Characterization and comparison of leuprolide degradation profiles in water and dimethyl sulfoxide

The effect of solvent on the rate of leuprolide degradation and on the stru cture of the degradation products was explored. Leuprolide solutions (370 m g/mL) were prepared in water and dimethyl sulfoxide (DMSO) for delivery in DUROSTM osmotic implants. Both solvent systems demonstrated better than 90% stability after 1 year at 37 degrees C, where the DMSO formulation afforde d better stability man the aqueous formulation and was used in subsequent c linical trials. The rate of leuprolide degradation in DMSO was also observe d to accelerate with increasing moisture content, indicating that the aprot ic solvent minimized chemical degradation. Interestingly, leuprolide degrad ation products varied with formulation vehicle. The proportions of leuproli de degradation products observed to form in water and DMSO at 37 degrees C were hydrolysis > aggregation > isomerization > oxidation and aggregation > oxidation > hydrolysis > isomerization, respectively. Specifically, more N -terminal hydrolysis and acetylation were observed under aqueous conditions , and increased Trp oxidation and Ser beta-elimination were seen under non- aqueous conditions. Furthermore, the major chemical degradation pathway cha nged with temperature in the DMSO formulation (decreasing oxidation with in creasing temperature), but not in the aqueous formulation.