Quantitative NMR external standard fit-for-purpose method for fluorine-containing compounds: Expanding the application of aSSICO signal method to 19F nuclei

Abstract

The design of fluorinated pharmaceuticals has become an important approach in drug discovery given fluorine's ability to modulate properties such as lipophilicity, pK_a, metabolic stability, and bioavailability offering desired therapeutic advancements over a drug's hydrogen counterpart. Characterizing these compounds builds our understanding of how fluorine's structural and positional attributes influence the properties of these pharmaceuticals. NMR spectroscopy is a powerful structural characterization tool well-suited for this purpose. In this paper we present a quantitative pharmaceutical application using fluorine NMR and aSICCO (artificial Signal Insertion for Calculation of Concentration Observed) for analyzing pure or crude samples containing fluorinated pharmaceuticals and fluorinated residual solvents. We demonstrate that the method can be applied to samples measured with routine NMR instrumentation, achieving reproducible results to within ± 5 percent.