title: Impact of Ice Morphology on Design Space of Pharmaceutical Freeze-Drying.
abstract: It has been known that the sublimation kinetics of a freeze-drying product is affected by its internal ice crystal microstructures. This article demonstrates the impact of the ice morphologies of a frozen formulation in a vial on the design space for the primary drying of a pharmaceutical freeze-drying process. Cross-sectional images of frozen sucrose-bovine serum albumin aqueous solutions were optically observed and digital pictures were acquired. Binary images were obtained from the optical data to extract the geometrical parameters (i.e., ice crystal size and tortuosity) that relate to the mass-transfer resistance of water vapor during the primary drying step. A mathematical model was used to simulate the primary drying kinetics and provided the design space for the process. The simulation results predicted that the geometrical parameters of frozen solutions significantly affect the design space, with large and less tortuous ice morphologies resulting in wide design spaces and vice versa. The optimal applicable drying conditions are influenced by the ice morphologies. Therefore, owing to the spatial distributions of the geometrical parameters of a product, the boundary curves of the design space are variable and could be tuned by controlling the ice morphologies.
authors.affiliation: Takeda Pharmaceutical Company Ltd., Osaka 532-8686, Japan.
authors.forename: Hiroshika
authors.initials: H
authors.lastname: Goshima
authors.affiliation: Department of Bioenvironmental and Agricultural Engineering, College of Bioresource Science, Nihon University, Fujisawa, Kanagawa 252-0880, Japan.
authors.forename: Gabsoo
authors.initials: G
authors.lastname: Do
authors.affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan. Electronic address: kyuya@kais.kyoto-u.ac.jp.
authors.forename: Kyuya
authors.initials: K
authors.lastname: Nakagawa
mesh_terms: D000818:Animals; D002417:Cattle; D005612:Freeze Drying / Q000379:methods; D007053:Ice / Q000032:analysis; D012710:Serum Albumin, Bovine / Q000032:analysis / Q000737:chemistry*; D013395:Sucrose / Q000032:analysis / Q000737:chemistry*; D013678:Technology, Pharmaceutical / Q000379:methods*; D014867:Water / Q000032:analysis / Q000737:chemistry
chemical_list: D007053:Ice; D014867:Water; D012710:Serum Albumin, Bovine; D013395:Sucrose
keywords: design space; freeze-drying; ice morphology; lyophilization; mathematical model