Mechanism and Processing Parameters Affecting the Formation of Methyl Methanesulfonate from Methanol and Methanesulfonic Acid: An Illustrative Example for Sulfonate Ester Impurity Formation

Sulfonate salts offer useful modification of physicochemical properties of active pharmaceutical ingredients (APIs) containing basic groups, but there are regulatory concerns over the presence of sulfonate esters as potential genotoxic impurities (PGIs). Whilst sulfonate esters could theoretically result from interaction between sulfonic acids and alcohols, literature on their formation is sparse. GC−MS analysis of reactions of methanesulfonic acid (MSA) and isotopically labeled methanol (18O-label) confirm methanol C−O bond cleavage in the formation of the methyl methanesulfonate (MMS), consistent with reversal of well-established mechanisms for solvolysis of sulfonate esters. Studies of reaction profiles quantify methyl methanesulfonate formation under a range of conditions relevant to API processing. Maximum conversion to MMS in reaction mixtures was 0.35%, determined by analytical methods developed specifically for reaction mixture analysis. Sulfonate ester formation is dramatically reduced at lower t...