Impact of Formulation Ingredient Compatibility on Encapsulation of Hydrophobic Substances in Polymeric Nanocarriers Prepared by Nanoprecipitation

As a versatile platform technology, polymer nanoparticles enable the effective delivery of hydrophobic drug substances. To achieve therapeutic efficacy, adequate drug loading is required, which requires a quantitative understanding of formulation component affinities. In this study, we investigate how the choice of organic solvent affects drug loading in poly(lactic‐ co ‐glycolic) acid (PLGA) nanoparticles prepared by nanoprecipitation. For the encapsulation of various 1,4‐naphthoquinone derivatives used as model substances, we observe a correlation between drug loading and the Hansen solubility parameter distance ( R a ) between the drug and the organic solvents. To elucidate the interactions at the nanoscale level thin polymer films are analyzed using atomic force microscopy (AFM), quantifying surface pore formation as an indicator of interaction. Additionally, scanning electron microscopy (SEM) and differential scanning calorimetry (DSC) were utilized to investigate drug–polymer miscibility. A concentration‐dependent phase separation in drug‐polymer matrices was observed, which correlates with the drug loading in the nanoparticles. This work emphasizes the need to move beyond trial‐and‐error approaches by the incorporation of predictive parameters like Hansen solubility parameter‐derived affinities and solid‐state solubility metrics into formulation strategies.