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.
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BibTeX
@article{uchiyama2026absolute,
title = {{Absolute ¹⁹F-qNMR Quantification of Fluorinated Pharmaceuticals: Fluorometholone, Flurbiprofen, and Flutamide}},
author = {Nahoko Uchiyama and Junko Hosoe and Naoki Sugimoto and Kyoko Ishizuki and Tatsuo Koide and Mika Murabayashi and Kohei Kiyota and Taeko Shinozaki and Mizuho Uchida and Yoshinori Fujimine and Katsuya Ofuji and Kazuhiro Fujita and Takashi Hasebe and Yumi Asai and Eri Ena and Yoshinobu Makino and Toru Miura and Yasuhiro Muto and Shinya Takaoka and Takahiro Nakayama and Katsuo Asakura and Takako Suematsu and Hitomi Abe and Ai Kohama and Takashi Goto and Masu Yasuda and Tomohiko Ueda and Yukihiro Goda},
journal = {Chemical and Pharmaceutical Bulletin},
year = {2026},
month = jul,
doi = {10.1248/cpb.c26-00123},
url = {https://www.jstage.jst.go.jp/article/cpb/74/7/74_c26-00123/_article},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Absolute ¹⁹F-qNMR Quantification of Fluorinated Pharmaceuticals: Fluorometholone, Flurbiprofen, and Flutamide
AU - Nahoko Uchiyama
AU - Junko Hosoe
AU - Naoki Sugimoto
AU - Kyoko Ishizuki
AU - Tatsuo Koide
AU - Mika Murabayashi
AU - Kohei Kiyota
AU - Taeko Shinozaki
AU - Mizuho Uchida
AU - Yoshinori Fujimine
AU - Katsuya Ofuji
AU - Kazuhiro Fujita
AU - Takashi Hasebe
AU - Yumi Asai
AU - Eri Ena
AU - Yoshinobu Makino
AU - Toru Miura
AU - Yasuhiro Muto
AU - Shinya Takaoka
AU - Takahiro Nakayama
AU - Katsuo Asakura
AU - Takako Suematsu
AU - Hitomi Abe
AU - Ai Kohama
AU - Takashi Goto
AU - Masu Yasuda
AU - Tomohiko Ueda
AU - Yukihiro Goda
PY - 2026
DA - 2026/07/25
JO - Chemical and Pharmaceutical Bulletin
DO - 10.1248/cpb.c26-00123
UR - https://www.jstage.jst.go.jp/article/cpb/74/7/74_c26-00123/_article
AB - 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.
SN - 1347-5223
SN - 0009-2363
ER -