Heat and Mass Transfer Scale-up Issues during Freeze Drying: II. Control and Characterization of the Degree of Supercooling

Heat and Mass Transfer Scale-up Issues during Freeze Drying: II. Control and Characterization of the Degree of Supercooling
August 2004
Shailaja Rambhatla, Roee Ramot, Chandan Bhugra, and Michael J. Pikal
AAPS PharmSciTech 2004
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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. Asignificant 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.