Freeze-Drying From Organic Cosolvent Systems, Part 1: Thermal Analysis of Cosolvent-Based Placebo Formulations in the Frozen State

The use of cosolvent systems has been demonstrated to shorten lengthy freeze-drying processes and improve the solubility and stability of certain active pharmaceutical ingredients. The goal of the present study was to evaluate the suitability of 2 thermal characterization techniques, differential scanning calorimetry and freeze-dry microscopy, and to identify an optimal cosolvent system. Binary mixtures of a cosolvent (tert-butanol, dimethyl sulfoxide, 1,4-dioxane, acetone, or ethanol) and water were investigated. Ternary mixtures of frequently used excipients (50 mg/g mannitol, sucrose, glycine, or polyvinylpyrrolidone [PVP]) and a solvent-water system were then analyzed for their thermal properties. PVP presented a particularly high glass transition temperature (Tg′) in 70% tert-butanol at −17.9°C. Large needle-shaped crystals that have been shown to be associated with improved processability were observed with mannitol and PVP in 40% 1,4-dioxane. A heterogeneous sublimation rate of the solvent and water whose impact on product stability remained unclear was observed with PVP in 40% 1,4-dioxane. Freeze-dry microscopy analysis demonstrated a possible extension of the process time for PVP in 99% dimethyl sulfoxide due to a slowly moving sublimation front. Conceivable negative consequences and the need for special treatment for low-melting cosolvents, such as ethanol and acetone, were predicted and discussed.