Elucidating the role of TPGS in felodipine/PVPVA amorphous solid dispersions during water uptake: dissipative particle dynamics simulations using quantum chemistry-based interaction parameters.

Amorphous solid dispersions (ASDs) are an effective formulation approach for improving the solubility of poorly water-soluble drugs. Nevertheless, their drug-release performance depends on the phase separation morphology during the dissolution process. Although the addition of surfactants has been experimentally reported to improve the dissolution behavior of ASDs, experimental methods alone are insufficient to resolve the complex and heterogeneous intermolecular interactions between drugs and excipients in multicomponent systems at the molecular level. In this study, we used dissipative particle dynamics simulations, which efficiently analyze mesoscopic phenomena such as phase separation, to elucidate the mechanisms of drug aggregation, water uptake, and phase separation, and to discuss their potential implications for drug-release behavior. Interaction parameters (χ) were derived from quantum chemical calculations and used to parameterize the coarse-grained model. We compared binary ASDs composed of felodipine and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA) with ternary ASDs that additionally contained the surfactant d-α-tocopherol polyethylene glycol 1000 succinate (TPGS), focusing on the functional role of the surfactant. Results suggested that the balance between water uptake and drug aggregation may influence drug release behavior from ASDs, potentially through interfacial liquid-liquid phase separation (LLPS)-related organization. In particular, simulations of the ternary system containing TPGS showed reduced mesoscale drug aggregation through accelerated hydration, suppression of interfacial energy growth, and steric stabilization by TPGS molecules. These structural features may facilitate drug diffusion into the aqueous phase. These simulation-derived behaviors are consistent with previous experimental observations. Overall, this study provides a mechanistic, simulation-based framework for understanding phase separation behavior and its potential influence on drug release processes in ASDs, drug release processes in ASDs, thereby guiding formulation design, particularly for surfactant-containing systems.