Rate and equilibrium constants for the epimerization of the endothelin receptor antagonist J-104,132 in aqueous solution

The degradation of [5S- [5 alpha ,6 beta ,7 alpha (R*)]]-2-butyl-5-(1,3-ben zodioxol-5-yl)-7-[(2-carboxypropyl)-4-methoxyphenyl]-6-dihydro-5H-cyclopent a[b]pyridine-6-carboxylic acid (J-104,132) was studied in aqueous solution as a function of temperature and pH, The degradation reaction does not proc eed to completion; rather, a stable equilibrium is attained in which approx imately 2% of the degradate is produced. Kinetic data for the formation of the degradate are analyzed using an integrated form of the rate law for a r eversible first-order reaction, and the forward and reverse rate constants and overall equilibrium constants are presented, Isolation and spectroscopi c structural determination indicate that the degradate is the C7 beta -epim er of the drug. A mechanism for the epimerization reaction involving a nove l enamine-like intermediate is proposed and shown to be consistent with the kinetic data. The rate and equilibrium constants are used to predict the r oom temperature stability of an injectable formulation of J-104,132, and th ese predictions are compared to actual data from long-term stability studie s. It is concluded that the preformulation kinetic studies provide essentia l data needed for optimum drug product development.