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′gs) maintained their cylindrical structure following freeze-drying below both of the T′gs (<−24°C). Primary drying of the dextran-rich systems at temperatures between the two T′gs (− 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 (Tc1) and severe structural change (Tc2). 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.