Effects of temperature ramp rate during the primary drying process on the properties of amorphous-based lyophilized cake, Part 1: Cake characterization, collapse temperature and drying behavior

摘要

In the lyophilization process for injectable pharmaceuticals, the shelf of the lyophilizer is heated to the target temperature at a constant ramp rate during the primary drying process. Although the shelf temperature (T-s) and chamber pressure (P-c) have mainly been investigated to optimize the primary drying process, the impact of the ramp rate on the lyophilized cake properties is poorly understood. We evaluated the relationship between the ramp rate and cake properties using a model formulation containing 10% trehalose as a bulking agent. Elegant lyophilized cakes were obtained when lyophilization was conducted at a fast ramp rate. In contrast, the lyophilized cakes collapsed at slow ramp rate cycles. To identify the cause of collapse, the impact of the ramp rate on the collapse temperature (T-c) was evaluated by light transmission freeze-dry microscopy. The T-c decreased with the decrease in the ramp rate. Lower T-c and higher resistance of the dried matrix in the low sublimation state were hypothesized as the cause of the collapse. Numerous lyophilization runs were executed at different T-s and ramp rates. We confirmed that an increased ramp rate led to successful lyophilization at a higher T-s and that the drying time was significantly reduced. (c) 2017 Elsevier B.V. All rights reserved.