Immobilized Artificial Membrane Chromatography Using Acetonitrile-Rich Mobile Phase for Comparison of Retention Properties Between Phospholipidosis-Inducing and Non-inducing Basic Drugs

Immobilized artificial membrane chromatography has been reported providing a rough estimation of phospholipidosis induction risk of drugs. Unfortunately, however, the accurate assessment of basic drugs remains a challenge. In this study, we aimed to evaluate the hydrophobic interactions and ionic/polar interactions between a basic drug and an immobilized artificial membrane to clearly discriminate between phospholipidosis inducers and non-inducers. The retention of 14 model basic drugs was determined using mobile phases with varying acetonitrile contents. The Van't Hoff plot using an acetonitrile-rich mobile phase revealed that most of the inducers showed biphasic retention, whereas the retention of non-inducers was monophasic. Then, effect of the ionic/polar interactions on the discrimination between DIPL inducers and non-inducers was then studied. For this aim, salts concentration was increased in the acetonitrile-rich mobile phase. No significant difference was observed between chlorpromazine (inducer) and pindolol (non-inducer) as the model drugs. We then compared the acetonitrile concentration when the dominant interaction was shifted from the reversed phase retention to the ionic/polar interactions. We found that the acetonitrile levels when the dominant interaction of the inducers shifted from the hydrophobic interaction to the ionic/polar interactions were higher than those of non-induces. In addition, at the optimized acetonitrile content, the inducers and non-inducers can be correctly discriminated. Shift of the dominant interaction in retention to the immobilized artificial membrane shows a possibility as a novel tool for the risk prediction of phospholipidogenisity.