Secondary Drying: The Removal of Unfrozen Water - Freeze-drying of Pharmaceuticals and Biopharmaceuticals - page 115

such as protein aggregation, previously retarded by the very low diffusion
rates in the glass, are then also likely to proceed, often at rates substantially
higher than in dilute solution at ambient temperatures. This is but one
example of how product quality can be sacrificed in efforts to improve
process economy.
9.2 Removal of Unfrozen Water by Diffusion
Although the process of unfrozen water removal from the material,
subsequent to ice sublimation, is commonly referred to as ''desorption'',
this is misleading. It has been shown that the residual water forms a
mobile component of a solid solution, so that ''diffusion'' more correctly
describes the mechanism of its removal. Compared to the diffusion rate
of water from the bulk to the surface, its eventual desorption from the
surface is rapid and can in practice almost be neglected. As will be
shown later, secondary drying kinetics can be modelled adequately by
standard treatments of diffusive processes. The effects of many variables
on the kinetics of secondary drying may be found in Pikal et al. 118
9.3 Effects of Pressure
For the reason mentioned earlier, and in contrast to primary drying,
chamber pressure (a controllable variable) does not appear to influence
secondary drying rates to a significant extent. It is also known that
neither mannitol (crystalline) nor a formulated amorphous moxalactam
product exhibit systematic effects of pressure on drying kinetics. How-
ever, although for a given product the drying rate is independent of
pressure, different products at the same pressure will experience differing
secondary drying rates. The almost universal practice of conducting
secondary drying at very low pressures, does not, as is popularly
supposed, increase the rate of water removal.
9.4 Effect of Water Content
At the completion of primary drying, the water content of an amor-
phous product is sometimes expressed as W g g water per g solid. The
actual value, typically 0.3-0.5 g g 1 , is governed by details of the
freezing process and will vary from product to product, or even from
vial to vial. For most practical purposes, however, it may be assumed
that the water content has little or no effect on secondary drying. This