DEGRADATION OF 4'-AZIDOTHYMIDINE IN AQUEOUS-SOLUTION

The kinetics of the degradation of 4'-azidothymidine (ADRT) in aqueous solution from pH 1 to 11 were studied by reverse phase and ion exchange HPLC. The pH-rate profiles at 50, 60 and 80-degrees-C were U-shaped with the rate law of k(obs) = k(H)a(H) + k(H2O) + k(OH)a(OH). The pH-rate profile of ADRT differs from that of 3'-azido-3'-deoxythymidine, AZT, which exhibits acid and water catalyzed degradation 340 and 130 times slower, respectively than ADRT and did not display base catalyzed degradation. Thymine and azide were identified by co-injection of authentic samples as major degradation products of ADRT at all pH values studied. In acidic solutions, 2-deoxy-4-hydroxy-pentose (1) which is the stable form of 2-deoxy-4-pentulose (2) was identified as an additional degradation product by mass spectral and H-1- and C-13-NMR analysis. The results suggest that stable aqueous formulations of ADRT can be prepared and that formation of azide by non-enzymatic routes may not be pharmacologically significant.