Primary Drying: The Sublimation of Ice - Freeze-drying of Pharmaceuticals and Biopharmaceuticals - page 97

CHAPTER 8
Primary Drying: The
Sublimation of Ice
8.1 Principles of Coupled Heat and Mass Transfer
In practice, at the beginning of the primary drying stage, more than 90%
of the water in the initial solution has frozen. The ice is then removed by
sublimation. Unlike the freezing process, ice sublimation is amenable to
some measure of control. The heat flow to the ice front must be adjusted
to balance exactly the heat absorbed by the sublimation of ice at the
operating temperature of sublimation. In this chapter, we discuss the
contributing mechanisms by which heat is transferred from the shelves
of the freeze-drier to the ice front and the mechanisms by which water
vapour is transferred to the condenser (mass transfer), and their relative
contributions to the overall sublimation process.
8.2 Model
A typical pharmaceutical formulation will serve as model, frozen aque-
ous solutions that are contained in loosely stoppered glass vials. They
stand directly on the freeze-drier shelves. Such a model appears decep-
tively simple but is in fact subject to considerable complexities that
bedevil the modelling of optimum processing conditions and the esti-
mation of a realistic drying cycle time. As emphasised in earlier chapters,
for the case where the product does not display eutectic behaviour, it is
imperative to freeze the solution to below T g , in order to ensure maximal
freeze-concentration and minimise deleterious chemical reactions that
have been shown to occur at high rates in part frozen, supersaturated
mixtures. 58,59 By the same token, the temperature during the removal of
ice by sublimation must on no account be allowed to rise above T g at
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