Novel processes for making- and a new crystalline form of- leflunomide

Abstract

New leflunomide Form III is disclosed, along with processes for preparing it. The present invention also provides an economic process for preparing leflunomide Form II and a process for preparing leflunomide Form I from leflunomide Form III. Pharmaceutical compositions and dosage forms containing the new form and methods of using them for the treatment of rheumatoid arthritis are also disclosed.

1 - 7 . (canceled).  
     
     
         8 . A process for preparing leflunomide Form II comprising the steps of 
 a) dissolving leflunomide in a solvent to form a leflunomide solution,    b) crystallizing leflunomide Form II from the leflunomide solution at a temperature of 0° C. or above, and    c) isolating leflunomide Form II.    
     
     
         9 . The process of  claim 8 , wherein the leflunomide is selected from any of leflunomide Forms I, II and III or their mixtures.  
     
     
         10 . The process of  claim 8 , wherein crystallization of leflunomide Form II is induced by adding an anti-solvent to the leflunomide solution or by cooling of the solution.  
     
     
         11 . The process of  claim 10 , wherein the anti-solvent is selected from the group consisting of water and C 5 -C 8  alkanes.  
     
     
         12 . The process of  claim 11 , wherein the C 5 -C 8  alkanes are selected from the group consisting of hexanes, and mixtures hexanes with pentanes.  
     
     
         13 . The process of  claim 12 . wherein the C 5 -C 8  alkane is n-hexane.  
     
     
         14 . The process of  claim 8 , wherein the step of dissolving the leflunomide in a solvent further comprises heating the solvent.  
     
     
         15 . The process of  claim 8 , wherein the solvent is selected from the group consisting of 2-ethoxyethanol, dimethylsulfoxide, isopropyl alcohol, methanol, dioxane, ethyl acetate, 1,3-dimethyl-2-imidazolidinone, 1,2-dimethoxyethane, acetone and N,N-dimethyl formamide.  
     
     
         16 . The process of  claim 15 , wherein the solvent is selected from the group consisting of N,N-dimethyl formamide, 1,3-dimethyl-2-imidazolidinone and dioxane.  
     
     
         17 . A process for preparing leflunomide Form III comprising the steps of 
 dissolving leflunomide in a solvent to form a leflunomide solution, crystallizing leflunomide Form III from the leflunomide solution, and isolating leflunomide Form III.    
     
     
         18 . The process of  claim 17  wherein the solvent is 2-pyrrolidone.  
     
     
         19 . The process of  claim 17  wherein the step of dissolving leflunomide in the solvent further comprises heating the solvent to an elevated dissolution temperature of 45° C. or above.  
     
     
         20 . The process of  claim 19  wherein the elevated dissolution temperature is about 55° C.  
     
     
         21 . The process of  claim 17  wherein the solvent is a mixture of 2-pyrrolidone and water.  
     
     
         22 . A process for preparing leflunomide Form III comprising the steps of 
 dissolving leflunomide in an amount of a water-miscible solvent to form a leflunomide solution;    adding water to the leflunomide solution; and    isolating crystals of leflunomide Form III.    
     
     
         23 . The process of  claim 22  wherein the solvent is 2-pyrrolidone.  
     
     
         24 . The process of  claim 23  wherein the ratio of water to solvent is about 2:5.  
     
     
         25 - 30 . (canceled).