Coordination of hydralazine with Cu2+ at acidic pH promotes its oxidative degradation at neutral pH

Abstract

Hydralazine (HL), a frequently prescribed oral antihypertensive drug, shows redox interactions with transition metals such as copper that are not fully understood. Copper may be present at high concentrations in the digestive tract and can affect oral drugs. An important parameter for such interactions is pH, which changes from acidic in the gastric juice to neutral pH in intestines. In this study, we examined interactions of HL with Cu²⁺ ions in conditions that mimic pH shift in the digestive tract using UV-Vis, Raman and EPR spectroscopy, cyclic voltammetry and oximetry. In the acidic solution, Cu²⁺ formed a stable mononuclear complex with two bidentate coordinated HL molecules. On the other hand, at neutral pH, Cu²⁺ initiated oxidation and degradation of HL. The degradation was more rapid in the HL-Cu²⁺ system that was initially prepared at acidic pH and then shifted to neutral pH. The formation of the complex at acidic pH increases the availability of Cu²⁺ for redox reactions after the shift to neutral pH at which Cu²⁺ is poorly soluble. These results imply that the change of pH along the digestive tract may promote HL degradation by allowing the formation of the complex at gastric pH which makes Cu²⁺ available for subsequent oxidation of HL at neutral pH.

Keywords: Complex; Copper; Hydralazine; Oxidative degradation.