title: Physical characterization of meso-erythritol as a crystalline bulking agent for freeze-dried formulations.
abstract: 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 Tg' (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.
authors.affiliation: Faculty of Pharmaceutical Sciences, Toho University; 2. R&D Laboratories, POLA Pharma Inc.
authors.forename: Kahori
authors.initials: K
authors.lastname: Fujii
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Izutsu
authors.forename: Migiwa
authors.initials: M
authors.lastname: Kume
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yoshino
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Yoshihashi
authors.forename: Kiyohiko
authors.initials: K
authors.lastname: Sugano
authors.forename: Katsuhide
authors.initials: K
authors.lastname: Terada
mesh_terms: D003460:Crystallization; D004896:Erythritol / Q000737:chemistry*; D005079:Excipients / Q000737:chemistry; D005612:Freeze Drying; D013696:Temperature
chemical_list: D005079:Excipients; D004896:Erythritol