Ozonation of Tamoxifen and Toremifene: Reaction Kinetics and Transformation Products
2018
Knoop, Oliver | Hohrenk, Lotta L. | Lutze, Holger V. | Schmidt, Torsten C.
The oxidation of the two antiestrogenic pharmaceuticals tamoxifen and toremifene with ozone in water was investigated concerning kinetics, reaction pathway, and transformation product formation. For both compounds a high dependency of second order rate constants and products on pH was determined. In case of full protonation of the amine (cation) ozone attacks with a second order rate constant of 1.57 × 10⁴ M–¹ s–¹ for tamoxifen and 4.37 × 10³ M–¹ s–¹ for toremifene. The neutral tertiary amine has an unexpected high second order rate constant of 3.17 × 10⁸ M–¹ s–¹ for tamoxifen and 1.46 × 10⁸ M–¹ s–¹ for toremifene. For the reaction of ozone and the tertiary amine only N-oxide formation was observed. pKₐ values for tamoxifen (9.49 ± 0.22) and toremifene (9.57 ± 0.22) can be reported based on experimental data. Eight transformation products (TPs) were observed and identified based on MS/MS spectra or a reference standard. Products observed derived from Criegee reaction and hydroxylation as well as N-oxide formation. Further TPs from reactions with TAM products were combinations of N-oxides, Criegee products and hydroxylation products. Thus, reaction pathways can be derived and primary and secondary TPs distinguished for the first time.
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