Heat and mass transfer scale-up issues during freeze drying: II. Control and characterization of the degree of supercooling |
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Authors: | Shailaja Rambhatla Roee Ramot Chandan Bhugra Michael J Pikal |
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Institution: | (1) School of Pharmacy, University of Connecticut, 06269 Storrs, CT;(2) Present address: Bayer Health Care, Biological Products, 27520 Clayton, NC;(3) Present address: School of Engineering, University of Connecticut, 06269 Storrs, CT |
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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”, there-by 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. |
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Keywords: | nucleation freeze-drying scale-up mass transfer |
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