3′-Azido-3′-deoxy-5′-O-isonicotinoylthymidine: A Novel Antiretroviral Analog of Zidovudine. II. Stability in Aqueous Media and Experimental and Theoretical Ionization Constants

Abstract

Degradation of 3′-azido-3′-deoxy-5′-O-isonicotinoylthymidine (AZT-Iso), an antiretroviral derivative of zidovudine, was investigated in buffer pH 7.4, µ = 300 mOsm at 37, 50 and 60°C, and in water (pH 6.6, 37°C), giving zidovudine (AZT) and isonicotinic acid (INA) as products. The rate constants were determined by reversed-phase HPLC showing pseudo-first-order kinetics related to the residual amount of AZT-Iso. In this way, the studied compound was demonstrated to be 153 times more stable in water than in buffer solution at 37°C. The analytical method was conveniently validated demonstrating to be a rapid and accurate stability-indicating technique. In addition, experimental and theoretical values of pKa were determined.

Key Words:

• Zidovudine analogs
• Antiretroviral
• Stability
• pKa

Acknowledgments

The authors gratefully acknowledge the Agencia Nacional de Promoción Científica (FONCYT), the Agencia Córdoba Ciencia and the Secretaría de Ciencia y Técnica de la Universidad Nacional de Córdoba (SECYT-UNC) of Argentina for financial support. The authors also wish to express their sincere thanks to Dra. L. Alassia (FILAXIS Laboratories, Buenos Aires, Argentina) for supplying zidovudine.