PTR-MS studies of the reactions of H₃O⁺ with a number of deuterated volatile organic compounds and the subsequent sequential reactions of the primary product ions with water under normal and humid drift tube conditions::implications for use of deuterated compounds for breath analysis

Product ion distributions resulting from the primary reactions of H3O+ with nine D-labeled volatile organic compounds and the subsequent sequential reactions with H2O have been determined using a Proton Transfer Reaction Time of Flight Mass Spectrometer (PTR-TOF 8000 (IONICON Analytik GmbH)) at various reduced electric field (E/N) values ranging from 80 up to 150 Td and for two different absolute humidity levels of air sample < 0.1% and 5%. The specific D-labeled compounds used in this study are acetone-d6, toluene-d8, benzene-d6, ethanol-d (C2H5OD), ethanol-d2 (CH3CD2OH), ethanol-d6, 2-propanol-d8, 2-propanol-d3 (CD3CH(OH)CH3), and isoprene-d5 (CH2CHC(CD2)CD3). With the exception of the two 2-propanol compounds, non-dissociative proton transfer is the dominant primary reaction pathway. For 2-propanol-d8 and 2-propanol-d3 the major primary reaction channel involved is dissociative proton transfer. However, unlike their undeuterated counterparts, the primary product ions undergo subsequent deuterium/hydrogen isotope exchange reactions with the ever present water in the drift tube, the extent of which of course depends on the humidity within that tube. This exchange leads to the generation of various isotopologue product ions, the product ion branching percentages of which are also dependent on the humidity in the drift tube. This results in complex mass spectra and the distribution of product ions leads to issues of reduced sensitivity and accuracy. However, the effect of D/H exchange considerably varies between the compounds under study. In the case of acetone-d6 it is very weak (<1%), because the exchange process is not facile when the deuterium is in the methyl functional group. In comparison, the H3O+/ benzene-d6 (C6D6) reaction and sequential reactions with water result in the production of the isotopologue ions C6Dn(H7-n)+ (where n = 0–6). Changing the value of E/N and/or the humidity in the drift tube considerably affects the amount of the isotope exchange reactions and hence the resulting sequential product ion distributions. An important conclusion of the findings from this work is that care must be taken in the choice of an exogenous deuterated compound for use in breath pharmacokinetic studies using proton transfer reaction mass spectrometry; otherwise the resulting D/H exchange processes impose interpretative problems. © 2018 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Application of Breath Analysis for the Detection of Drugs of Abuse

Human breath is a mixture of gases of which a small part is volatile organic compounds (VOCs), which can either be of endogenous or exogenous origin. This thesis focuses on the exogenous compounds that are metabolized in the human body, their detection in exhaled breath and their possible application as a forensic tool in the detection of drugs of abuse. Online real-time proton transfer reaction time-of-flight mass spectrometry (PTR-TOF-MS) was used for the analysis of breath after having consumed the equivalent of one unit of alcohol as a model system. These experiments showed ethanol could be very quickly detected and its metabolites appeared in the breath profile sometime later, showing the significance of mouth contamination while measuring ethanol via breath. Large differences were also observed when comparing the results between the fasted and non-fasted states of volunteers. Variability of ethanol in the breath profiles was also investigated, showing the importance of biological variation in such studies. The investigation of the ion distribution of alcohols using selective reagent ionization time-of-flight mass spectrometry (SRI-TOF-MS) is presented to better determine breath compounds produced via drug metabolism. The ion distribution of a selection of deuterated compounds was also investigated, showing the attention that needs to be taken when working with such compounds as markers in breath profiles. The PTR-TOF-MS system was applied further for the investigation of a more complex drug of abuse in breath, pseudoephedrine. Breath and blood profiles of drug metabolites were investigated and showed how variable the Tmax can be in blood samples, but also the homogeneity of breath profiles between volunteers making it difficult to decipher differences in the data set. Such studies show the challenging aspects of breath analysis as a detection method for drugs of abuse as biological variation is a major confounder. However, whilst the use of breath analysis should be approached with some caution it has potential for future forensic applications