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While mass spectrometry remains a gold-standard tool for analyte detection, characterization, and quantitation, isomer differentiation is often a challenge. Tandem mass spectrometry is a common approach to increase the selectivity of mass spectrometry and energy-resolved measurements can provide further improvements. However, not all mass spectrometers, especially those that are very compact and affordable, are amenable to such experiments. For instance, single-stage mass spectrometers with soft ionization provide no dissociation information and quadrupole ion trap instruments with resonant excitation do not necessarily provide as informative of energy-resolved curves, for instance when extensive sequential dissociation is responsible for much of the "fingerprint". In-source collision-induced dissociation (IS-CID) is one approach to overcoming these barriers to exploit the analytical selectivity of energy-resolved CID without the need for additional instrumentation; this approach could broaden the reach of these selectivity gains to additional user bases (e.g., educational settings, field portable devices). Here, we specifically investigate energy-resolved IS-CID with the goal of (1) comparing between energy-resolved appearance curves measured with true tandem mass spectrometry on a quadrupole time-of-flight instrument and those obtained using IS-CID, (2) evaluating the approach as a means of differentiating isomers/isobar sets, especially those with similar dissociation patterns, and (3) exploring additional analytical considerations relevant to method development and implementation. This proof-of-concept work establishes the analytical potential of this approach, opening doors for future method development for specific applications.

Beta blockers are a class of drugs commonly used to treat heart-related diseases; they are also regulated under the World Anti-Doping Agency. Tandem mass spectrometry is often used in the pharmaceutical industry, clinical analysis laboratory, and antidoping laboratory for detection and characterization of drugs and their metabolites. A deeper chemical understanding of dissociation pathways may eventually lead to an improved ability to predict tandem mass spectra of compounds based strictly on their chemical structure (or vice versa), which is especially important for characterization of unknowns such as emerging designer drugs or novel metabolites. In addition to providing insights into dissociation pathways, the use of energy-resolved breakdown curves can produce improved selectivity and lend insights into optimal fragmentation conditions for liquid chromatography-tandem mass spectrometry LC-MS/MS workflows. Here, we perform energy-resolved collision cell and multistage ion trap collision-induced dissociation-mass spectrometry (CID-MS) experiments, along with complementary density functional theory calculations, on five beta blockers (acebutolol, atenolol, bisoprolol, carteolol, and labetalol), to better understand the details of the pathways giving rise to the observed MS/MS patterns. Results from this work are contextualized within previously reported literature on these compounds. New insights into the formation of the characteristic product ion m/z 116 and the pathway leading to characteristic loss of 77 u are highlighted. We also present comparisons of breakdown curves obtained via qToF, quadrupole ion trap, and in-source CID, allowing for differences between the data to be noted and providing a step toward allowing for improved selectivity of breakdown curves to be realized on simple instruments such as single quadrupoles or ion traps., (© 2023 John Wiley & Sons, Ltd.)

Infrared multiple photon dissociation (IRMPD) spectroscopy is a powerful tool used to probe the vibrational modes-and, by extension, the structure-of an ion within an ion trap mass spectrometer. Compared to traditional FTIR spectroscopy, IRMPD spectroscopy has advantages including its sensitivity and its relative ability to handle complex mixtures. While IRMPD has historically been a technique for fundamental analyses, it is increasingly being applied in a more analytical fashion. Notable recent demonstrations pertinent to the clinical laboratory and adjacent interests include analysis of modified amino acids/residues and carbohydrates, structural elucidation (including isomeric differentiation) of metabolites, identification of novel illicit drugs, and structural studies of various biomolecules and pharmaceuticals. Improvements in analysis time, coupling to commercial instruments, and integration with separations methods are all drivers toward the realization of these analytical applications. Additional improvements in these areas, along with advances in benchtop tunable IR sources and increased cross-discipline collaboration, will continue to drive innovation and widespread adoption. The goal of this tutorial article is to briefly present the fundamentals and instrumentation of IRMPD spectroscopy, as an overview of the utility of this technique for helping to answer questions relevant to clinical analysis, and to highlight limitations to widespread adoption, as well as promising directions in which the field may be heading., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 THE AUTHORS.)