Drug substances presented as sulfonic acid salts: overview of utility, safety and regulation

Abstract

Controlling genotoxic impurities represents a significant challenge to both industry and regulators. The potential for formation of genotoxic short-chain alkyl esters of sulfonic acids during synthesis of sulfonic acid salts is a long-standing regulatory concern. This review provides a general overview of the utility of sulfonic acids as salt-forming moieties and discusses strategies for effectively minimizing the potential for alkyl sulfonate formation during the synthesis and processing of sulfonate salt active pharmaceutical ingredients. The potential implications of the recent establishment of a substantial human threshold dose for ethyl methanesulfonate for the safety assessment of alkyl sulfonates in general are also discussed. The formation of alkyl sulfonates requires highly acidic conditions, possibly combined with long reaction times and/or elevated temperatures, to generate significant amounts, and these conditions are most unlikely to be present in the synthesis of active pharmaceutical ingredient sulfonate salts. It is possible to design salt formation conditions, using a short-chain alcohol as solvent, to manufacture sulfonate salts that are essentially free of alkyl sulfonate impurities. Processes using non-acidic conditions such as ethanol recrystallization or wet granulation should not raise any concerns of alkyl sulfonate formation. An understanding of the mechanism of formation of alkyl sulfonates is critical in order to avoid restricting or over-controlling sulfonic acid salts, which have many technical advantages as pharmaceutical counterions. Recent regulatory acceptance of a human threshold limit dose of 2 mg/kg per day for ethyl methanesulfonate, indicating that its toxicological risks have previously been considerably overestimated, could signal the beginning of the end over safety concerns on alkyl sulfonate residues, thus removing a major constraint from the exploitation of sulfonic acid counterions.