Mechanism of collapse of amorphous-based lyophilized cake induced by slow ramp during the shelf ramp process.

We previously found that a slow ramp rate during the shelf ramp process induced product collapse. However, the cause of the collapse could not be explained by the hypothesized mechanism of collapse. To identify the cause, drying parameters such as sublimation rate and dry layer resistance (R) were calculated from cycle data by mathematical model. As a result, the behavior of these parameters in the slow ramp cycles showed a different profile from that of the fast ramp cycles. From the cross-sectional appearance of the lyophilized cakes, the point at which the onset of collapse occurred in vial lyophilization during the slowest ramp cycle was estimated, and collapse occurred as expected, at a dry layer thickness (L) = 1.5 mm in the R - L profile. The time-point of L = 1.5 mm corresponded to the shelf ramp process; the subliming ice front temperature (T) at this point was lower than the collapse temperature (T) measured by LT-FDM. Although T in the fastest ramp cycle exceeded the above temperature, no macroscopic collapse was observed. Thus, the real T during the shelf ramp process in vial lyophilization was decreased by the slow ramp rate, and this was considered the reason for collapse in the slow ramp cycle.