Unraveling the Link between Solvent-Mediated Proton Transfer and the Salt Formation of Saccharin and Sulfamethazine

Molecular tautomerism has been reported to play an important role in the crystallization of active pharmaceutical ingredients, particularly in the formation of pharmaceutical cocrystals and salts. In this work, by combining molecular modeling, crystallization experiments, and spectroscopic techniques, we investigate possible molecular mechanisms by which solvent can mediate proton transfer in a tautomerization process. We found that the salt formation of sulfamethazine-saccharin takes place in the presence of protic solvent (ethanol, water), but is prohibited in aprotic solvent such as toluene. Our density functional theory calculations reveal that protic (polar) solvents such as ethanol and water facilitate proton transfer, serving as catalysts of the transformation of saccharin into its tautomerized (enol) form, being a prerequisite to the formation of the salt. In line with these predictions, our FTIR results confirm that the proton transfer and the resulting transformation from the keto to enol form of saccharin does not take place in aprotic chloroform, but is clearly observed in protic ethanol solution. We believe that the mechanistic insight provided by our study will aid rational solvent selection for the crystallization processes involving molecules with propensity for tautomerization.