Formulation Development and Characterization of Ibrutinib-Loaded Liposomes with Molecular Dynamics Insights

This study explored the integration of molecular dynamics (MD) simulations with experimental formulation development toward the rational design of liposomal drug delivery systems using Ibrutinib as model drug. The simulation served as a computationally informed, mechanistically supportive component to aid interpretation of empirical formulation data.

Atomistic MD simulations were used to evaluate drug-lipid miscibility, guide lipid selection and inform the drug-loading method. Ibrutinib-loaded liposomes were prepared using a charge-assisted loading method and optimized through Design of Experiments (DOE). Physicochemical characterization included particle size, zeta potential, encapsulation efficiency, morphology, and in vitro drug release. Coarse-grained (CG) MD simulations were performed to investigate liposome self-assembly, drug localization, and PEGylation effects.

MD simulations predicted favorable miscibility between Ibrutinib and neutral phospholipids, supporting formulation design by the selection of phospholipid and drug-loading method. DOE optimization identified formulation and process parameters associated with high efficiency (> 90%) and nanoscale particle size. Experimental studies showed that lipid composition and PEGylation influenced liposome drug release behavior. CG simulations reproduced liposome self-assembly and suggested preferential localization of Ibrutinib near the lipid-water interface, consistent with charge-based interactions between the lipid and drug.

The combined computational and experimental approach provided complementary molecular-level insights into liposome formulation behavior. Although the simulations did not predict quantitative outcomes, they offered mechanistic context that supported empirical findings. This approach demonstrated the potential utility of integrating MD simulations with experimental studies during early-stage formulation development.