Mass Spectrometry Assay Development for Small Molecule Drug Therapies and Drugs of Abuse

Abstract

Mass spectrometry (MS) is a comprehensive and adaptable technique that is useful for addressing a wide range of complex analytical challenges. In this work MS-based assays were developed to address issues relating to the synthetic drug epidemic and failures in point-of-care situations. Chapter one is an overview of the history of mass spectrometry, the fundamental operation of a mass spectrometer, and the advancements made in ionization methods. Chapter two is a review focusing on drug surveillance programs, or lack thereof, and their impact on combating the synthetic drug epidemic in the United States. The work in chapter three describes the development of a novel untargeted semiquantitative paper spray mass spectrometry assay for synthetic drug screening in human plasma. This work implemented a 3D printed solid phase extraction cartridge that allowed for sample preconcentration. This method was tested using remnant patient plasma samples collected from local downtown Indianapolis hospitals. Chapter four introduces a comparison of mass spectrometry acquisition methods to determine the most sensitive and specific techniques. The acquisitions that are compared are parallel reaction monitoring (PRM), sequential windowed acquisition of all theoretical mass (SWATH), and data dependent acquisition (DDA). A small subset of synthetic drugs with known properties were chosen for this comparison and a confirmation study was conducted with real patient samples. Chapter five describes the development of a paper spray mass spectrometry assay for the detection and semi quantitation of � -Lactam antibiotics to improve point-of-care therapeutic drug monitoring in critical care patients in the pediatric population. A liquid chromatography mass spectrometry method was also developed to compare limits of detection between these two methods. Single lot patient plasma samples were tested using both methods and the lower limits of detection and quantitation were compared. Chapter six details a combined approach for the determination of methylpyridine derivative isomers utilizing gas chromatography infrared spectroscopy (GC-IR), gas chromatography mass spectrometry (GC-MS), and density functional theory (DFT) calculations. The projects detailed herein show the extensive range with which mass spectrometry can be used for the detection of a wide range of drugs and synthetic compounds.