Freeze‐Drying of Mannitol–Trehalose–Sodium Chloride‐Based Formulations: The Impact of Annealing on Dry Layer Resistance to Mass Transfer and Cake Structure

Abstract

The objective of this article was to study the mechanism by which annealing increases the primary drying time in mannitol–trehalose–sodium chloride‐based formulations. The thermal events occurring during annealing and the glass transition of the frozen solutions were monitored with differential scanning calorimetry (DSC). Manometric temperature measurement was used to evaluate the dry layer resistances during primary drying. The morphologies of the freeze‐dried cakes were examined by scanning electron microscopy (SEM). The degrees of crystallinity of mannitol and sodium chloride (NaCl) in freeze‐dried cakes were determined by powder X‐ray diffraction (XRD). DSC results indicated that annealing during freezing did not increase the glass transition temperature (Tg′) significantly, but there was a distinct decrease of ΔCp at Tg′ with annealing, suggesting a decrease in amorphous content. SEM revealed that most mannitol crystallized as the delta‐form during annealing at − 23° C, and further crystallized as th...