Reversible ring-opening reactions of nimetazepam and nitrazepam in acidic media at body temperature.

Hydrolytic reactions of nimetazepam and nitrazepam in acidic solutions at body temperature were studied spectrophotometrically. The open-ring compounds produced by hydrolysis were in equilibrium with the corresponding closed-ring compounds (protonated nimetazepam and nitrazepam). Forward-reaction rate constants of both drugs were greater than the rate constant of diazepam. In nimetazepam, the forward-reaction rate constant was smaller than the reverse-reaction rate constant; in nitrazepam, the reverse-reaction rate constant was much smaller than the forward-reaction rate constant, and possible amide bond cleavage was indicated. The activation energies of the forward and reverse reactions of nimetazepam and the forward reaction of nitrazepam were calculated from Arrhenius-type plots, whereas no clear temperature dependency was observed in the reverse-reaction rate constant of nitrazepam. The effect of pH on these reactions also was examined. In addition, the pKa values of nimetazepam and nitrazepam were calculated to be 2.53 and 2.77, respectively.