Use of manometric temperature measurements (MTM) to characterize the freeze-drying behavior of amorphous protein formulations.

The freeze-drying behavior and cake morphology of a model protein in an amorphous formulation were studied at varying protein concentrations using conservative (-25 degrees C) and aggressive (+25 degrees C) shelf temperatures at constant chamber pressure during primary drying. The two cycles were characterized by manometric temperature measurements (MTM) in a SMART freeze dryer that estimates the sublimation rate (dm/dt), product temperature at the freeze-drying front (T(p-MTM)) and product resistance (R(p)) during a run. The calculated sublimation rates (dm/dt) were 3-4 times faster in the aggressive cycle compared to the conservative cycle. For conservatively dried cakes R(p) increased with both dry layer thickness and protein concentration. For aggressively dried cakes (where freeze-drying occurs at the edge of microcollapse), R(p) also increased with protein concentration but was independent of the dry layer thickness. The sublimation rate was influenced by R(p), dry layer thickness and T(p-MTM) in the conservative cycle, but was governed mainly by T(p-MTM) in the aggressive cycle, where R(p) is independent of the dry layer thickness. The aggressively dried cakes had a more open and porous structure compared to their conservatively dried counterparts.