The graphical design space for the primary drying phase of freeze Drying: Factors affecting the dried product layer resistance

An emerging approach to process development of a lyophilized pharmaceutical product is to construct a graphical design space for primary drying as an aid to process optimization. The purpose of this paper is to further challenge the assumption in earlier work that the maximum values of the resistance of dried product layer, Rp, is approximately constant and is independent of process conditions within the “acceptable” region of the design space. Three model formulations containing bovine serum albumin as the model protein were chosen to represent: (a) an amorphous system, (b) a crystalline system, and (c) a mixed system where both an amorphous and a crystalline component were present. Low temperature differential scanning calorimetry (DSC) and freeze dry microscopy (FDM) experiments were conducted to estimate critical product temperature. A conservative lyophilization cycle was conducted for each formulation to collect mass flow data and individual design spaces were then established. A series of lyophilization cycles were then conducted using process conditions that resided within the individual design space and the resultant product temperature and resistance of dried product layer (Rp) values were compared between the individual cycles within each formulation. The data indicated that the Rp was component dependent with the mannitol formulation exhibiting higher Rp values than the sucrose formulation. Interestingly, when mannitol was retained amorphous, the formulation exhibited a lower Rp, similar to that of the sucrose formulation. The mixed formulation exhibited intermediate Rp values. Crystallization of mannitol is hypothesized to facilitate a decrease in the size of the ice porous structure by making the water vapor flow path tortuous, thereby increasing the Rp of mannitol formulations. Within the “acceptable” zone of the individual design space, Rp was dependent on the process condition with more aggressive shelf temperature cycles resulting in lower Rp. Specific Surface Area measurements of freeze-dried solids demonstrated that more aggressive conditions resulted in smaller surface area. Freeze-dried solids of crystalline formulations consistently exhibited higher specific surface area than the amorphous formulations.