Investigation of lyophilized formulation susceptible to the ramp rate of shelf temperature in the primary drying process

Abstract

In a series of our studies, we revealed that the ramp rate of shelf temperature in the primary drying process affects final product quality in an aggressive cycle (macroscopic collapse occurs at the slow ramp rate whereas acceptable lyophilized cake appearance is observed at the fast ramp rate). However, the studies were performed by disaccharide-based formulations, and whether the other formulations are susceptible to the ramp rate remained unclear. In the present study, the aqueous solutions of a representative bulking agent (mannitol, glycine, dextran, sucrose, trehalose and lactose) and protein model formulation with different levels of bovine serum albumin were lyophilized at different ramp rates. Macroscopic collapse occurred at the slow ramp cycle in a high concentration of disaccharide solutions, which have a low collapse temperature (Tc), and slow ramp-induced collapse was inhibited as the concentration was decreased. Also, drying failure in the slow ramp cycle was not confirmed in mannitol, glycine and dextran formulations. Furthermore, the slow ramp-induced collapse was inhibited as the concentration of the protein was increased. Thus, the amorphous-based formulation with low Tc containing a large amount of bulking agent was considered to be the formulation susceptible to the ramp rate.