Mannitol Crystallization at Sub-Zero Temperatures: Time/Temperature-Resolved Synchrotron X-ray Diffraction Study and the Phase Diagram

Mannitol, a common pharmaceutical ingredient, exhibits complex polymorphism even in simple binary mannitol/water mixtures, with four crystalline forms observed. In this investigation, time/temperature-resolved synchrotron X-ray diffraction measurements are performed during freezing and thawing of mixtures. Mannitol crystallization depends strongly on the cooling rate is initiated cooling, if lower than critical rate; otherwise, mannitol remains amorphous crystallizes subsequent heating above -30 °C. A temperature-composition phase diagram constructed, reflecting eutectic peritectic points lower-temperature equilibria involving hemihydrate, hexagonal ice, β-mannitol. Comparison experimental data reveals that behavior does not follow equilibrium but appears to obey Ostwald rule. Novel insights kinetics relationships systems could lead improved formulations manufacturing processes for pharmaceuticals biopharmaceuticals.