Ozonation of the 5-fluorouracil anticancer drug and its prodrug capecitabine: Reaction kinetics,oxidation mechanisms,and residual toxicity

Specific second-order rate constants were determined for 5-FU and CAP with ozone. Reaction sites were confirmed by kinetics, Fukui analysis, and products. The olefin moiety was the main ozone reaction site for 5-FU and CAP. Carboxylic acids comprised most of the residual TOC for 5-FU. Ozonation removed the toxicity associated with 5-FU and products but not CAP. Anticancer drugs (ADs) have been detected in the environment and represent a risk to aquatic organisms, necessitating AD removal in drinking water and wastewater treatment. In this study, ozonation of the most commonly used antimetabolite ADs, namely 5-fluorouracil (5-FU) and its prodrug capecitabine (CAP), was investigated to determine reaction kinetics, oxidation mechanisms, and residual toxicity. The specific second-order rate constants between aqueous ozone and 5-FU, 5-FU^?, 5-FU^2?, CAP, and CAP^? were determined to be 7.07(±0.11)×10⁴ M^?1·s^?1, 1.36(±0.06)×10⁶ M^?1·s^?1, 2.62(±0.17)×10⁷ M^?1·s^?1, 9.69(±0.08)×10³ M^?1·s^?1, and 4.28(±0.07)×10⁵ M^?1·s^?1, respectively; furthermore, the second-order rate constants for ^?OH reaction with 5-FU and CAP at pH 7 were determined to be 1.85(±0.20)×10⁹ M^?1·s^?1 and 9.95(±0.26)×10⁹ M^?1·s^?1, respectively. Density functional theory was used to predict the main ozone reaction sites of 5-FU (olefin) and CAP (olefin and deprotonated secondary amine), and these mechanisms were supported by the identified transformation products. Carboxylic acids constituted a majority of the residual organic matter for 5-FU ozonation; however, carboxylic acids and aldehydes were important components of the residual organic matter generated by CAP. Ozone removed the toxicity of 5-FU to Vibrio fischeri, but the residual toxicity of ozonated CAP solutions exhibited an initial increase before subsequent removal. Ultimately, these results suggest that ozone is a suitable technology for treatment of 5-FU and CAP, although the residual toxicity of transformation products must be carefully considered.