Mutagenic Alkyl-Sulfonate Impurities in Sulfonic Acid Salts: Reviewing the Evidence and Challenging Regulatory Perceptions

Abstract

Alkyl sulfonates are direct-acting bacterial mutagens and are almost universally regarded by regulatory authorities to be potential impurities in drug substances presented as sulfonic acid salts, particularly if synthesized using an alcohol solvent. A detailed review of the available public domain data indicates that regulatory policy appears to be based on speculation, assumption, and assertion rather than actual evidence. Ester formation from a sulfonic acid in the presence of an alcohol is an extremely slow and thermodynamically unfavored reaction requiring strongly acidic conditions to produce even minimal conversion. Following addition of an equimolar amount of a sulfonic acid to a pharmaceutical base (the active), proton transfer to form an acid salt occurs instantaneously, thus neutralizing the acid and precluding any ester formation as a side reaction even if an alcoholic solvent is employed. Other possible routes to sulfonic acid ester formation by interaction of an alcohol with preformed sulfoni...