Absolute purity determination of an organic fluorine pharmaceutical voriconazole via quantitative 19F NMR and method validation

The 19 F NMR spectrum has a smaller number of signals than 1 H NMR, therefore, quantitative 19 F NMR ( 19 F-qNMR) can replace quantitative 1 H NMR ( 1 H-qNMR) for the absolute quantitation of organic fluorine-bearing compounds. In this study, we determined the purity of voriconazole (VCZ), an organic fluorine pharmaceutical, using 19 F-qNMR, validated the results in multiple laboratories, and compared them with those obtained using an established 1 H-qNMR method. 3,5-Bis(trifluoromethyl)benzoic acid (3,5-BTFMBA) was selected as the reference standard for both 19 F-qNMR and 1 H-qNMR owing to its solubility characteristics and 19 F-qNMR and 1 H-qNMR chemical shifts. Since VCZ contains three fluorines, the 19 F-qNMR spectrum of VCZ showed three major fluorine signals (FA, FB, and FC). 19 F-qNMR measurements were performed under three conditions with each 19 F signal of VCZ (FA, FB, and FC) and the 19 F signal of RS as the center (offset) of each observation. The quantitative values of the three target signals FA, FB, and FC were calculated and were comparable; 99.40 %, 99.66 %, and 99.49 %, respectively. Owing to a difference of up to 8.8 % between the quantitative values of the two signals other than the targeted quantitative signal, the average FA, FB, and FC quantitative values were considered for purity (%). The purity of VCZ determined by 1 H- and 19 F-qNMR was comparable (99.65±0.29 % and 99.52±0.44 %, respectively), exhibiting variations within an acceptable range. Compared to conventional 1 H-qNMR methods, the developed 19 F-qNMR method has been proven efficient and highly promising for determining the accurate purity of organic fluorine pharmaceuticals. • Absolute purity determination of voriconazole via 19 F-qNMR and method validation.