Hydrogen-Bond Synthon Preferences in Cocrystals of Acetazolamide

Acetazolamide (ACZ) is an active pharmaceutical ingredient with three main functional groups that can participate in a variety of hydrogen bond interactions. Here, we describe a series of cocrystals incorporating ACZ and cocrystal formers (CCFs) containing only aromatic nitrogen acceptor sites. We demonstrate one cocrystal wherein the CCF engages with ACZ at both of its hydrogen-bond donor sites, a behavior not commonly observed in ACZ cocrystals. We expand to include CCFs containing acceptor and donor moieties, and perform pK_a calculations for ACZ, CCFs in this work, and previously reported pyridine-based CCF–ACZ cocrystals. Finally, we discuss pK_a values, basicity, and geometric complementarity as methods for predicting synthon formation in ACZ cocrystals.