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 0 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 0 g ) induced physical collapse during primary drying above the transition temperatures (>T 0 g ). Phase-separating PVP 29,000 and dextran 35,000 mixtures (two T 0 g s) maintained their cylindrical structure following freeze-drying below both of the T 0 g s (<ร248C). Primary drying of the dextran-rich systems at temperatures between the two T 0 g s (ร20 to ร148C) 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.