It is time for a paradigm shift in drug discovery bioanalysis: from SRM to HRMS

Abstract

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 excellent mass accuracy, mass resolution, 10-250 ms scan speeds and no NCE-related MS parameter optimization, makes the uHPLC-HRMS techniques suitable for quantitative analysis of NCEs while preserving maximum qualitative information about other drug-related and endogenous components such as metabolites, degradants, biomarkers and formulation materials. In this perspective article, we provide some insight into the evolution of the hybrid quadrupole-time-of-flight (Qq-TOF) mass spectrometer and propose some of the desirable specifications that such HRMS systems should have to be integrated into the drug discovery bioanalytical workflow for performing integrated qualitative and quantitative bioanalysis of drugs and related components.

High-resolution mass spectrometry for integrated qualitative and quantitative analysis of pharmaceuticals in biological matrices

“…To define which acquisition mode between HR-SIM and HR-SRM is optimum for quantification performance, and which RP is required, remains a difficult task. Certainly a resolving power of 10,000 is not sufficient and it is considered that an RP of 30,000 seems to be adequate for HR-SIM analysis [15]. However, HR-SRM gains from better signal-to-noise ratio and, in general, several product ions are available for quantitative analysis.…”

Neonicotinoids and their Metabolites in Human Biomonitoring: A Review

“…Analysis was accomplished by liquid chromatography high-resolution mass spectrometry (LC-HRMS) using an Obritrap system. HRMS has already proved its eff ectiveness in the drug discovery domain (Ramanathan et al, 2011), in metabolomics studies (Xiao et al, 2012) and recently was reported in human exposure evaluation. This approach made eff ective the investigation of molecules on the basis of the theoretical mass of their quasi-molecular ions.…”

Triple Quadrupole Versus High Resolution Quadrupole-Time-of-Flight Mass Spectrometry for Quantitative LC-MS/MS Analysis of 25-Hydroxyvitamin D in Human Serum

“…Mass analyzers of medium/high mass resolving power such as time-of-flight (TOF), Orbitrap, and Fourier transform ion cyclotron resonance (FTICR) have not yet routinely entered clinical practice, even though their potential has been clearly recognized [13,14]. Furthermore, a few recent studies have successfully demonstrated the potential of HRMS in the quantification of vitamin D compounds [15][16][17][18].…”