The degradation of the antitumor agent gemcitabine hydrochloride in an acidic aqueous solution at pH 3.2 and identification of degradation products

A study of the degradation kinetics of gemcitabine hydrochloride (2'-deoxy- 2',2'-difluorocytidine) in aqueous solution at pH 3.2 was conducted. The de gradation of gemcitabine followed pseudo first-order kinetics, and rate con stants were determined at four different temperatures. These rates were use d to construct an Arrhenius plot from which degradation rates at lower temp eratures were extrapolated and activation energy calculated. Four major deg radation products were identified. Only one of these degradation products, the uridine analogue of gemcitabine, was a known degradation product of gem citabine and was identified by comparison with synthesized material. The ot her three degradation products were isolated and characterized by spectrosc opic techniques. Two of these products were determined to be the diastereom eric 6-hydroxy-5,6-dihydro-2'-deoxy-2',2'-difluorouridines and the other pr oduct was determined to be O-6,5'-cyclo-5,6-dihydro-2'-deoxy-2',2'-difluoro uridine. The mechanisms of formation of these degradation products are disc ussed. (C) 2000 Wiley-Liss, Inc. and the American Pharmaceutical Associatio n.