An exploration of the solvent- and acid-catalyzed mutarotation mechanisms of lactose in aqueous solution

Abstract

Lactose, the characteristic carbohydrate of milk, is a high-value product applied as an excipient in pharmaceutical formulations and as a carrier in dry-powder inhalers when purified. Usually, lactose is in the mutarotation equilibrium of two anomers in solution, the α and the β forms. This work has dealt theoretically with the mutarotation mechanisms of α-lactose catalyzed by solvent water molecules and acid molecules, including acetic acid (HAc) and trifluoroacetic acid (TFA). The whole mutarotation process is comprised of three stages, i.e., the initial ring-opening step, the isomerization of anomeric carbon C1 followed by the ring-closing step, in which, the ring-opening step involves the highest activation energy and therefore is the rate-determining step. The activation energies along the optimum mutarotation routes catalyzed by H₂O, HAc and TFA molecules are 22.1, 13.5 and 8.7 kcal mol⁻¹, respectively. All the transition states involved in the optimum ring-opening/closing reaction coordinates are octatomic ring structures with the presence of two solvent water molecules or one acid molecule. For the acid-catalyzed rate-determining step, the reaction driving force originates from the protonation of the sugar ring O5 atom by the carboxyl hydrogen atom, whereas for the solvent-catalyzed process, it originates from the transfer of C1–hydroxyl hydrogen. The ease of lactose mutarotation depends greatly on the acidity of the catalyst. The obtained observation can provide more valuable information for pharmaceutical science.