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

Abstract

The 19F NMR spectrum has a smaller number of signals than 1H NMR, therefore, quantitative 19F NMR (19F-qNMR) can replace quantitative 1H NMR (1H-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 19F-qNMR, validated the results in multiple laboratories, and compared them with those obtained using an established 1H-qNMR method. 3,5-Bis(trifluoromethyl)benzoic acid (3,5-BTFMBA) was selected as the reference standard for both 19F-qNMR and 1H-qNMR owing to its solubility characteristics and 19F-qNMR and 1H-qNMR chemical shifts.Since VCZ contains three fluorines, the 19F-qNMR spectrum of VCZ showed three major fluorine signals (FA, FB, and FC). 19F-qNMR measurements were performed under three conditions with each 19F signal of VCZ (FA, FB, and FC) and the 19F 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 1H- and 19F-qNMR was comparable (99.65±0.29 % and 99.52±0.44 %, respectively), exhibiting variations within an acceptable range. Compared to conventional 1H-qNMR methods, the developed 19F-qNMR method has been proven efficient and highly promising for determining the accurate purity of organic fluorine pharmaceuticals.

Keywords

• Quantitative 19F NMR
• Voriconazole
• Absolute purity
• Organic fluorine pharmaceutical
• Certified reference material