Essential Chemistry and Biochemistry Associated with Low Temperature and Freezing - Freeze-drying of Pharmaceuticals and Biopharmaceuticals - page 65

Figure 10 Solid/liquid state diagram of the sucrose-water system showing also the glass
transition profile. Symbols correspond to data taken from diverse sources
A particularly striking example is provided by Miller et al. 72 for a,a-
trehalose. Their long-term equilibration experiments led to a eutectic
point of -2.51C (29.8% w/w), in reasonable agreement with a value of -
4.41C, 73 but differing substantially from -18.81C, earlier reported. 74
Such uncertainties in the correct equilibrium properties inevitably pro-
duce even larger uncertainties in the correct value of T g and C g , the
unfrozen water content at maximal freeze-concentration. Miller et al.
cite recent literature values of T g , ranging from -22 to -351C, to
demonstrate the large uncertainties in this number, which is of unique
importance in the calculation of primary drying times (ice sublimation);
see Chapter 8. Of almost equal importance is C g , the independent
determination of which is also beset by considerable experimental
problems (see Chapter 9).
From the earlier definition of the glass transition, it might be expected
that below T g , crystallisation is inhibited, and this is generally the case,
at least for practical time scales. There are, however, reports describing
crystallisation of polymers in real time at temperatures well below the
glass transition. 75 It must of course be remembered that, on a molecular
basis, glasses are undercooled liquids, and they differ from ordinary
liquids mainly in the rates of their transport properties. These differences
can be usefully exploited in the formulation of pharmaceutical prepa-
rations, as will presently be discussed.