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

Abstract

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.