The Dried Product - Freeze-drying of Pharmaceuticals and Biopharmaceuticals - page 155

The isotropic reorientation of the ''hydrated complex'' has the same
t value as that found for sugars by 13 C relaxation. Below 270 K, no
dynamic equilibrium between bulk and hydrate water is detected;
the correlation times diverge and T o values are no longer identical.
At c 4 60%, the mobility of sugar and hydrate water freezes out
at T o 200 K. In the water phase, free rotation persists down to
T

120 K! The calorimetric T g values correspond solely to those of
the PHC matrices.

E

In summary, the results can be treated in terms of three distinct
concentration domains:
(i) c r 30%: PHC molecules perform uncorrelated motions, and the
solution viscosity exhibits a minimal concentration dependence. The
dynamics of water molecules are governed by co-operative fluctu-
ations within the hydrogen-bonded water network. In undercooled
solutions, the network increasingly inhibits the orientations and the
rotational correlation time increases steeply with decreasing tem-
perature. Hydrostatic pressure distorts the network and, in the
metastable phase, it inhibits the generation of ordered domains
with linear H-bonds; molecular motions thus remain rapid. Dis-
solved PHC molecules, because of their incompatible -OH orientat-
ions, produce a similar effect. This makes it possible to undercool
PHC solutions far into the metastable region, resulting in eventual
vitrification.
(ii) c 4 40%: Hydrated PHC molecules form aggregates that develop
into a network. The resulting change in the short-range structure
leads to a distribution of correlation times. The water molecules
are integrated into the network, and their rotational and transla-
tional motions are affected. This is strikingly demonstrated in
Figure 10, which shows the ratio of sugar:water t values as a
function of concentration. An increasing coupling of diffusive
motions (microheterogeneity) between sugar and water is evident
in a complex mixture; it reaches its maximum value at c ¼ 50%. At
higher concentrations, PHC molecules form networks via direct
H-bond links, with the expelled water molecules collecting in
microscopic droplets; their mobility is facilitated in this quasi-
heterogeneous system. At this stage, PHC and water motions lose
their coupled motions, with a sharp rise in the t ratio.
(iii) c 4 70%: A three-dimensional PHC network is formed. With
decreasing temperature, the network forms a macroscopic gel and
the PHC molecules are unable to adopt the crystal configurations