Methods for producing viloxazine salts and novel polymorphs thereof

Abstract

Provided here are methods of manufacture of viloxazine and its various salts, as well as viloxazine-related compounds, such as novel intermediate reaction products and polymorphs thereof. In particular, the methods provide a substantially pure API of viloxazine HCl while avoiding undesirable impurities. The methods further provide for separating, identifying, and characterizing novel polymorphs of viloxazine. Further provided are methods for synthesis and identification and characterization of novel intermediates of viloxazine, as well as for some important metabolites and precursors of metabolites of viloxazine.

1 .- 32 . (canceled) 
     
     
         33 . A substantially pure composition consisting essentially of viloxazine or its pharmaceutically acceptable salt and comprising genotoxic impurities, per daily viloxazine dose of up to 800 mg, less than 1.6 ppm of epichlorohydrin, less than 1.6 ppm of 1-(ethoxyphenoxy)-2,3-epoxypropane, less than 1.6 ppm of para-toluenesulfonate ethyl ester (EE), less than 1.6 ppm of para-toluenesulfonate isopropyl ester (IE), less than 1.6 ppm of para-toluenesulfonate 2-aminoethyl ester (AE), less than 1.6 ppm of para-toluenesulfonate N-benzyl-2-aminoethyl ester (BE). 
     
     
         34 . A substantially pure composition consisting essentially of viloxazine or its pharmaceutically acceptable salt, wherein viloxazine or its pharmaceutically acceptable salt comprises, per daily viloxazine dose of up to 800 mg, less than 1.6 ppm of epichlorohydrin. 
     
     
         35 . A substantially pure composition consisting essentially of viloxazine or its pharmaceutically acceptable salt, wherein viloxazine or its pharmaceutically acceptable salt comprises, per daily viloxazine dose of up to 800 mg, less than 1.6 ppm of 1-(ethoxyphenoxy)-2,3-epoxypropane. 
     
     
         36 . A substantially pure composition consisting essentially of viloxazine or its pharmaceutically acceptable salt, wherein viloxazine or its pharmaceutically acceptable salt comprises, per daily viloxazine dose of up to 800 mg, less than 1.6 ppm of para-toluenesulfonate ethyl ester (EE). 
     
     
         37 . A substantially pure composition consisting essentially of viloxazine or its pharmaceutically acceptable salt, wherein viloxazine or its pharmaceutically acceptable salt comprises, per daily viloxazine dose of up to 800 mg, less than 1.6 ppm of para-toluenesulfonate isopropyl ester (IE). 
     
     
         38 . A substantially pure composition consisting essentially of viloxazine or its pharmaceutically acceptable salt, wherein viloxazine or its pharmaceutically acceptable salt comprises, per daily viloxazine dose of up to 800 mg, less than 1.6 ppm of para-toluenesulfonate 2-aminoethyl ester (AE). 
     
     
         39 . A substantially pure composition consisting essentially of viloxazine or its pharmaceutically acceptable salt, wherein viloxazine or its pharmaceutically acceptable salt comprises, per daily viloxazine dose of up to 800 mg, less than 1.6 ppm of para-toluenesulfonate N-benzyl-2-aminoethyl ester (BE). 
     
     
         40 . A substantially pure composition consisting essentially of viloxazine or its pharmaceutically acceptable salt and comprising genotoxic impurities epichlorohydrin, 1-(ethoxyphenoxy)-2,3-epoxypropane, para-toluenesulfonate ethyl ester (EE), para-toluenesulfonate isopropyl ester (IE), para-toluenesulfonate 2-aminoethyl ester (AE), and para-toluenesulfonate N-benzyl-2-aminoethyl ester (BE). 
     
     
         41 . A substantially pure composition consisting essentially of viloxazine or its pharmaceutically acceptable salt, wherein viloxazine or its pharmaceutically acceptable salt comprises, per daily viloxazine dose of up to 800 mg, less than 2.1 ppm of the total of the four p-toluene sulfonate impurities (para-toluenesulfonate ethyl ester (EE), para-toluenesulfonate isopropyl ester (IE), para-toluenesulfonate 2-aminoethyl ester (AE), and para-toluenesulfonate N-benzyl-2-aminoethyl ester (BE)). 
     
     
         42 . A substantially pure composition consisting essentially of viloxazine or its pharmaceutically acceptable salt and comprising less than 5 micrograms of genotoxic impurities per daily viloxazine dose of up to 800 mg. 
     
     
         43 . A substantially pure composition consisting essentially of viloxazine or its pharmaceutically acceptable salt and comprising:
 a) the genotoxic impurity epichlorohydrin having the formula   
       
         
           
           
               
               
           
         
         b) the genotoxic impurity 1-(ethoxyphenoxy)-2,3-epoxypropane having the formula 
       
       
         
           
           
               
               
           
         
         c) the genotoxic impurity para-toluenesulfonate ethyl ester (EE) having the formula 
       
       
         
           
           
               
               
           
         
         d) the genotoxic impurity para-toluenesulfonate isopropyl ester (IE) having the formula 
       
       
         
           
           
               
               
           
         
         e) the genotoxic impurity para-toluenesulfonate 2-aminoethyl ester (AE) having the formula 
       
       
         
           
           
               
               
           
         
       
       and
 f) the genotoxic impurity para-toluenesulfonate N-benzyl-2-aminoethyl ester (BE) having the formula