Novel polymorphs of efavirenz

Abstract

The present invention relates to novel amorphous and crystalline forms of efavirenz, processes for their preparation and pharmaceutical compositions containing them. In accordance with the present invention efavirenz crude is dissolved in acetone at 25° C.-30° C., the solution is slowly added to water for 30 minutes at 0° C.-5° C., stirred for 1 hour at the same temperature, the separated solid is filtered, washed with water and dried at 55° C.-60° C. for 5 hours to give amorphous efavirenz.

1 . Amorphous efavirenz.  
   
   
       2 . A process for preparation of amorphous efavirenz of  claim 1 , which comprises: 
 a) precipitating from a solution of efavirenz in a C 3 -C 8 -ketonic solvent by using water as precipitating solvent at below about 15° C. and collecting the precipitated solid; and    b) drying the solid collected at about 40° C.-65° C. to obtain amorphous efavirenz.    
   
   
       3 . The process according to  claim 2 , wherein the ketonic solvent is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone and diethyl ketone.  
   
   
       4 . The process according to  claim 3 , wherein the ketonic solvent is selected from acetone and diethyl ketone.  
   
   
       5 . The process according to  claim 4 , wherein the ketonic solvent is acetone.  
   
   
       6 . The process according to  claim 2 , wherein the precipitation in step (a) is carried out at about 0° C.-10° C.  
   
   
       7 . The process according to  claim 6 , wherein the precipitation is carried out at about 2° C.-5° C.  
   
   
       8 . The process according to  claim 2 , wherein the temperature range of drying is at about 50° C.-60° C.  
   
   
       9 . The process according to  claim 8 , wherein the temperature range is at about 55° C.-60° C.  
   
   
       10 . The process according to  claim 2 , wherein the process is carried out by precipitating from a solution of efavirenz in a C 3 -C 8 -ketonic solvent by adding the said solution to water at about 0° C.-10° C., collecting the precipitated solid by filtration or centrifugation and drying the solid collected at about 40° C.-65° C. to obtain amorphous efavirenz.  
   
   
       11 . The process according to  claim 10 , wherein the ketonic solvent is acetone, the precipitation is carried out at about 2° C.-5° C. and drying is carried out about 55° C.-60° C.  
   
   
       12 . A crystalline efavirenz form H1, characterized by an x-ray powder diffraction spectrum having peaks expressed as 29 at about 5.4, 10.4, 11.6, 12.5, 15.3, 20.1, 20.8, 22.5, 23.1, 25.7, 27.9, 28.5, 28.8, 29.5, 30.2 and 38.2 degrees.  
   
   
       13 . A crystalline efavirenz form H1 as defined in  claim 12 , further characterized by a x-ray powder diffraction spectrum as in  FIG. 2 .  
   
   
       14 . A process for preparation of efavirenz form H1 as defined in  claim 12 , which comprises: 
 a) precipitating from a solution of efavirenz in a C 1 -C 6 -alcoholic, C 3 -C 8 -ketonic solvent or a mixture thereof by using water as precipitating solvent at below about 15° C., collecting the precipitated solid;    b) drying the solid collected at about 25° C.-35° C. until the water content falls in the range 2-10 % of the solid by weight; and    c) drying the solid obtained in (b) at about 40° C.-55° C. to obtain crystalline efavirenz form H1.    
   
   
       15 . The process according to  claim 14 , wherein the alcoholic solvent is selected from ethanol, n-propanol, n-butanol, isopropanol and methanol.  
   
   
       16 . The process according to  claim 15 , wherein the alcoholic solvent is n-propanol.  
   
   
       17 . The process according to  claim 14 , wherein the ketonic solvent is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone and diethyl ketone.  
   
   
       18 . The process according to  claim 17 , wherein the ketonic solvent is selected from acetone and diethyl ketone.  
   
   
       19 . The process according to  claim 18 , wherein the ketonic solvent is acetone.  
   
   
       20 . The process according to  claim 14 , wherein the precipitation in step (a) is carried out at about 0° C.-10° C.  
   
   
       21 . The process according to  claim 20 , wherein the precipitation is carried out at about 2° C.-5° C.  
   
   
       22 . The process according to  claim 14 , wherein the drying in step (b) is carried out until the water content falls in the range 2-5% of the solid by weight.  
   
   
       23 . The process according to  claim 14 , wherein the temperature range of drying in step (c) is at about 40° C.-50° C.  
   
   
       24 . The process according to  claim 23 , wherein the temperature range is at about 40° C.-45° C.  
   
   
       25 . The process according to  claim 14 , wherein the process is carried out by precipitating from a solution of efavirenz in a C 1 -C 6 -alcoholic solvent, C 3 -C 8 -ketonic solvent or a mixture thereof by adding the said solution to water al about 0° C.-10° C.; collecting the precipitated solid by filtration or cenlrifligation; drying the precipitated solid at about 25° C.-35° C. until the water content is 2-5%; and drying the solid obtained at about 40° C.-55° C. to obtain crystalline efavirenz form H1.  
   
   
       26 . The process according to  claim 25 , wherein the alcoholic solvent is n-propanol or isopropanol, ketonic solvent is acetone or diethyl kpione, the precipitation is carried out at about 2° C.-5° C. and drying is carried out about 40° C.-50° C.  
   
   
       27 . A pharmaceutical composition comprising amorphous efavirenz of  claim 1  and a pharmaceutically acceptable excipeint.  
   
   
       28 . A pharmaceutical composition comprising crystalline efavirenz form H1 of  claim 14  and a pharmaceutically acceptable excipeint.