Modelling lung permeability of pharmaceuticals: The effectiveness of biomimetic open tubular capillary electrochromatography and immobilised artificial membrane chromatography coupled with mass spectrometry

In this study, the potential of mass spectrometry (MS) -compatible biomimetic chromatography (BMC) was explored to assess drug permeability across biological membranes, pioneering a comparison of its application to model pulmonary absorption. Two BMC techniques were evaluated i.e., immobilised artificial membrane liquid chromatography (IAM-LC) and open-tubular capillary electrochromatography (OT-CEC) on fused silica capillaries coated with phospholipid vesicles. This application was validated on a dataset of 53 structurally diverse compounds whose pulmonary permeability is already evidenced in scientific literature. The IAM-LC model exhibited a stronger correlation with conventional n-octanol/water partitioning metrics (log P_o/w and log D_7.4) than OT-CEC. Analytical retention appeared to be influenced by a complex interplay of hydrophobic, electrostatic, and structural factors, leading to weaker correlations particularly with log P_o/w. Coupling these techniques with MS enabled high-throughput analysis of mixtures and allowed detection of compounds lacking UV chromophores. The MS-based IAM-LC approach demonstrated excellent robustness with data obtained using a CE setup with UV detection (R² = 0.95). On the other hand, stable phospholipid coatings were achieved in OT-CEC-MS providing effectiveness across varying liposomal compositions. IAM-LC, mimicking a phosphatidylcholine (PC) -based lipid bilayer, displayed a strong correlation between log k_w^IAM and log P_app, with an R² value of 0.72 observed for compounds with molecular masses > 300 g mol^-1 where paracellular diffusion is negligible. Meanwhile, OT-CEC-MS allowed for the incorporation of phospholipids other than PC in the stationary phase, offering complementary insights into drug-membrane interactions beyond partitioning. The strongest correlations between IAM-LC and OT-CEC parameters were observed for cationic species with log K_D > 1.5. These techniques demonstrated significant potential to support drug development programmes in both industrial and academic settings by facilitating high-throughput permeability screening and pharmacokinetics -focused lead optimisation.