Stability of lidocaine in aqueous solution: effect of temperature, pH, buffer, and metal ions on amide hydrolysis

The degradation of lidocaine in aqueous solution obeys the expression kobs = (kH+[H+] + ko) [H+]/([H+] + Ka) + k'oKa/([H+] + Ka) where kH+ is the rate constant for hydronium ion catalysis, and ko and k'o are the rate constants for the spontaneous (or water-catalyzed) reactions of protonated and free-base lidocaine. At 80 degrees C, the rate constants for these processes are 1.31 x 10(-7) M-1 sec-1, 1.37 x 10(-9) sec-1, and 7.02 x 10(-9) sec-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 approximately 3-6 and that lidocaine is more reactive in the presence of metal ions such as Fe2+ and Cu2+. The dissociation constant, Ka, for lidocaine at 25-80 degrees C was also measured at 0.1 M ionic strength and a plot of pKa versus 1/T gave a slope of (1.88 +/- 0.05) x 10(3) K-1 and intercept 1.56 +/- 0.16.