Molecular Insights into the Wet Granulation Mechanisms of Drugs with Different Solubilities

Abstract Wet granulation is an interfacial reconstruction process mediated by liquid binders. However, the mechanisms underlying the distinct granulation behaviors of drugs with different solubilities remain poorly understood due to a lack of molecular-level insight. Here, we elucidate these mechanisms using density functional theory (DFT) calculations and molecular dynamics (MD) simulations. Three model drugs with distinct solubilitiesaminophylline (AMI), metformin hydrochloride (MET), and diclofenac sodium (SD)were selected. The results show that differences in granulation behavior cannot be attributed solely to solubility; rather, they arise from variations in interfacial interactions may be governed by crystal structure. Molecular simulations further reveal that crystal structure contributes to macroscopic granulation outcomes by regulating the dynamics of interfacial water molecules.