Essential Physics of Low Temperature and Freezing - Freeze-drying of Pharmaceuticals and Biopharmaceuticals - page 35

ultra-fast quenching methods, thin films or microdroplets of liquid water
can even be vitrified. 30
4.6 Nucleation and Crystallisation of Ice and Solutes in
Aqueous Solutions
In the following discussion, emphasis is placed on the classes of solutes
that are of importance in pharmaceutical freeze-drying; they include salts
and some water-soluble organic compounds, specifically those that can
act as hydrogen-bond donors and/or acceptors. As shown in Figure 10,
solutes exert a major influence on ice nucleation and, hence, also on ice
crystallisation rates and crystal habits. An additional factor to be taken
into account is the fate of the solutes during freeze-concentration.
According to the equilibrium phase behaviour of the NaCl-water
system, see Figure 12, NaCl 2H 2 O precipitates (crystallises) from the
part-frozen solution at 211C, the eutectic point, T e ; the NaCl concen-
tration in the residual liquid phase, i.e. its saturation solubility at this
temperature is ca. 4M.T e is defined formally as the temperature below
which no (liquid) solution phase exists in equilibrium with any crystalline
phase(s); under equilibrium conditions the system below its eutectic point
consists entirely of a mixture of ice and NaCl.2H 2 Ocrystals w The
dihydrate is not stable, in the sense that it does not melt at a well-defined
temperature. Instead it decomposes at a so-called peritectic point (274 K)
into anhydrous NaCl and ice. Of even greater importance than the
crystallisation of water is the fate of the solutes during freezing, because
the ice will eventually be removed by sublimation, whereas the remaining
solutes will make up ''the freeze-dried product''. The crystallisation of the
salt from its saturated solution also depends on the existence of a given
density of nuclei on which Na 1 and Cl ions,aswellaswatermolecules,
can condense, thus enabling the NaCl 2H 2 O crystals to grow. Just as in
the case of ice, the formation of nuclei depends on random density
fluctuations within the body of the now highly concentrated liquid phase.
In practice, it is found that few salts will spontaneously crystallise at T e ,so
that a certain degree of supersaturation ( undercooling) is unavoidable,
directly analogous to the transient undercooling of water. Such delayed
crystallisation (precipitation) of solutes from a freezing solution, giving
rise to supersaturation, is a common phenomenon and has important
implications for successful freeze-drying of biopharmaceuticals; these are
discussed in more detail in the following chapters.
w T e is very carefully defined here because the commercial freeze-drying literature contains many
instances in which a glass temperature is mistakenly referred to as a ''eutectic temperature''.