Development of an immobilised artificial membrane liquid chromatography /mass spectrometry-based platform to assess the pulmonary permeability of drug candidates.

Summer Studentship Report 2023.

By Dorota Orzel, Amy Dillon and Giacomo Russo- Edinburgh Napier University.

Hyphenated biomimetic analytical method (IAM-LC/DAD/QDa) utilising both UV and MS detection has significantly influenced the advancement of pharmaceutical development over the past few decades. In the current study, immobilized artificial membrane (IAM) has served as a powerful tool for mimicking the interactions between a molecule and a biological membrane. Phospholipophilicity data was obtained for 49 structurally unrelated drug-like molecules by implementation of fast-gradient liquid chromatography method as well as isocratic separation with both UV and MS detection. The results were compared with apparent pulmonary permeability values obtained from Calu-3 cell lines (log Papp). The relationships between logarithmic chromatographic hydrophobicity index CHIIAM/ log kwIAM and log Papp data as well as calculated n-octanol/water partition and distribution coefficients (clog PN, clog D7.4) were investigated.

The study indicated that CHI log D was moderately related to clog PN values and poorly related to clog D7.4, suggesting that phospholipid partitioning supports both hydrophobic/lipophilic forces as well as electrostatic interactions occurring between ionised drugs and charged phospholipid moieties.

A significant correlation was observed between log Papp and CHI log D values for compounds with molecular weight (MW) > 300 Da for which paracellular diffusion is a negligible transport route. Phospholipophilicity predictions for small hydrophilic compounds (MW < 300 Da) and drug transported by membrane transporters were not representative with respect to data collected.

The commonly used in pharmaceutical industry hyphenated analytical approach utilising IAM-LC/DAD/QDa system has proven to be an accurate, reliable, and quick screening method suitable for processing drug-like samples.

The first publication from this work is shared instead of a project report.

ChromSoc/BMSS Summer Studentship program information.