Absolute ¹⁹F-qNMR Quantification of Fluorinated Pharmaceuticals: Fluorometholone, Flurbiprofen, and Flutamide

Quantitative NMR (qNMR) provides a direct approach for determining the absolute purity of pharmaceutical substances. In this study, 19F- and 1H-qNMR measurement conditions were systematically optimized and validated for three fluorinated pharmaceuticals listed in the Japanese Pharmacopoeia—fluorometholone (FM), flurbiprofen (FP), and flutamide (FT)—using interlaboratory data. Building on our prior experience with 31P-qNMR, careful selection of solvents and reference standards was emphasized. The aprotic solvent dimethyl sulfoxide-d6 (DMSO-d6) was employed to suppress proton–deuterium exchange, and the International System of Units (SI)-traceable certified reference material 3,5-bis(trifluoromethyl)benzoic acid (3,5-BTFMBA) was used as the reference standard for both 19F- and 1H-qNMR. For 1H-qNMR of FT, sodium 4,4-dimethyl-4-silapentanesulfonate-d6 (DSS-d6) was used as an alternative reference standard to avoid spectral overlap. Key qNMR parameters, including relaxation delay, spectral width, and pulse offset, were optimized. We then validated 19F-qNMR against the more established 1H-qNMR technique across multiple laboratories (n = 6–10). The average purity values determined by 19F-qNMR were 98.79 ± 0.62% (n = 7) or 98.62 ± 0.34% (n = 6) for FM, 99.84 ± 0.40% (n = 9) for FP, and 99.84 ± 0.48% (n = 9) for FT; these values were in good agreement with those determined by 1H-qNMR (99.23 ± 0.41% (n = 9), 100.04 ± 0.34% (n = 10), and 99.67 ± 0.38% (n = 10), respectively). Collectively, these results indicate that 19F-qNMR is a reliable and reproducible technique for absolute quantification of fluorinated pharmaceuticals, supporting its application in pharmaceutical quality control and regulatory assessment.