Studies Investigating Sub-2 μm Particle Stationary Phase Supercritical Fluid Chromatography and Application to Profiling of Natural Products and Drug Discovery Research

Abstract

The aim of this thesis was to investigate a novel prototype supercritical fluid chromatography instrumentation optimized to exploit the theoretical benefits of sub-2 µm particle stationary phases and determine the benefits of its applied use towards the discovery and early drug development of new chemical entities found in natural products. The protoype supercritical instrument was designed to reduce the system and extra-column volumes in order to reach the theoretical efficiencies of a sub-2 µm particle stationary phase. The system was also designed to decrease baseline noise and drift via design improvements of the CO2 solvent delivery by the pump, updated backpressure regulator needle and seat designs, and optimization of UV detector design that accounts for CO2 refractive indices rather than typical liquid mobile phases used in reversed phase liquid chromatography. The prototype instrument was also designed to improve the sample introduction to the flow stream, thus to improve the applied use of the instrument allowing the analyst to attain highly reproducible results that would be required for improved qualitative separations, semi-quantitative statistical profiling, and quantitative commercial use determinations. Supercritical fluid chromatography utilizes CO2-based mobile phases with unique properties associated with improving solvation, lowering mobile phase viscosity and exploring a wide range of polarity of solutes. Natural products have a complexity of compounds varying in polarity requiring a variety of analytical techniques resulting in numerous chromatographic profiles. The goal of this research is to prove the benefits of this novel technology to natural product research, specifically in the field of discovering new molecular entities and drug discovery workflows. Establishing the usefulness of a new technology and its potential impact to new therapeutic discovery requires a large gap of experimentation and education to be filled prior to any immediate implementation.

Date of Award	2017
Original language	English
Awarding Institution	King's College London
Supervisor	Norman Smith (Supervisor) & Cristina Legido Quigley (Supervisor)