Elucidating the Mechanistic Shortcomings of Acetazolamide Cocrystals in Harnessing the Anticipated Solubility and Permeability Advantages

The previously reported pharmaceutical cocrystals of acetazolamide (ACZ) with highly soluble and lipophilic coformers, including 4-hydroxybenzoic acid (4HBA), salicylamide (SAL), and 4,4′-bipyridine (BIPY), were investigated to enhance the solubility and permeability profiles of ACZ. However, in vitro solubility and dissolution studies revealed that the cocrystals exhibited minimal to no advantage over their respective physical mixtures and/or pure ACZ. To elucidate the underlying mechanism, lattice energy calculations were performed, demonstrating that the high lattice stability of the cocrystals restricted solubility and dissolution enhancement. Additionally, solution-state 1H NMR spectra confirmed that cocrystals and physical mixtures exhibit similar molecular states, further explaining the lack of solubility and dissolution improvement. Caco-2 permeability studies of cocrystals and the pure drug indicated no significant enhancement in ACZ permeability, which was supported by in silico molecular dynamics simulations showing unchanged stability of the ACZ-efflux transporter complex in the presence of coformers. These findings emphasize the limitations of conventional coformer selection strategies and highlight the necessity for predictive tools in pharmaceutical cocrystal design. This study proposes an in combo predictive model to predict cocrystal properties before synthesis, reducing trial-and-error approaches.