Mechanism of Hydrolytic Instability of ZIF-8 in Aqueous and Buffered Media: Implications on Drug Delivery Applications

Despite widespread assumptions of ZIF-8 stability in aqueous media, we demonstrate that the apparent endurance of ZIF-8 is largely misconceived as thermodynamic stability rather than correctly ascribed as kinetic stability under a certain experimental setup. In unbuffered solutions, the rapid release of zinc and 2-methylimidazole ligands causes an instantaneous pH spike, which inhibits further degradation. This self-protective mechanism is, however, nullified in buffered environments, where ZIF-8 undergoes a rapid and spontaneous decomposition. Our findings ascertain a critical thermodynamic instability of ZIF-8 under physiologically relevant conditions. The findings of this investigation necessitate a fundamental re-evaluation of ZIF-8 suitability for water-based applications, particularly drug delivery. Furthermore, the insights and methodology presented herein provide a crucial framework for predicting the stability of similar metal–organic frameworks in aqueous solutions under biologically relevant conditions.