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.