Author ORCID Identifier

https://orcid.org/0009-0003-3864-1903

Semester

Fall

Date of Graduation

2025

Document Type

Dissertation

Degree Type

PhD

College

Eberly College of Arts and Sciences

Department

Chemistry

Committee Chair

Stephen Valentine

Committee Co-Chair

Lisa Holland

Committee Member

Glen Jackson

Committee Member

Matthew Johnson

Committee Member

Michelle Richards-Babb

Abstract

Mass spectrometry (MS) is a technique that is used in fields in which both complex and non-complex mixtures are analyzed. The state-of-the-art ion sources that are utilized for MS are being demonstrated to be functional for direct infusion of samples as well as for use with online separations. However, ion sources, such as electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) can encounter problems such as ion suppression and an inability to ionize based on size and/or polarity, respectively. Further these sources are bulky and require gas flow, heat sources, and additional high voltage power supplies for optimal performance. A spray-based technique, Capillary Vibrating Sharp-Edge Spray Ionization (cVSSI), that has been demonstrated to perform as well, or better than, ESI has been successfully coupled with a corona discharge to create cVSSI-APCI. Initial work performed to demonstrate the utility of cVSSI-APCI with a 4-component mixture that contained an easily ionizable species (cocaine) and difficult-to-ionize species (Vitamin D2). With ESI, cocaine suppressed all 3 of the other analytes in the mixture. When utilizing cVSSI-APCI, the signal for cocaine increased 10-fold while the suppressed species saw 180- to 250- fold increases in ion intensity. Further, the S/N for cVSSI-APCI increased 5- to 40- fold compared to HESI. This increased ion signal for cVSSI-APCI was maintained in multiple solvent systems (methanol, water, and methanol/water). Finally, for two of the difficult-to-ionize species analyzed using cVSSI-APCI. calibration curves were linear over a wide range from 0.19 μM to 400 μM. To further assess the utility of cVSSI-APCI, the complexity of a sample matrix was increased. In this work, drugs of abuse were spiked into human serum and analyzed following proteins being crashed out with cold methanol. Typically for drug analysis, separations are required due to the complexity of not only the biofluid but also the mix of drugs and their metabolites that can be present. As was observed previously, cocaine suppressed other analytes, specifically heroin and its metabolites. Additionally, fentanyl suppressed the ion signal of cocaine. cVSSI-APCI allowed all 3 drugs and their major metabolites to be observed simultaneously in equimolar concentrations. Calibration curves demonstrated LODs within the range that would be biologically relevant for drug analysis in humans, and percent recoveries from serum were demonstrated to be 40-90%. Finally, with all drugs spiked into serum, the drugs and their major metabolites were able to be detected indicating they can overcome not only the matrix of the serum but also of the other drugs present. The last demonstration of this technique is for use in metabolomics studies. Three important observations came from this study. The first is that within a mixture of 33 analytes, about half are preferentially ionized with ESI while the other half are preferentially ionized with cVSSI-APCI. This indicates that only one ionization source is not always going to be sufficient for data collection. The second is that while the analyte physicochemical property most correlated to ESI is Ka/Kb, the analyte property most correlated to cVSSI-APCI is PA. Finally, cVSSI-APCI can detect some analytes in a separation that are not detected via ESI while other analytes are detected by ESI and not cVSSI-APCI.

This development and application work of cVSSI-APCI has given insight to improvements that can be made to the technique and investigations for the future of the ion source. The first future work is to combine field-enabled cVSSI with cVSSI-APCI to overcome the limitations observed with each individual ion source. The second is to determine the effects that solvents have on the ionization process and the impact of the physicochemical properties of both the solvents and the analytes being evaluated. The final of these is the evaluation of droplet size, voltage, and inlet temperature to determine the most effective route to ionization.

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