Secondary Drying: The Removal of Unfrozen Water - Freeze-drying of Pharmaceuticals and Biopharmaceuticals - page 114

process, this amount of water will not be removed completely by
sublimation, at least not during a normal primary drying process. In
the case of mannitol, the hydrate contains only 9%w/w of water. On the
other hand, a typical formulation is likely to contain substantially more
mannitol than NaCl, so that damage caused during decomposition of
the crystalline hydrate, with the concomitant liberation of water, would
cause more damage to the product.
In general, no distinct boundary exists between primary and secondary
drying because the removal of unfrozen water from the amorphous matrix
above the receding ice front may commence even while ice is still subliming
from lower regions of the frozen plug. Compared to ice sublimation, the
secondary drying process is poorly understood and less accessible to
quantitative analytical treatment. Thus, a safe required drying period
can only be estimated. The most important point is that, even after ice
sublimation is complete, an amorphous product must be maintained at
temperatures close to the glassy state, T g . This is in stark contrast to advice
sometimes found, especially in the technical literature, that immediately
heating the material to room temperature does not produce adverse
effects. 115 If, during the drying process, T g is exceeded for any length of
time, the fragile structure of the drying cake will begin to collapse because
the viscosity of the solid matrix decreases rapidly with increases in tem-
perature above T g . This phenomenon is illustrated in more detail in
Section 7. Figure 1 illustrates the onset of such collapse in a solution
during the initial stage of secondary drying, even when carefully per-
formed. Apart from progressive structural collapse, deleterious processes,
Figure 1 Scanning electron micrograph of freeze-dried sucrose; the scale bar corresponds
to 10 mm. Globules, formed at the ends of the filaments, are evidence of minor
collapse during drying, when the temperature exceeded the softening point for
short periods