Prediction and mechanism elucidation of analyte retention on phospholipid stationary phases (IAM-HPLC) by in silico calculated physico-chemical descriptors

Russo, Giacomo; Grumetto, Lucia; Barbato, Francesco; Vistoli, Giulio; Pedretti, Alessandro

Abstract

The present study proposes a method for an in silico calculation of phospholipophilicity. Phospholipophilicity is intended as the measure of analyte affinity for phospholipids; it is currently assessed by HPLC measures of analyte retention on phosphatidylcholine-like stationary phases (IAM – Immobilized Artificial Membrane) resulting in log kW^IAM values. Due to the amphipathic and electrically charged nature of phospholipids, retention on these stationary phases results from complex mechanisms, being affected not only by lipophilicity (as measured by n-octanol/aqueous phase partition coefficients, log P) but also by the occurrence of polar and/or electrostatic intermolecular interaction forces. Differently from log P, to date no method has been proposed for in silico calculation of log kW^IAM.

The study is aimed both at shedding new light into the retention mechanism on IAM stationary phases and at offering a high-throughput method to achieve such values. A wide set of physico-chemical and topological properties were taken into account, yielding a robust final model including four in silico calculated parameters (lipophilicity, hydrophilic/lipophilic balance, molecular size, and molecule flexibility). The here presented model was based on the analysis of 205 experimentally determined values, taken from the literature and measured by a single research group to minimize the interlaboratory variability; such model is able to predict phospholipophilicity values on both the two IAM stationary phases to date marketed, i.e. IAM.PC.MG and IAM.PC.DD2, with a fairly good degree (r² = 0.85) of accuracy.

The present work allowed the development of a free on-line service aimed at calculating log kW^IAM values of any molecule included in the PubChem database, which is freely available at http://nova.disfarm.unimi.it/logkwiam.htm.

• Journal Article Type: Article
• Acceptance Date: Nov 28, 2016
• Online Publication Date: Dec 3, 2016
• Publication Date: Mar 1, 2017
• Deposit Date: Mar 31, 2020
• Journal: European Journal of Pharmaceutical Sciences
• Print ISSN: 0928-0987
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 99
• Pages: 173-184
• DOI: https://doi.org/10.1016/j.ejps.2016.11.026
• Keywords: Immobilized artificial membrane; Prediction of phospholipid affinity; IAM-HPLC; Quantitative structure-property relationship models; Biochromatography
• Public URL: http://researchrepository.napier.ac.uk/Output/2649506