A Systematic Degradation Kinetics Study of Gemcitabine Hydrochloride Injection Solution

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

Strategies to stabilize dalbavancin in aqueous solutions: Section 4—identification of heat degradation products in 2-hydroxypropyl-β-cyclodextrin and divalent metal ion solutions at pH 4.5 and 7.0

Abstract Heat stress studies have been conducted in support of developing a heat-stable liquid solution of dalbavancin. The degradation products that form in heat-stressed buffered dalbavancin solutions have been identified, including the known major degradation product, mannosyl aglycone (MAG), and four previously uncharacterized compounds. Liquid chromatography-mass spectrometry/mass spectrometry (LC–MS/MS) was used to identify the degradation products of dalbavancin in acetate- and phosphate-buffered solutions under thermal stress at 70 °C and the changes in the degradation pattern in the presence of 2HPβCD and divalent metal ions. Although Ca2+, Mg2+, and Zn2+ did not reduce dalbavancin degradation under thermal stress in acetate buffer, 2HPβCD significantly reduced its overall degradation, in particular, the formation of MAG. This protective effect was enhanced by the addition of Ca2+ to the formulation. In phosphate buffer, MAG formation was also reduced by the addition of 2HPβCD, although significant increases in other degradation products were observed in this case. The addition of Mg2+ to 2HPβCD significantly reduced the overall degradation while increasing MAG formation somewhat. The results strongly suggest that 2HPβCD forms a complex with the hydrophobic glycone tail of dalbavancin, suppressing hydrolysis of the glycosidic bond