Essential Chemistry and Biochemistry Associated with Low Temperature and Freezing - Freeze-drying of Pharmaceuticals and Biopharmaceuticals - page 55

NaCl.2H 2 O is of a fairly simple nature and that the ionic interactions
favouring nucleation and crystal growth are strong compared to ionic
hydration interactions.
The situation can, however, be quite different. Consider the system
sucrose-water: during freezing, even at moderate cooling rates, sucrose
does not crystallise spontaneously at its eutectic temperature, -9.91C, or
thereafter, in real time. With continued cooling, the solution viscosity
increases, eventually in a steep, highly non-Arrhenius manner until, at
321C, and a sucrose concentration of ca. 80% w/w, the mixture
solidifies into a glass, i.e. without crystallising. Compared to the eutectic
point, the vitrification point is reached at a supersaturation degree of
43% w/w and a degree of undercooling of 8.4%. The point of maximum
freeze-concentration is now commonly referred to as ''T g ''. The fact that
sucrose does not (cannot) crystallise during freeze-concentration is an
indication of its very complex crystal structure, which makes for a low
nucleation rate, compared to the imposed rate of cooling. Thus, sucrose
will not crystallise in real time. w Instead, it will yield a highly concen-
trated solid solution in water. This property, which is common to most
polyhydroxy compounds (PHCs), is extensively exploited in the formu-
lation of pharmaceutical preparations destined for drying. The impor-
tant thermophysical characteristics of amorphous PHCs, and their
impact on pharmaceutical product quality, will be described in more
detail in Chapters 6, 7 and 10.
Knowledge of the kinetics of salt precipitation becomes particularly
important for the correct choice of pH buffering mixtures of labile
biopharmaceutical preparations during freezing. Returning once again
to the crystallisation of phosphate buffer mixtures under equilibrium
conditions, it needed to be established whether this behaviour does
actually exist in real formulations and under freezing conditions. It was
found that the fractions of the two phosphates that do actually precipitate
depend on the buffer composition, but not in an additive manner, as well
as on the initial buffer concentration and the cooling rate. 56 Where one or
the other salt in the buffer mixture precipitates spontaneously during
cooling or annealing, the pH of the remaining solution phase will suffer a
shift at that point, particularly if the other buffer component is subject to
long-term supersaturation. A striking example of this type of behaviour is
shown in Figure 5 for a Na 2 HPO 4 -citric acid buffer (nominally at pH
6.5). The solution was seeded with an ice crystal to initiate freezing at -
0.51C (the ice/sodium phosphate eutectic point). No salt precipitated at
w The expression ''real time'' is used in this topic to denote the observable duration of a physical/
chemical process or of an experimental observation, or the shelf life of a dried product. In other
words, ''real time'' will be expressed in a range of 10 1 -10 8 s (seconds to years)