National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya, Tokyo 158-8501, Japan.
J Pharm Sci. 2010 Nov;99(11):4710-9. doi: 10.1002/jps.22170.
The purpose of this study was to elucidate the effect of solute miscibility in frozen solutions on their micro- and macroscopic structural integrity during freeze-drying. Thermal analysis of frozen solutions containing poly(vinylpyrrolidone) (PVP) and dextran showed single or multiple thermal transitions (T'g: glass transition temperature of maximally freeze-concentrated solutes) depending on their composition, which indicated varied miscibility of the concentrated noncrystalline polymers. Freeze-drying of the miscible solute systems (e.g., PVP 10,000 and dextran 1060, single T'g induced physical collapse during primary drying above the transition temperatures T'g). Phase-separating PVP 29,000 and dextran 35,000 mixtures (two T'g s) maintained their cylindrical structure following freeze-drying below both of the T'g s (<-24 °C). Primary drying of the dextran-rich systems at temperatures between the two T'g s (-20 to -14 °C) resulted in microscopically disordered "microcollapsed" cake-structure solids. Freeze-drying microscopy (FDM) analysis of the microcollapsing polymer system showed locally disordered solid region at temperatures between the collapse onset (T(c1)) and severe structural change (T(c2)). The rigid dextran-rich matrix phase should allow microscopic structural change of the higher fluidity PVP-rich phase without loss of the macroscopic cake structure at the temperature range. The results indicated the relevance of physical characterization and process control for appropriate freeze-drying of multicomponent formulations.
本研究的目的是阐明冷冻溶液中溶质混溶性对其在冷冻干燥过程中微观和宏观结构完整性的影响。含有聚乙烯吡咯烷酮（PVP）和右旋糖酐的冷冻溶液的热分析显示，根据其组成，存在单一或多个热转变（Tg：最大冷冻浓缩溶质的玻璃化转变温度），这表明浓缩无定形聚合物的混溶性不同。可混溶性溶质体系（例如，10,000 PVP 和 1060 右旋糖酐，在高于转变温度 Tg 的一级干燥期间，单一 Tg 引起物理塌陷）的冷冻干燥。相分离的 PVP 29,000 和右旋糖酐 35,000 混合物（两个 Tg）在低于两个 Tg（<-24°C）的温度下保持其圆柱结构。在两个 Tg 之间的温度（-20 至-14°C）下对富含右旋糖酐的体系进行一级干燥会导致微观上无序的“微塌陷”蛋糕状固体。对微塌陷聚合物体系的冷冻干燥显微镜（FDM）分析表明，在塌陷起始温度（T(c1)）和严重结构变化温度（T(c2)）之间的温度下，存在局部无序的固体区域。富含右旋糖酐的刚性基质相应允许较高流动性的 PVP 富含相在宏观蛋糕结构不变的温度范围内进行微观结构变化。结果表明，对于多组分配方的适当冷冻干燥，物理特性表征和过程控制具有相关性。
