Importance of purity evaluation and the potential of quantitative ¹H NMR as a purity assay

• Published in: Journal of medicinal chemistry 2014-11, Vol.57 (22), p.9220-9231
• Main Authors: Pauli, Guido F, Chen, Shao-Nong, Simmler, Charlotte, Lankin, David C, Gödecke, Tanja, Jaki, Birgit U, Friesen, J Brent, McAlpine, James B, Napolitano, José G
• Format: Article
• Language: English
• Subjects: Calibration; Chemistry, Pharmaceutical - methods; Chemistry, Pharmaceutical - standards; Chromatography - methods; Drug Contamination; Magnetic Resonance Spectroscopy - methods; Magnetic Resonance Spectroscopy - standards; Reference Standards; Reproducibility of Results; Technology, Pharmaceutical - standards
• ISSN: 1520-4804
• DOI: 10.1021/jm500734a

In any biomedical and chemical context, a truthful description of chemical constitution requires coverage of both structure and purity. This qualification affects all drug molecules, regardless of development stage (early discovery to approved drug) and source (natural product or synthetic). Purity assessment is particularly critical in discovery programs and whenever chemistry is linked with biological and/or therapeutic outcome. Compared with chromatography and elemental analysis, quantitative NMR (qNMR) uses nearly universal detection and provides a versatile and orthogonal means of purity evaluation. Absolute qNMR with flexible calibration captures analytes that frequently escape detection (water, sorbents). Widely accepted structural NMR workflows require minimal or no adjustments to become practical ¹H qNMR (qHNMR) procedures with simultaneous qualitative and (absolute) quantitative capability. This study reviews underlying concepts, provides a framework for standard qHNMR purity assays, and shows how adequate accuracy and precision are achieved for the intended use of the material.