Investigation of Two Different Pressure-Based Controlled Ice Nucleation Techniques in Freeze-Drying: The Integral Role of Shelf Temperature After Nucleation in Process Performance and Product Quality

Design of Vacuum-Induced Freezing Protocols for High Fill Volume Formulations in Freeze-Drying: A Strategic Approach

“…19,21 On the other hand, an increase in intra-vial pore size heterogeneity and an increase in the heterogeneity of product temperatures during primary drying, residual moisture and reconstitution time has been reported. 19,20 The thermal data presented here shows that this increase in heterogeneity is likely caused by the temperature increase at the middle and bottom of the solution and consequently a lower percentage of the solution instantly freezing. Thus, while nucleation is induced at the liquid interface, the temperature gradient throughout the entire solution at the time of nucleation can be important for SF nucleation.…”

“…The 100 mg/mL SAM system was selected based on previous experience with the formulation with vacuum-induced surface freezing. 20 Sucrose and mannitol were formulated at a concentration of 50 mg/mL. They were chosen as an example of the main component in typical pharmaceutical freeze-drying formulations.…”

“…While some generalized recommendations based on our experience with the technology and previous investigations [15][16][17][18][19][20][21] are summarized in Fig. 7, the reader should keep in mind that this is based on data that was obtained with simple model systems.…”

“…While at first glance the implementation of the SF technology may appear to be complicated, our previous results have shown that some model systems may experience more favorable effects on pore morphology and process data from SF nucleation compared to other CN technologies. 20 This is likely due to the unique temperature gradient of SF during nucleation and its effect on the ice crystal morphology.…”

“…18 The temperature gradient during vacuum-induced surface freezing has been reported to be minimal throughout the product solution for fill depths smaller than 1 cm. 18,19 Wenzel et al have reported that the product temperature decreases to À6 C at the bottom of a product solution with a fill depth of 1.5 cm during nucleation induction of a solution by vacuum-induced surface freezing at a T s of À3 C. 20 Previously published studies reported on some details of the degassing procedure and its necessity; the initial experiments by Kramer et al were performed with mannitol, glycine, sodium chloride and sucrose solutions at a fill depth of approximately 0.8 cm and with no degassing procedure. The authors reported no issues with product defects because of the pressure reduction.…”