| dc.description.abstract | This study was carried out to systematically evaluate the degradation kinetics of gemcitabine hydrochloride injection solution over the pH region 1–12 at 70°C. The degradation kinetics of gemcitabine were determined based on several parameters such as pH, buffer composition, temperature, ionic strength, and drug concentration. A pH-rate profile was constructed using pseudo first-order kinetic rates at 70°C after buffer effect corrections; the observed pH-rate profile was characteristically U-shaped. The degradation reactions of gemcitabine were found to be largely dependent on pH and were catalyzed by protons or hydroxyl groups at extreme pH values. Gemcitabine shows maximum stability in the pH region 7–9.5.; however, due to its solubility limitations at pH ≥ 6, the gemcitabine injection solution stability at this pH range was not determined. The gemcitabine injection solution at pH 2.5 showed a maximum stability of more than two years under the refrigerated conditions; this was derived from an Arrhenius plot. The degradation of gemcitabine in 1 N HCl at 70°C for 4 weeks did not show any anomerization. In contrast, α (0.01%) and -uridine (~ 40%) as analogues of gemcitabine were formed upon 4 weeks incubation under thermal conditions at 70°C. In this case, the water molecules acted as both acid and base to form α- and -uridines. A high level of anomerization to generate the α-anomer of gemcitabine and α-uridine was found in 0.1 N NaOH at 70°C for four weeks, while the -uridine (~ 20%) was observed at lower levels in this condition. Under basic conditions, a significant degradation product was formed; using NMR spectroscopy and mass spectrometry, it was determined to be 1-(2-deoxy-2,2-difluoro-α-D-erythro-ribopyranosyl)pyrimidin-2,4(1H,3H)-dione. | |
