Fardus-Reid, Fahmina (2017) Extending metrological traceability in qNMR beyond the first dimension. (PhD thesis), Kingston University, .
Abstract
After decades as a niche analytical technique, quantitative NMR (qNMR) has recently gained mainstream sttention largely due to its implementation as a primary ratio measurement method with SI traceability to determine the amount of substance. This method enables rapid and inexpensive value assignment for high-purity, organic small-molecule materials. However, the method is inconsistently applied, particularly in the analysis of high order reference materials; therefore a more comprehensive evaluation of its uncertainties is required for use in certification. Industries such as the pharmaceutical and nutraeuticals are increasingly seeking alternative methods for the measurement of large, structurally complex molecules that are unsuited to standard ID proton qNMR due to spectral overlap. Increased resolution can be achieved through employment of spectral editing and multi-dimensional experiments, such as heteronuclear single coherence spectroscopy (HSQC). However, the inherent direct proportionality of proton content and signal intensity of [sup]1H qNMR is lost through signal attenuation due to various chemical phenomena. Despite this complication, these 2D approaches can be calibrated and optimized for quantification of select analyte species within complex matrices and chemical mixtures. The additional biases seen, such as those arising as a result of imperfect pulses, variations of J-coupling constants and inadequate relaxation delays can be in many cases compensated for. Although such calibration approaches can never be as accurate as [sup]1H qNMR, they provide significant advantages over competing analytical approaches as it is a primary ratio method and therefore does not require a reference material/standard for the analyte. In order to provide value assignments with the highest degree of measurement science, the total uncertainty of the measurement method must be evaluated in a manner, which is both comprehensive and metrologically sound. Presented are well documented approaches to validating [sup]1H qNMR methods and understanding and quantifying biases and uncertainties seen in 2D HSQC qNMR.
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