavirenz is also reported in US Patent No. 5,663,467 and its equivalent PCT Patent Application WO 9622955.
US Patent No. 6,639,071 and US Patent No. 5,965,729 describe crystalline polymorphic forms of efavirenz designated as Form I, II and III. The specification of the '071 Patent comments that efavirenz previously crystallized from a heptane-tetrahydrofuran (THF) solvent system by the crystallization procedure which require the use of high temperatures (about 90°C) to
dissolve the final product produces crystals by nucleation during the cooling process. The crystals which were produced were Form II and are converted to the desired Form I while drying under vacuum at 90°C. This crystallization provides minimal purification and produced material with inconsistent physical properties. The final product slurry is extremely difficult to mix and handle due to its high viscosity and heterogeneous nature.
US Patent No. 6,673,372 further provide polymorphic forms of efavirenz designated as Form 2 and Form 5.
The present inventors have now prepared efavirenz in novel polymorphic form, designated as Form a of efavirenz. The novel polymorphic Form a has characteristically different XRD and DSC pattern as compared with the known polymorphic forms of efavirenz.
A first aspect of the present invention provides novel polymorphic form a of efavirenz having typical XRD pattern as depicted in Figure 1 of the accompanied drawing. The XRD of Form a shows characteristic 20 values at 3.4, 6.8, 11.96, 12.76, 13.0, 13.16, 13.64, 14.36, 15.12, 15.92, 16.5, 17.2, 18.14, 19.06, 19.56, 19.84, 20.32, 20.70, 21.16, 21.88, 22.22, 23.04, 23.50, 23.98, 24.34, 24.70, 24.86, 25.18, 25.76, 26.06, 26.48, 27.52, 28.10, 28.88, 30.40, 31.04, 31.44, 32.32, 32.52, 32.90, 33.48, 34.46 and 38.02. The novel polymorphic Form a has characteristic DSC thermogram as depicted in Figure 2 of the accompanied drawing. The DSC thermogram shows three characteristic endothermic peaks at 70-85°C, 85-95°C and 130-145°C.
A second aspect of the present invention provides a process for the preparation of novel polymorphic Form a of efavirenz which comprises of
a) dissolving efavirenz in a mixture of halogenated hydrocarbon and hydrocarbon organic solvent,
b) partially concentrating the solution obtained in step a),
c) isolating Form a of efavirenz from the reaction mass thereof.
Efavirenz prepared by any method known in the art and present in any polymorphic form known to a person of ordinary skills in the art can be used as starting material. Efavirenz is firstly dissolved in a mixture of halogenated hydrocarbon and hydrocarbon organic solvent. The solution is partially concentrated under vacuum. The reaction mixture is stirred and precipitated compound is filtered off to get Form a of efavirenz having characteristic XRD (Figure 1) and DSC (Figure 2).
A third aspect of the present invention provides a process for the preparation of novel polymorphic Form a of efavirenz which comprises of
a) treating efavirenz with C5-7 alkane, petroleum ether or C5-7 cycloalkane solvent
b) isolating Form a of efavirenz from the reaction mass thereof.
Efavirenz prepared by any method known in the art and present in any polymorphic form known to a person of ordinary skills in the art can be used as starting material. Efavirenz is treated with C5.7 alkane, petroleum ether or C5-7 cycloalkane solvent. The reaction mixture is stirred at a lower temperature and precipitated compound is filtered off to get Form a of efavirenz having characteristic XRD (Figure 1) and DSC (Figure 2).
A fourth aspect of the present invention provides a pharmaceutical composition comprising polymorphic Form a of efavirenz optionally containing an excipient / diluent.
A fifth aspect of the present invention provides a method of treating HIV-1 infections which comprises of administering to a mammal in need thereof a therapeutically effective amount of polymorphic Form a of efavirenz.
Figure 1 depicts XRD of Form a of efavirenz. Figure 2 depicts DSC of Form a of efavirenz
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE 1
PREPARATION OF FORM a OF EFAVIRENZ
Efavirenz (1.0 g) was dissolved in DCM (4 ml) and hexane (50 ml) was added to it. 25 ml of the solvent mixture was evaporated under vacuum at 40°C and 5 ml under vacuum at room temperature. Reaction mixture was stirred for 10 min and precipitated compound was filtered off to get the title compound.
EXAMPLE 2
PREPARATION OF FORM a OF EFAVIRENZ
Efavirenz (5.0 g) was dissolved in cyclohexane by heating to 55°C. The solution was cooled to 45°C and seeded with Form a. The solution was further cooled to 25°C and again seeded with Form α. The resultant mass was stirred at 7°C for 20 min and filtered to get title compound.

WE CLAIM:
1. Polymorphic Form a of efavirenz.
2. Polymorphic Form α of efavirenz having X-Ray Powder Diffraction (XRPD) pattern as depicted in Figure 1.
3. Polymorphic Form a of efavirenz having a XRPD pattern wherein characteristic 26 values are obtained at 3.4, 6.8, 11.96, 12.76, 13.0, 13.16, 13.64, 14.36, 15.12, 15.92, 16.5, 17.2, 18.14, 19.06, 19.56, 19.84, 20.32, 20.70, 21.16, 21.88, 22.22, 23.04, 23.50, 23.98, 24.34, 24.70, 24.86, 25.18, 25.76, 26.06, 26.48, 27.52, 28.10, 28.88, 30.40, 31.04, 31.44, 32.32, 32.52, 32.90, 33.48, 34.46 and 38.02.
4. Polymorphic Form α of efavirenz having a DSC thermogram as depicted in Figure 2.
5. Polymorphic Form a of efavirenz having a DSC thermogram wherein three characteristic endothermic peaks are obtained at 70-85°C, 85-95°C and 130-145°C.
6. A process for preparation of polymorphic Form a of efavirenz wherein the said process comprises of

a) dissolving efavirenz in a mixture of halogenated hydrocarbon and hydrocarbon organic solvent,
b) partially concentrating the solution obtained in step a),
c) isolating Form a of efavirenz from the reaction mass thereof.
7. A process according to claim 6, wherein the halogenated hydrocarbon is selected from
dichloromethane, 1,1,1-trichloroethane, tetrachloroethylene, trichloroethylene or
mixtures thereof.

8. A process according to claim 6, wherein the hydrocarbon organic solvent is selected from C5.7 alkane, petroleum ether, cycloalkane or mixtures thereof.
9. A process for preparation of polymorphic Form a of efavirenz wherein the said process comprises of

a) treating efavirenz with C5-7 alkane, petroleum ether or C5-7 cycloalkane solvent
b) isolating Form a of efavirenz from the reaction mass thereof.

10. A pharmaceutical compositions comprising polymorphic Form a of efavirenz optionally containing a pharmaceutically acceptable diluents or excipients.
11. A method of treating HIV-1 infections which comprises of administering to a mammal in need thereof a therapeutically effective amount of polymorphic Form a of efavirenz.