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Evaluation of Non-target Analyses of Novel Psychoactive Substances; Inherent Variation in GCMS Relative Abundances and Gas Phase Hydrogen Deuterium Exchange Isomer Discrimination Kristin Michelle Kelly Novel psychoactive substances (NPSs) are synthetically derived compounds designed to mimic the effects of other illicit drugs. An endless cycle of NPSs continually reach the drug market due to limitations in drug legislation creating two problems: (1) non-availability of standards and (2) multiple isobars indistinguishable even to high resolution mass spectrometry. Gas chromatography-mass spectrometry (GCMS) is the most common instrument used for compound identification in non-targeted seized drug analysis. Compound identification using this technique relies on mass spectra where the percent relative abundances (%RAs) of all m/z values are compared manually or searched against a library database. Lacking standards, laboratories rely on published GCMS spectra to postulate compound identification. The ability to make such identifications provides vital investigative data and may help uncover new structural variants. However, central to such identifications is an understanding of how much spectral patterns vary across laboratories; the assumption that variation is minimized through the use of a standard tuning compound perfluorotributylphosphine (PFTBA) has yet to be rigorously tested and demonstrated. The first focus of this research was the often-unappreciated aspect to any mass spectral comparison or searchthe inherent variation in RAs. In the first study, the variation of mass spectral fragmentation patterns characterized by %RA was evaluated using three GCMS instruments and 16 NPS compounds. The variation of retention indices was also studied. Retention indices showed <0.35% variation across all systems; mass spectral data showed much greater variation across all compounds and systems. Tuning frequency was one factor correlated with a small, but significant, effect on the variance. A t-test comparison of mean ion %RA did not clearly identify general patterns. The identity of the base peak changed for three compounds. Alternating base peaks on a single instrument, i.e. one instrument produced multiple base peak ions over the course of the study, generated a ripple effect, where variation across all %RAs in the effected spectra increased. However, alternating base peaks between instrument, i.e. each instrument produced a single base peak but the ion identity was not necessarily the same, did not produce these ripple effects. The variance in %RA caused by alternating base peaks has the potential to skew compound identification during nontargeted analyses, which are common in a forensic drug chemistry setting. Decades ago, the Environmental Protection Agency (EPA) established tune check compounds as a means to control systematic variation across vendor platforms, which was the focus of the second study. The goal of the second study was to evaluate whether the decafluorotriphenylphosphine (DFTPP) criteria, as defined by the EPA, could be used to reduce the RA variation in mass spectra produced by NPSs. Instruments from two vendors were used to analyze 6 NPSs: 4 cannabinoids and 2 cathinones. Each NPS was analyzed 100 times per instrument; 10 replicates per tune repeated under 10 different tunes. Results showed that passing a DFTPP tune check was not correlated with reduced RA variation. Tuning algorithm differences between vendors did impact the %RA variance, but the frequency of instrument tuning was found to be the most critical factor for controlling RA variation. The results of this work suggest that forensic laboratories should develop quantitative metrics to evaluate autotuning results and define how these metrics will be used to dictate maintenance. This practice, coupled with tuning before each analytical batch, will reduce the variation of %RA values as much as practicable. Because GCMS usually cannot distinguish constitutional isomers, the second focus of this research was to develop a novel methodology for the NPS isomer discrimination. Ion mobility spectrometry-mass spectrometry (IMS-MS) is used as a non-confirmatory screening technique for illicit substances in high traffic areas. Through the years, advancements in instrumentation have improved detection limits, increased resolving power, and allowed for unique instrument modifications which improve structural inferences. Gas-phase hydrogen deuterium exchange (HDX) is one such modification technique. HDX-IMS-MS has been used primarily for proteomic and metabolomic applications, but it is also effective in discriminating of small biomolecules (glycan linkages). For the final study, NPSs containing labile heteroatom hydrogens were evaluated for HDX reactivity in the presence of either deuterated water (D2O) or ammonia (ND3) within the drift tube. An initial evaluation of exchange propensity was performed for six NPSs. Five of the initial NPSs exchanged in the presence of ND3, while only one NPS (benzyl piperazine) exchanged with D2O. The exchange mechanism of D2O requires stabilization with a nearby charged site; the diamine ring of benzyl piperazine provided this charge site at a fixed length. Three disubstituted benzene isomers (ortho-, meta-, and para-) containing the diamine ring structure and a fluorine atom were analyzed to determine if isomer discrimination was possible. These isomers had nearly identical collisional cross sections and isotopic distributions in the drift gas, therefore IMS and MS alone cannot discriminate between the isomers. A t-test of means (α=0.05) showed that discrimination was possible if the exchange data from both reagent gases were included. Molecular dynamics simulations showed that the proximity of the fluorine to the diamine ring hinders the dihedral angle between the benzene ring and the diamine ring. The angle limitation partially accounts the observed exchange differences. One clear limitation of this technique is that the substance must exchange in the presence of both reagent gases. Nevertheless, this technique was shown to be capable of isomer discrimination in non-targeted analyses of NPSs

Non-target Analyses of Novel Psychoactive Substances; Inherent Variation in GCMS Relative Abundances and Gas Phase Hydrogen Deuterium Exchange Isomer Discrimination