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The purpose of this study was to identify and characterize new crystalline bulking agents applicable to freeze-dried pharmaceuticals. Thermal analysis of heat-melt sugar and sugar alcohol solids as well as their frozen aqueous solutions showed high crystallization propensity of meso-erythritol and D-mannitol. Experimental freeze-drying of the aqueous meso-erythritol solutions after their cooling by two different methods (shelf-ramp cooling and immersion of vials into liquid nitrogen) resulted in cylindrical crystalline solids that varied in appearance and microscopic structure. Powder X-ray diffraction and thermal analysis indicated different crystallization processes of meso-erythritol depending on the extent of cooling. Cooling of the frozen meso-erythritol solutions at temperatures lower than their T g ′ (glass transition temperature of maximally freeze-concentrated phase, 59.7°C) induced a greater number of nuclei in the highly concentrated solute phase. Growth of multiple meso-erythritol anhydride crystals at around 40°C explains the powder-like fine surface texture of the solids dried after their immersion in liquid nitrogen. Contrarily, shelf-ramp cooling of the frozen solution down to 40°C induced an extensive growth of the solute crystal from a small number of nuclei, leading to scale-like patterns in the dried solids. An early transition of the freezing step into primary drying induced collapse of the non-crystalline region in the cakes. Appropriate process control should enable the use of meso-erythritol as an alternative crystalline bulking agent in freeze-dried formulations.Key words meso-erythritol; crystallization; freeze-drying; sugar alcohol; thermal analysis Freeze-drying is a popular method for formulating various therapeutic proteins, liposomes, and antibiotics that are not sufficiently stable during storage in aqueous solutions or during drying at high temperatures.1,2) The process is also used to prepare amorphous solid formulations that foster better dissolution rates and bioavailability of poorly soluble pharmaceuticals. Various active pharmaceutical ingredients (APIs) and excipients composing the freeze-dried solids are either in their amorphous or crystalline states.3) The component crystallinity is determined by various factors including their intrinsic properties, co-solute compositions, and thermal history of the process. 4)Many freeze-dried formulations contain amorphous or crystalline bulking agents to prevent loss of the APIs during handling and/or provide better appearance. Some disaccharides (e.g., sucrose and trehalose) form glass-state amorphous dried solids that protect the conformation of embedded proteins and supramolecular assembly of liposomes from dehydration-induced irreversible conformational changes during the process and from their chemical degradation during storage.5,6) Some excipients (e.g., D-mannitol and glycine) are used to obtain superior appearance of stable crystalline solids, although they do not show protein-stabilizing effects. 7) They crystallize mainly ...

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