The effects of cooling rate on solid phase transitions and associated vial breakage occurring in frozen mannitol solutions.

When mannitol solutions were frozen in glass vials at typical rates (0.3–1°C/min) and warmed while monitoring the electrical resistance of the frozen solution, a sharp increase in resistance was often seen between –30 and –16 °C. This increase was associated with the breakage of the vial which also occurred during warming. The increase in resistance and vial breakage are thought to result from “recrystallization” in the frozen solution. The magniude of the recrystallization and the vial breakage are shown to be related to the freezing rate. Vial breakage tended to increase with increase in concentration and fill volume. Methods of lyophilizing mannitol solutions with little or no breakage are described.