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

Dillon, Amy; Perera, Dumidu; Orzel, Dorota; Wiedmer, Susanne K.; Russo, Giacomo

Abstract

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 Po/w and log D7.4) 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 Po/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 C 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 kwIAM and log Papp, 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 KD > 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.

Citation

Dillon, A., Perera, D., Orzel, D., Wiedmer, S. K., & Russo, G. (2025). Modelling lung permeability of pharmaceuticals: The effectiveness of biomimetic open tubular capillary electrochromatography and immobilised artificial membrane chromatography coupled with mass spectrometry. International Journal of Pharmaceutics. Advance online publication. https://doi.org/10.1016/j.ijpharm.2025.126356

• Journal Article Type: Article
• Acceptance Date: Nov 1, 2025
• Online Publication Date: Nov 7, 2025
• Deposit Date: Nov 7, 2025
• Publicly Available Date: Nov 7, 2025
• Journal: International Journal of Pharmaceutics
• Print ISSN: 0378-5173
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1016/j.ijpharm.2025.126356
• Keywords: Biomimetic chromatography, Mass spectrometry, Drug/phospholipid interactions, Immobilised artificial membrane chromatography, Open-tubular capillary electrochromatography, Pulmonary drug permeability