The effect of bulking agents on the chemical stability of acid-sensitive compounds in freeze-dried formulations: Sucrose inversion study

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.