Kinetics and mechanisms of etodolac degradation in aqueous solutions

The extent and mechanisms of etodolac (1; 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]-indole-1-acetic acid) decomposition, as a function of pH and temperature, were investigated. Three main degradation products derived from 1 are identified as 7-ethyl-2-(1-methylenepropyl)-1H-indole-3-ethanol (2), the decarboxylated product of etodolac (3), and 7-ethyltryptophol (4). The main pathway for the degradation of 1 is followed by consecutive first-order kinetics: 1----2 in equilibrium 3----4. No appreciable buffer effect on the degradation of 1 is observed for any of the buffer species in the study. The rate-pH profile exhibits a specific acid catalysis at acidic (kH) and neutral (k'H) pH regions, and an inflection point at pH 4.65 corresponding to the pKa value. From Arrhenius plots, the activation energies (Ea) for kH and k'H were found to be 26 and 24 kcal/mol, respectively. The small positive entropy of activation (delta S) indicates that a unimolecular decomposition mechanism is favored for the decomposition reaction of 1.