The Dried Product - Freeze-drying of Pharmaceuticals and Biopharmaceuticals - page 157

content of an amorphous product is generally expressed as W 0 g g per g
solid. The actual value, as shown in Figure 9 in Chapter 5, typically
0.2-0.3 g g 1 , is partly determined by the freezing behaviour of the
formulation during cooling. It is likely to vary from product to product
or even from vial to vial. DSC is commonly employed to obtain an
estimate of this residual water, which forms part of the glassy phase, and
that must be wholly or partly removed by secondary drying.
A ''correct'' definition of ''dry'' has already been commented upon
because even the most hydrophobic organic substances, e.g. polystyrene,
absorb water vapour to some extent. Water has therefore been called
Nature's ''ubiquitous plasticiser''. Apart from this softening role, water,
being itself a very reactive and versatile molecule, might also have other
effects on amorphous solid substrates, some of them unexpected, and
most of them deleterious. The role of low water contents ( o 1% w/w) in
affecting the behaviour of solid solutions is a subject that deserves
further investigation.
The reliable estimation of residual water in dried solids is of impor-
tance but is beset by several problems, 152 mainly related to the shape and
interpretation of DSC heating traces, as illustrated in Figure 11 for a
typical aqueous mixture, maximally frozen, from which any relaxation
enthalpy contribution has been removed by annealing. 117 The drawn-
out DSC heating trace represents the superposition of several distinct
processes: T g of the mixture, the heat of dilution, produced by ice
Temperature
Figure 11 Contributions (not drawn to scale) to the total measured glass transition and
ice-melting endotherm for a frozen aqueous solution: crosses represent contri-
bution from the heat of dilution of the supersaturated solution, circles denote
the enthalpic relaxation contribution and the broken line is the glass transition.
The drawn out curve represents the measured overall heat flow, and the area
under that scan corresponds to the total enthalpy change.