Ozonation of Tamoxifen and Toremifene: Reaction Kinetics and Transformation Products.

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. p Ka 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.