Formulation optimization and real-time size monitoring in the semi-continuous production of edaravone-loaded...

Recently, we established a semi-continuous top-down process enabling the solvent-free production of drug-free lipid-based nanosystems. In this study, the applicability of the established process line to drug-loaded nanosystems was evaluated, focusing on whether process parameters require adjustment upon drug incorporation. Edaravone was selected as a model drug and encapsulated in nanostructured lipid carriers (NLC) composed of Precirol® ATO 5 or Gelucire® 43/01 as solid lipids, combined with Labrafac™ Lipophile WL 1349 or Capryol® 90 as liquid lipids, as well as in nanoemulsions (NEs) consisting solely of the liquid lipids. Integration of the NanoFlowSizer enabled real-time size monitoring via spatially resolved dynamic light scattering (SR-DLS) during Microfluidizer® processing and allowed detection of potential formulation instabilities caused by altered intermolecular interactions following drug incorporation. Design of Experiments (DoE) was employed to optimize encapsulation efficiency (EE%) and loading capacity (LC%). Initial lipid screening revealed superior compatibility of Labrafac™ Lipophile WL 1349 over Capryol® 90 with both solid lipids and edaravone. Gelucire®-based NLC achieved EE% and LC% up to 47 % and 0.9 %, respectively, while Labrafac™-based NEs reached 86 % EE% and 1.7 % LC%. Higher drug concentrations (2 %) led to increased NLC sizes compared to lower concentrations (0.8 %). Lipid type was identified as the most influential formulation parameter, while the solid to liquid lipid ratio and drug concentration had minor effects. Combining inline and offline SR-DLS measurements enabled early detection of subtle instabilities such as micelle formation and particle agglomeration, outperforming conventional offline DLS. Overall, the findings underscore the versatility and robustness of the semi-continuous, solvent-free production line with integrated SR-DLS as a powerful platform for the efficient development of lipid-based nanocarriers with improved drug loading, stability, and process control.