Stability of Lidocaine in Aqueous Solution: Effect of Temperature, pH, Buffer, and Metal Ions on Amide Hydrolysis

Abstract

The degradation of lidocaine in aqueous solution obeys the expression k _obs = (k _H+[H ⁺] + k _o ) [H⁺]/([H ⁺ ] + K _a + k′_o K _a([H ⁺ ] + K _a) where k _H+ is the rate constant for hydronium ion catalysis, and k _o and k′_o are the rate constants for the spontaneous (or water-catalyzed) reactions of protonated and free-base lidocaine. At 80°C, the rate constants for these processes are 1.31 × 10⁻⁷ M ^−l sec⁻¹, 1.37 × 10⁻⁹ sec⁻¹, and 7.02 × 10⁻⁹sec⁻¹; the corresponding activation energies are 30.5, 33.8, and 26.3 kcal mol⁻¹, respectively. It was found that the room temperature pH of maximum stability is ∼3–6 and that lidocaine is more reactive in the presence of metal ions such as Fe²⁺ and Cu²⁺. The dissociation constant, K _a, for lidocaine at 25–80°C was also measured at 0.1 M ionic strength and a plot of pK _a versus 1/T gave a slope of (1.88 ± 0.05) × 10³ K⁻¹ and intercept 1.56 ± 0.16.