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.