DEGRADATION KINETICS OF 3 GONADORELIN ANALOGS - DEVELOPING A METHOD FOR CALCULATING EPIMERIZATION PARAMETERS

Purpose. To develop a method for calculating epimerisation parameters, find out if the kinetics of the independent reactions can be establis hed, and elucidate primary structure-chemical degradation relationship s in the degradation kinetics of three gonadorelin analogues. Methods. The influences of pH, temperature, and buffer concentration on the de gradation of the three gonadorelin analogues buserelin. goserelin, and triptorelin were investigated using RP-HPLC. A method was developed t o calculate epimerisation and hydrolysis rate constants independently. Results. Explicit structure-degradation mechanism relations were foun d in the degradation of all three compounds. The L-serine residue was found to be involved in both a solvent-catalysed backbone hydrolysis a nd a hydroxyl-catalysed epimerisation whereas, the O-tertiary butyl D- serine residue was only involved in proton-catalysed ether hydrolysis. The kinetics of identical reactions in different analogues were gener ally comparable. Conclusions. The degradation of the gonadorelin analo gues is located at a relatively small number of chemical residues and prediction of the degradation mechanisms and kinetics of other peptide s with similar structural elements appears to be possible.