Essential Chemistry and Biochemistry Associated with Low Temperature and Freezing - Freeze-drying of Pharmaceuticals and Biopharmaceuticals - page 49

If this were indeed the case, it would be beneficial in countering the
stresses due to freeze-concentration (see later).
5.3 Changing Phase Relationships during Freezing
The fact that freezing is itself a drying process is not universally realised.
That may in part be due to the conventional terminology used to
describe phase equilibria, and also to the conventional representation
of solid-liquid phase diagrams, where the composition of a mixture is
plotted as a function of temperature, as shown in Figure 1a in Chapter 4
for the simple binary system water-KCl. The left-hand side of the phase
diagram is described as ''liquidus'', whereas the right-hand side is
termed ''solidus''. Thus, the liquidus measures the equilibrium freezing
point depression caused by the addition of KCl to water and the
coexistence of ice and the unsaturated aqueous solution; it could equally
well be regarded as a measure of the precipitation of water from the
saturated solution. Similarly, the solidus could be regarded as a measure
(hypothetically) of the freezing point depression of KCl due to added
water and the increasing solubility of water with decreasing temperature.
The liquidus terminates at the so-called eutectic point T e , which, by the
law of the phase rule, is the only temperature at which crystalline water
and crystalline KCl can coexist in equilibrium with the (saturated) liquid
solution. The phase diagram of the NaCl-water system is of more
immediate relevance to freeze-drying because buffered saline solution
is commonly used as an isotonic reconstitution medium. On the phase
diagram, shown in Figure 12 in Chapter 4, the eutectic point occurs at
21.131C, at a NaCl concentration of 4 M (23.3% w/w). However, the
substance that actually crystallises at T e is not NaCl, but the dihydrate
NaCl.2H 2 O. That makes the construction of the solidus complicated,
because the dihydrate is converted to anhydrous NaCl and water at 11C
at the peritectic, because NaCl.2H 2 O decomposes below its hypothetical
melting point. Because of its universal importance, and because it is
inexpensive and easily purified, the NaCl-water system has been studied
over a wide range of pressures and temperatures. 52 Additional eutectic
points have been detected, but they are of no relevance to processes that
occur under ambient or near-ambient conditions. The fact that only one
hydrate has been found cannot be taken to mean that other hydrates
might not exist. As will be shown later, the presence of previously
unknown hydrates can cause severe problems in freeze-drying opera-
tions when they inadvertently decompose with the liberation of water.
The properties of eutectic mixtures are further explored in Chapter 11.