Practical Kinetics III: Benzodiazepine Hydrolysis

Abstract

The velocity constants for chlordiazepoxide hydrolysis were measured by independent techniques. A quantitative TLC kinetic procedure is compared with an extractive method. The data derived from both processes are in approximate agreement, further exemplifying the feasibility of TLC for rapid stability evaluation of liquid formulations as well as solution kinetic studies. In the extractive procedure, benzodiazepine‐substrate was separated from the lactam product by methylene chloride extraction of acidic aqueous solution. The TLC procedure consisted of separation on silica gel plates followed by elution and subsequent analysis. The log k‐pH relationship for the hydrolysis representing water addition coupled with expulsion of methylamine is presented. This function is characterized by water and hydroxide‐ion attack on monoprotic species along with specific hydrogen‐ion catalysis at higher hydronium‐ion concentrations, and the rate law for the decomposition of chlordiazepoxide is given. Through several halftimes (pH 0.15–11.5, 79.5°), this hydrolytic reaction generating lactam predominated; however, more benzophenone was formed as the pH decreased. Velocity constants were invariant over a 200‐fold concentration range. The subsequent acid‐facilitated cleavage of lactam to benzophenone was not further investigated. Both general acid catalysis and general base catalysis were evidenced, with borate, acetate, formate, and phosphate buffers accelerating the conversion of chlordiazepoxide to lactam. At pH values below neutrality, nonlinear dependency of the rate constant on buffer concentration was observed. This finding may be explained by a change in the rate‐determining step as buffer concentration varied.