Small molecule drug metabolite synthesis and identification: why, when and how?

[Display omitted] •Commentary on when and how drug metabolite synthesis fits into the overall drug development pathway and the influence of regulatory guidelines.•The tool box of techniques used by a specialist contract research organisation to make phase I and II metabolites.•Case studies illustrating recent examples, including the significance of selected drug metabolites and their synthesis. The drug discovery and development process encompasses the interrogation of metabolites arising from the biotransformation of drugs. Here we look at why, when and how metabolites of small-molecule drugs are synthesised from the perspective of a specialist contract research organisation, with particular attention paid to projects for which regulatory oversight is relevant during this journey. To illustrate important aspects, we look at recent case studies, trends and learnings from our experience of making and identifying metabolites over the past ten years, along with with selected examples from the literature.