Applications of Molecular Rotational Resonance Spectroscopy to Challenging Analysis Challenges in Pharmaceutical Chemistry

Author: ORCID icon
Sonstrom, Reilly, Chemistry - Graduate School of Arts and Sciences, University of Virginia
Pate, Brooks, University of Virginia

This work presents the use of molecular rotational resonance (MRR) spectroscopy to perform the structure analysis of molecules of high importance to pharmaceutical chemistry with a focus on isomers that are difficult to analyze using existing techniques (NMR, MS). MRR has many attractive features over other analytical techniques. The technique, enabled by advances in high speed digital electronics, has high spectral resolution and a large dynamic range that allows for simultaneously detection of multiple species. Additionally, the high sensitivity and spectral resolution allows analysis of crude reaction mixtures with no additional purification needed. Finally, rotational spectra can be identified with a high degree of accuracy by comparison between experimental and theoretical spectroscopic parameters, enabling “library free” identification. MRR spectra are extremely sensitive to changes in mass distribution, making it well suited to tackle challenging structural problems. This work contains various projects that demonstrates the ability of MRR to perform difficult analyses that are of high importance in pharmaceutical chemistry, including analysis of diastereomers and regioisomers, enantiomers, and isotopic isomers. These projects include the online reaction monitoring of diastereomers to optimize synthesis of an active pharmaceutical ingredient (API) precursor, characterization of novel synthetic methods, routine chiral analysis using a universally applicable chiral tagging technique, and analysis of deuterated compounds. In some cases, comparison against established methods was available providing validation of the analysis by MRR. In other cases, MRR was used to tackle challenging problems that were unsolvable by other analytical techniques. Overall, MRR has the potential to make a big impact on pharmaceutical process chemistry.

PHD (Doctor of Philosophy)
molecular rotational resonance spectroscopy
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