Enzalutamide polymorphic forms and its preparation

Abstract

The present application relates to crystalline and amorphous forms of Enzalutamide. The present application further relates to amorphous solid dispersions of Enzalutamide with pharmaceutically acceptable carriers. The present application also relates to a process for the preparation of Form R1 of Enzalutamide.

1 . A process for preparing crystalline form R1 of enzalutamide, which comprises:
 a) providing a solution of enzalutamide in a solvent; and   b) isolating crystalline enzalutamide form R1.   
     
     
         2 . The process of  claim 1 , wherein the solvent in step a) is selected from C 1 -C 6  alcohols, nitriles, amides, sulfoxides, halogenated hydrocarbons, aromatic hydrocarbons, esters, ethers, ketones, water, acetic acid or mixtures thereof 
     
     
         3 . The process of  claim 2 , wherein the solvent is selected from methanol, ethanol, 1-propanol, isopropyl alcohol, 1-butanol, 2-butanol, t-butyl alcohol, acetonitrile, propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethylsulfoxide, dichloromethane, toluene, xylene, ethyl acetate, n-propyl acetate, n-butyl acetate, isopropyl acetate, isobutyl acetate, t-butyl acetate, diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, anisole, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, water, acetic acid or mixtures thereof. 
     
     
         4 . The process of  claim 1 , wherein the isolation of crystalline form R1 in step b) is carried out by cooling, crash cooling, concentrating, adding an anti-solvent, adding seed crystals or evaporation or combinations thereof. 
     
     
         5 . The process of  claim 4 , wherein the anti-solvent is selected from water, saturated, unsaturated, linear, branched, cyclic or acyclic C 1  to C 10  hydrocarbons or ethers or mixtures thereof. 
     
     
         6 . The process of  claim 5 , wherein the anti-solvent is selected from hexanes, heptane, cyclohexane, methylcyclohexane, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or dimethoxyethane or mixtures thereof. 
     
     
         7 . Crystalline form R2 of enzalutamide. 
     
     
         8 . The crystalline form R2 of enzalutamide of  claim 7 , further characterized by its powder X-ray diffraction pattern having additional peaks at about 9.7±0.2, 14.5±0.2, 15.6±0.2, 16.9±0.2 and 25.5±0.2 degrees 2-theta. 
     
     
         9 . The crystalline form R2 of enzalutamide of  claim 7 , characterized by a PXRD pattern substantially as illustrated by  FIG. 2 . 
     
     
         10 . A process for preparing the crystalline form R2 of enzalutamide of  claim 7 , which comprises:
 a) providing a solution of enzalutamide in methanol or formic acid; and   b) isolating crystalline enzalutamide Form R2.   
     
     
         11 . An amorphous form of enzalutamide. 
     
     
         12 . A process for preparing the amorphous form of enzalutamide of  claim 11  comprising:
 a) providing a solution of enzalutamide in a solvent; and 
 b) isolating amorphous form of enzalutamide. 
 
     
     
         13 . Amorphous solid dispersion comprising enzalutamide and one or more pharmaceutically acceptable carriers. 
     
     
         14 . A process for preparing the amorphous solid dispersion comprising enzalutamide of  claim 13  comprising:
 a) providing a solution of enzalutamide and one or more pharmaceutically acceptable carriers in a suitable solvent or mixture of solvents; and 
 b) isolating amorphous solid dispersion comprising enzalutamide and one or more pharmaceutically acceptable carriers. 
 
     
     
         15 . The crystalline form R2 of enzalutamide of  claim 7 ,
 characterized by its powder X-ray diffraction (PXRD) pattern having one or more peaks at about 4.8±0.2, 11.3±0.2 and 20.2±0.2 degrees 2-theta.