Lu Enxian, Ewing Susan, Gatlin Larry, Suryanarayanan Raj, Shalaev Evgenyi
Department of Pharmaceutics, University of Minnesota, 308 Harvard St. SE, Minneapolis, Minnesota 55455, USA.
J Pharm Sci. 2009 Sep;98(9):3387-96. doi: 10.1002/jps.21727.
The goal of the study was to evaluate the impact of amorphous bulking agents on the chemical stability of freeze-dried materials. Polyvinylpyrrolidone and dextran of different molecular weights and lactose were used as bulking agents, and sucrose was used as an example of an acid-sensitive compound. Lyophiles containing bulking agent and sucrose at 10:1 (w/w) ratio, citrate buffer, and optionally bromophenol blue (pH indicator) were tested by X-ray powder diffractometry, differential scanning calorimetry, and Karl Fischer titrimetry. Diffuse reflectance UV-vis spectroscopy was used to obtain the concentration ratio of the deprotonated (In(2-)) to the protonated (HIn(-)) indicator species, from which the Hammett acidity function (H(2-)) was calculated. The extent of sucrose inversion in lyophiles stored at 60 degrees C was quantified by HPLC. The bulking agent had a major impact on both the apparent solid-state acidity (H(2-)) and the degradation rate, with the degradation rate constants value highest for dextran lyophiles (most "acidic", lower H(2-)) followed by lactose and polyvinylpyrrolidone lyophile (least "acidic", higher H(2-)). The Hammett acidity function can be used as an empirical solid-state acidity scale, to predict the rank-order stability of acid-sensitive compounds in lyophiles prepared with different bulking agents.
