Molecular insight into hygroscopicity-driven stability in multicomponent piroxicam solid dispersions: Experimental and molecular dynamics studies

Formulation composition dictates hygroscopicity in multicomponent SDs. • Hydrophilic components promote water uptake and H-bond network formation. • Hygroscopicity-driven drug mobility accelerates aggregation and recrystallization. • MD simulations reveal water-distribution-controlled SD stability. • Hygroscopicity governs the solubility–stability balance in SD design. Multicomponent solid dispersions (SDs) show substantial potential for improving the solubility of poorly water-soluble drugs, yet the molecular-level factors influencing their long-term physical stability remain insufficiently understood. In this study, piroxicam binary (PRX-BSD), ternary (PRX-TSD), and quaternary (PRX-QSD) solid dispersions were systematically investigated by combining experimental characterization with molecular dynamics (MD) simulations. PRX-BSD and PRX-TSD established hydrophilic microenvironments and increased PRX solubility from 28.719 μg/mL to approximately 150 μg/mL, whereas PRX-QSD generated an alkaline microenvironment that further increased solubility to 2010.77 μg/mL. During storage, PRX-BSD and PRX-TSD exhibited limited hygroscopicity, gradual crystallinity evolution and well-preserved dissolution performance. In contrast, Na 2 CO 3 -containing PRX-QSD displayed pronounced hygroscopicity and accelerated amorphous recrystallization, leading to a marked reduction in solubility to 92.14 μg/mL. MD simulations provided molecular-level insights into the formulation-dependent hydration behavior and molecular mobility of PRX-SDs. In PRX-BSD and PRX-TSD, water molecules were preferentially localized around PVP VA64 and Tween 80, forming relatively sparse water-mediated hydrogen-bonding networks. In contrast, Na 2 CO 3 in PRX-QSD acted as a strong water-anchoring component, promoting localized water accumulation and denser hydrogen-bonding interactions, which were associated with increased PRX mobility and PRX-PRX interaction tendency. These molecular-level observations provided a further explanation for the experimentally observed recrystallization and solubility loss during storage. Overall, this study highlights the important role of formulation-dependent hygroscopicity in the balancing solubility enhancement and long-term physical stability, providing molecular insights for the rational design of multicomponent SDs. Download: Download high-res image (528KB) Download: Download full-size image