The Effect of Bulking Agents on the Chemical Stability of Acid-Sensitive Compounds in Freeze-Dried Formulations: Sucrose Inversion Study

ABSTRACT: 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 °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.