Heat and mass transfer scale-up issues during freeze drying: II. Control and characterization of the degree of supercooling

Abstract

This study aims to investigate the effect of the ice nucleation temperature on the primary drying process using an ice fog technique for temperature-controlled nucleation. In order to facilitate scale up of the freeze-drying process, this research seeks to find a correlation of the product resistance and the degree of supercooling with the specific surface area of the product. Freeze-drying experiments were performed using 5% wt/vol solutions of sucrose, dextran, hydroxyethyl starch (HES), and mannitol. Temperature-controlled nucleation was achieved using the ice fog technique where cold nitrogen gas was introduced into the chamber to form an "ice fog," thereby facilitating nucleation of samples at the temperature of interest. Manometric temperature measurement (MTM) was used during primary drying to evaluate the product resistance as a function of cake thickness. Specific surface areas (SSA) of the freeze-dried cakes were determined. The ice fog technique was refined to successfully control the ice nucleation temperature of solutions within 1°C. A significant increase in product resistance was produced by a decrease in nucleation temperature. The SSA was found to increase with decreasing nucleation temperature, and the product resistance increased with increasing SSA. The ice fog technique can be refined into a viable method for nucleation temperature control. The SSA of the product correlates well with the degree of supercooling and with the resistance of the product to mass transfer (ie, flow of water vapor through the dry layer). Using this correlation and SSA measurements, one could predict scaleup drying differences and accordingly alter the freeze-drying process so as to bring about equivalence of product temperature history during lyophilization.

Design of the Lyophilization Process of a Doxorubicin Formulation Based on Thermal Properties

“…This was to assure that the collapse temperature could not be surpassed during sublimation. Chamber pressure was determined by putting values in equation reported in literature [21,22] . The calculated value was con trolled by injecting dry air into the chamber.…”

Noncontact Infrared-Mediated Heat Transfer During Continuous Freeze-Drying of Unit Doses

“…These results do not match the product resistance profiles in function of the dried layer thickness provided from literature 17,18 . However, these resistance profiles were determined under different process conditions for both freezing and primary drying, which impacts the pore size of the dried cake and therefore the dried product mass transfer resistance 6,27 . For this reason, the literature values might not be representative for the thin layers, obtained under the applied process conditions.…”

“…Differences in heat and mass transfer between each equipment scale require re-optimisation and revalidation of these cycles 5,6 . Also, in general, the freeze-drying equipment is designed and optimised to process the maximum applicable amount of vials.…”

“…The ice crystal size in the frozen matrix corresponds to the final pore size in the dried layer during the sublimation process. As a reduced pore size is associated with a higher dried product mass transfer resistance and vice versa, the sublimation rate during primary drying is highly influenced by the pore size in the dried layer 6 . Eventually, the uncontrolled freezing step causes vial-to-vial variability of the sublimation rate within a batch and between batches 8 .…”

Effect of freezing methods on the properties of lyophilized porous silk fibroin membranes

“…The freezing step results in conversion of most of the water into ice, leaving the solute in a glassy and/or crystalline phase. The drying step is divided into primary and secondary drying, to remove the frozen water by sublimation and the non-frozen "bound" water by desorption 5,9,10 . The freezing step plays a crucial role in the damage incurred by proteins during lyophilization.…”