Processes for preparation of crystalline mycophenolate sodium

Abstract

Provided are crystalline mycophenolate sodium forms and processes for their preparation.

1 . A process for preparing anhydrous crystalline mycophenolate sodium (Form M2) characterized by a powder XRD pattern with peaks at 5.3, 8.0, 9.8, 10.7, and 21.9±0.2 degrees 2-theta comprising the steps of: 
 (a) preparing a solution of mycophenolic acid in a C 1 -C 4  alcohol;    (b) combining a base and a source of sodium with the solution to obtain a reaction mixture;    (c) crystallizing the crystalline form the mixture; and    (d) recovering the crystalline form.    
     
     
         2 . The process of  claim 1 , wherein the C 1 -C 4  alcohol is methanol.  
     
     
         3 . The process of  claim 1 , wherein the base or source of sodium is sodium methoxide.  
     
     
         4 . The process of  claim 1 , wherein crystallization is carried out by cooling.  
     
     
         5 . The process of  claim 1 , wherein step (d) is carried out after at least 5 hours of crystallization.  
     
     
         6 . The process of  claim 1 , wherein the reaction is carried out at room temperature or above.  
     
     
         7 . The process of  claim 1 , wherein the reaction mixture is heated to a temperature of at least about 35° C. before the crystallizing step.  
     
     
         8 . The process of  claim 1 , further comprising drying the crystalline form.  
     
     
         9 . A process for preparing anhydrous crystalline mycophenolate sodium (Form M2) characterized by a powder XRD pattern with peaks at 5.3, 8.0, 9.8, 10.7, and 21.9±0.2 degrees 2-theta comprising the steps of: 
 (a) preparing a solution of sodium mycophenolate in 1-butanol;    (b) crystallizing the crystalline form from the solution; and    (c) recovering the crystalline form.    
     
     
         10 . The process of  claim 9 , further comprising heating the solution of step (a) at a temperature of at least about 80° C.  
     
     
         11 . The process of  claim 9 , further comprising heating the solution of step (a) at reflux.  
     
     
         12 . A process for preparing anhydrous crystalline mycophenolate sodium (Form M2) characterized by a powder XRD pattern with peaks at 5.3, 8.0, 9.8, 10.7, and 21.9±0.2 degrees 2-theta comprising the steps of: 
 (a) preparing a solution of sodium mycophenolate in ethanol;    (b) crystallizing the crystalline form from the solution;    (c) recovering the crystalline form; and    (d) drying the recovered crystalline form.    
     
     
         13 . The process of  claim 12 , wherein the solution of step (a) is heated to a temperature of at least about 60° C.  
     
     
         14 . The process of  claim 12 , wherein the solution of step (a) is heated to reflux.  
     
     
         15 . The process of  claim 12 , wherein the ethanol is absolute ethanol.  
     
     
         16 . The process of  claim 12 , wherein the recovered crystalline form is dried under atmospheric pressure at room temperature.  
     
     
         17 . A process for preparing anhydrous crystalline mycophenolate sodium (Form M2) characterized by a powder XRD pattern with peaks at 5.3, 8.0, 9.8, 10.7, and 21.9±0.2 degrees 2-theta comprising the steps of: 
 (a) preparing a solution of sodium mycophenolate in methanol;    (b) combining an antisolvent with the solution to precipitate the crystalline form;    (c) recovering the crystalline form; and    (d) drying the recovered crystalline form,    wherein the antisolvent is selected from the group consisting of C 3  to C 8  ketone, ester and mixtures thereof.    
     
     
         18 . The process of  claim 17 , wherein the solvent is selected from the group consisting of ethyl acetate, methyl-tert-butyl ether and mixtures thereof.  
     
     
         19 . The process of  claim 17 , wherein the recovered crystalline form is dried at room temperature.  
     
     
         20 . The process of  claim 17 , wherein recovered crystalline form is dried under atmospheric pressure.  
     
     
         21 . A process for preparing anhydrous crystalline mycophenolate sodium (Form M2) characterized by a powder XRD pattern with peaks at 5.3, 8.0, 9.8, 10.7, and 21.9±0.2 degrees 2-theta comprising the steps of: 
 (a) preparing a solution of sodium mycophenolate in methanol;    (b) combining the solution with an antisolvent to precipitate the crystalline form; and    (c) recovering the crystalline form,    wherein the antisolvent is selected from the group consisting of C 3  to C 8  ketone, C 3  to C 8  ester, C 2  to C 8  ether, C 2  to C 4  alcohol, nitromethane, tetrahydrofuran and mixtures thereof.    
     
     
         22 . The process of  claim 21 , wherein the solvent is selected from the group consisting of acetone, isopropanol, tetrahydrofuran, diisopropyl ether, nitromethane, isobutanol, and mixtures thereof.  
     
     
         23 . A process for preparing anhydrous crystalline mycophenolate sodium (Form M2) characterized by a powder XRD pattern with peaks at 5.3, 8.0, 9.8, 10.7, and 21.9±0.2 degrees 2-theta comprising the steps of: 
 (a) preparing a solution of mycophenolic acid in a mixture of dichloromethane and methanol; and    (b) combining a base and a source of sodium with the solution to precipitate the crystalline form; and    (c) recovering the crystalline form.    
     
     
         24 . The process of  claim 23 , wherein sodium methoxide in methanol is added to the solution.  
     
     
         25 . The process of  claim 23 , further comprising a C 5  to C 7  cyclic or acyclic saturated hydrocarbon before the crystalline form.