Effects of solute miscibility on the micro- and macroscopic structural integrity of freeze-dried solids

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.