The present invention relates to novel polymorphic form of efavirenz. The novel polymorphic form is designated as Form y2 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 y2 of efavirenz.
(4S)-6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2/-/-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 2 of efavirenz. The novel polymorphic Form y2 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 2 of efavirenz having typical XRD pattern as depicted in Figure 1 of the accompanied drawing. The XRD of Form 2 shows characteristic 29 values at 12.12, 12.38, 12.98, 13.16, 15.64, 16.90, 17.22, 18.14, 18.42, 18.76, 19.34, 19.48, 19.90, 20.06, 20.32, 21.18, 21.74, 22.04, 23.08, 23.30, 23.98, 24.42, 24.60, 24.94, 25.34, 26.14, 26.36, 27.06, 27.30, 28.04, 28.38, 28.98, 29.24 and 31.64. The novel polymorphic Form 2 has characteristic DSC thermogram as depicted in Figure 2 of the accompanied drawing. The DSC thermogram shows one characteristic endothermic peak at130-140°C.
A second aspect of the present invention provides a process for the preparation of novel polymorphic Form 2 of efavirenz which comprises of
a) dissolving efavirenz in a lower alkanol,
b) adding the solution obtained in step a) to a mixture of lower alkanol and salt solution or mixture of lower alkanol and salt solution to the solution obtained in step a) in optional order of succession,
c) stirring the resultant mass for a period exceeding 1.5 hours,
d) isolating Form 2 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 lower alkanol. The solution is added to a mixture of lower alkanol and water in optional order of succession at low temperature. The resultant mass is stirred for a period over 1.5 hours and then filtered. The product obtained is dried under vacuum at about 30-35°C to get Form y2 of efavirenz having characteristic XRD (Figure 1) and DSC (Figure 2).
A third aspect of the present invention provides a pharmaceutical composition comprising polymorphic Form of efavirenz optionally containing an excipient / diluent.
A fourth 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 y2 of efavirenz.
Figure 1 depicts XRD of Form 2 of efavirenz. Figure 2 depicts DSC of Form 2 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 72 OF EFAVIRENZ
Efavirenz (1.0 gm) was dissolved in methanol (1.0 ml) under stirring. This solution was added drop-wise in to a pre-cooled mixture of 15% sodium chloride in water (30 ml) and methanol (3 ml) while maintaining the temperature below -8°C. The resultant mass was stirred at -8 to 5°C for about 3 hours. Then it was filtered and washed with water. The solid was dried in a vacuum oven at a temperature of 30-35°C for 6 hours to get the title compound. Yield: 0.82 gm

WE CLAIM:
1. Polymorphic Form y2 of efavirenz.
2. Polymorphic Form y2 of efavirenz having X-Ray Powder Diffraction (XRPD) pattern as depicted in Figure 1.
3. Polymorphic Form y2 of efavirenz having a XRPD pattern wherein characteristic 2G values are obtained at 12.12, 12.38, 12.98, 13.16, 15.64, 16.90, 17.22, 18.14, 18.42, 18.76, 19.34, 19.48, 19.90, 20.06, 20.32, 21.18, 21.74, 22.04, 23.08, 23.30, 23.98, 24.42, 24.60, 24.94, 25.34, 26.14, 26.36, 27.06, 27.30, 28.04, 28.38, 28.98, 29.24 and 31.64.
4. Polymorphic Form y2 of efavirenz having a DSC thermogram as depicted in Figure 2.
5. Polymorphic Form y2 of efavirenz having a DSC thermogram wherein a characteristic endothermic peak is obtained at 130-140°C.
6. A process for preparation of polymorphic Form y2 of efavirenz wherein the said process comprises of

a) dissolving efavirenz in a lower alkanol,
b) adding the solution obtained in step a) to a mixture of lower alkanol and salt solution or mixture of lower alkanol and salt solution to the solution obtained in step a) in optional order of succession,
c) stirring the resultant mass for a period exceeding 1.5 hours,
d) isolating Form y2 of efavirenz from the reaction mass thereof.
7. A process according to claim 6, wherein the lower alkanol is selected from a group
comprising of methanol, ethanol, n-propanol. isopropanol, n-butanol, isobutanol and t-
butanol or mixtures thereof.

8. A process according to claim 6, wherein the salt is sodium chloride.
9. A process according to claim 8, wherein sodium chloride solution is 10-20% W/V.
10. A pharmaceutical compositions comprising polymorphic Form y2 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 y2 of efavirenz.