National Institute of Health Sciences, Setagaya, Tokyo 158-8501, Japan.
J Pharm Sci. 2011 Dec;100(12):5244-53. doi: 10.1002/jps.22706. Epub 2011 Jul 20.
The purpose of this study was to elucidate the effect of heat treatment on the miscibility of multiple concentrated solutes that mimic biopharmaceutical formulations in frozen solutions. The first heating thermal analysis of frozen solutions containing either a low-molecular-weight saccharide (e.g., sucrose, trehalose, and glucose) or a polymer (e.g., polyvinylpyrrolidone and dextran) and their mixtures from -70°C showed a single transition at glass transition temperature of maximally freeze-concentrated solution (T(g) ') that indicated mixing of the freeze-concentrated multiple solutes. The heat treatment of single-solute and various polymer-rich mixture frozen solutions at temperatures far above their T(g) ' induced additional ice crystallization that shifted the transitions upward in the following scan. Contrarily, the heat treatment of frozen disaccharide-rich solutions induced two-step heat flow changes (T(g) ' splitting) that suggested separation of the solutes into multiple concentrated noncrystalline phases, different in the solute compositions. The extent of the T(g) ' splitting depended on the heat treatment temperature and time. Two-step glass transition was observed in some sucrose and dextran mixture solids, lyophilized after the heat treatment. Increasing mobility of solute molecules during the heat treatment should allow spatial reordering of some concentrated solute mixtures into thermodynamically favorable multiple phases.
本研究旨在阐明热处理对模拟生物制药制剂冷冻溶液中多种浓缩溶质混合的影响。对包含低分子量糖（如蔗糖、海藻糖和葡萄糖）或聚合物（如聚乙烯吡咯烷酮和葡聚糖）及其混合物的冷冻溶液从-70°C 进行的首次加热热分析显示，在最大冷冻浓缩溶液的玻璃化转变温度（T(g) '）处有单一转变，表明冷冻浓缩多种溶质的混合。在远高于其 T(g) '的温度下对单溶质和各种聚合物富混合物冷冻溶液进行热处理会诱导额外的冰晶形成，从而使转变在随后的扫描中向上移动。相反，富含二糖的冷冻溶液的热处理会引起两步热流变化（T(g) '分裂），这表明溶质分离成多个组成不同的非晶相。T(g) '分裂的程度取决于热处理温度和时间。在一些经热处理后冻干的蔗糖和葡聚糖混合物固体中观察到两步玻璃化转变。在热处理过程中，溶质分子的迁移率增加，这应该允许一些浓缩溶质混合物通过空间重排进入热力学有利的多相状态。
