Determination of drugs and drug metabolites by ion mobility-mass spectrometry: A review

Highlights: • IM-MS landscape of the large chemical space of drugs. • Multimodal distribution of protomers of drugs in IM separation. • Characterization and identification of isomeric drug metabolites. • Theoretical approaches for the calculation and prediction of collision cross sections. Ion mobility-mass spectrometry (IM-MS) has gained increased applications in the characterization and identification of drugs and drug metabolites, largely owning to the complementary separation of analyte ions based on their gas-phase size and shape in the IM dimension in addition to their mass-to-charge ratios. In this review, we discuss recent advances in such applications. We first introduce various types of IM techniques, focusing on those that allow the measurement of collision cross section (CCS), the physical property of an ion that reflects its gas-phase size and shape. Next, we discuss the IM-MS landscape of the large chemical space of drugs and multimodal distributions of certain drugs in IM separation due to the presence of protomers. We then review drug metabolism reactions and discuss the application of IM-MS in separation and identification of isomeric drug metabolites. Subsequently, we discuss various approaches to generate theoretical and predicted CCS data, including theory-based calculation methods and data-driven prediction models, and currently available resources on these approaches. Finally, current limitations and future directions of application of IM-MS are discussed.