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It can be argued that the last true paradigm shift in the bioanalytical (BA) arena was the shift from high‐performance liquid chromatography (HPLC) with ultraviolet (UV) detection to HPLC with tandem mass spectrometry (MS/MS) detection after the commercialization of the triple quadrupole mass spectrometer in the 1990s. HPLC‐MS/MS analysis based on selected reaction monitoring (SRM) has become the gold standard for BA assays and is used by all the major pharmaceutical companies for the quantitative analysis of new drug entities (NCEs) as part of the new drug discovery and development process. While LC‐MS/MS continues to be the best tool for drug discovery bioanalysis, a new paradigm involving high‐resolution mass spectrometry (HRMS) and ultrahigh‐pressure liquid chromatography (uHPLC) is starting to make inroads into the pharmaceutical industry. The ability to collect full scan spectra, with …