Systematic Screening of Antioxidants for Maximum Protection Against Oxidation: An Oxygen Polarograph Study

Abstract

The development of a simple method for rapid screening of antioxidants in the preformulation phase of drug development is reported. Using an easily oxidizable drug substance containing a tetrahydroisoquinoline nucleus, the relative antioxidant efficacies was determined by simultaneous measurement of dissolved oxygen depletion and drug disappearance rates in presence and absence of antioxidants by oxygen polarographic and high performance liquid chromatographic (HPLC) methods, respectively. Results showed an inverse correlation between oxygen depletion and drug disappearance rates (R² > 0.85). In contrast, such a high correlation was not obtained when the standard redox potential of these antioxidants was used as a predictor of drug disappearance rates (R² > 0.50). The rate at which sodium metabisulfite (BIS) and glutathione depleted dissolved oxygen was reduced in the presence of drug, indicating possible reaction between either of the two antioxidants and drug (OHM-11252). Hence, BIS and glutathione may not be suitable antioxidants for stabilizing OHM-11252 in solution. The oxygen depletion rate constants and percent of intact drug remaining were higher in presence of ascorbic acid (ASC) than BIS. Analysis of the reaction mixtures by HPLC diode array detection showed that the number and percent peak area of non-drug peaks formed from ASC-stabilized drug were lower than for BIS. Hence, ASC provides the drug better protection from oxidative degradation.