Sulfonate esters of lower alcohols possess the capacity to react with DNA and cause mutagenic events, which in turn may be cancer inducing. Consequently, the control of residues of such substances in products that may be ingested by man (in food or pharmaceuticals) is of importance to both pharmaceutical producers and to regulatory agencies. Given that a detailed study of sulfonate ester reaction dynamics (mechanism, rates, and equilibria) has not been published to date, a detailed kinetic and mechanistic study was undertaken and is reported herein as a follow-up to our earlier communication in this journal. The study definitively demonstrates that sulfonate esters cannot form even at trace level if any acid present is neutralized with even the slightest excess of base. A key conclusion from this work is that the high level of regulatory concern over the potential presence of sulfonate esters in API sulfonate salts is largely unwarranted and that sulfonate salts should not be shunned by innovator pharmaceutical firms as a potential API form. Other key findings are that (1) an extreme set of conditions are needed to promote sulfonate ester formation, requiring both sulfonic acid and alcohol to be present in high concentrations with little or no water present; (2) sulfonate ester formation rates are exclusively dependent upon concentrations of sulfonate anion and protonated alcohol present in solution; and (3) acids that are weaker than sulfonic acids (including phosphoric acid) are ineffective in protonating alcohol to catalyze measurable sulfonate ester even when a high concentration of sulfonate anion is present and water is absent. Implications of the mechanistic and kinetic findings are discussed under various situations where sulfonic acids and their salts are typically used in active pharmaceutical ingredient (API) processing, and kinetic models are presented that should be of value to process development scientists in designing appropriate controls in situations where risk for sulfonate ester formation does exist.

The use of a reaction calorimeter in combination with kinetic modeling software to obtain nonisothermal kinetic data is presented. The Diels−Alder reaction of maleic anhydride and isoprene in DMF was used as a model to demonstrate the feasibility of the method. The Arrhenius A factor and the activation energy could be achieved from a single experiment with a reaction calorimeter (Mettler RC1) by fitting the experimental heat generation curve to a second-order kinetic model using commercially available software packages. The use of fitting software revealed a discrepancy between the experimental reaction heat and the heat calculated from the rate parameters. This discrepancy could be resolved by reintegration of the heat generation curve using an adjusted baseline derived from the rate data. The methodology was applied by varying reaction conditions (starting concentrations, heat rate, temperature range), and the results appeared to be independent of these variations within the experimental errors (E a = 58.5 ± 2.0 kJ mol-1, A factor 4.02 × 106 L mol-1 s-1). It is shown by comparison with literature data that this fast method generates kinetic parameters with a sufficient reliability to be used with process-modeling tools for computer-supported scale-up.