The Dried Product - Freeze-drying of Pharmaceuticals and Biopharmaceuticals - page 138

recorded T g at 631C, which was replaced by the melting endotherm of
raffinose.5H 2 O. Thus, overnight storage had resulted in the complete
sequestration of water from the amorphous phase by the crystallisation of
the pentahydrate. This type of water removal has been termed ''self-
stabilisation'', because it can be employed to protect the stability of labile
pharmaceuticals against inadvertent exposure to water vapour during
processing and/or long-term storage.
Compared to crystalline materials, the production and handling of
amorphous substances are subject to serious complexities. Whereas the
formation of crystalline materials can be described in terms of the phase
rule, and solid-solid transformations (polymorphism) are well charac-
terised in terms of pressure and temperature, this is not the case for
glassy preparations that, in terms of phase behaviour, are classified as
''unstable''. Their apparent stability derives from their very slow relax-
ations towards equilibrium states. Furthermore, where crystal structures
are described by atomic or ionic coordinates in space, that which is not
possible for amorphous materials, by definition, lack long-range order.
Structurally, therefore, positions and orientations of molecules in a glass
can only be described in terms of atomic or molecular distribution
functions, which change over time; the rates of such changes are defined
by time correlation functions (relaxation times).
It is not immediately obvious where the glass transition fits into this
picture of the amorphous state. Few reports exist of structural compar-
isons between crystalline, glassy and fused states of the same substance.
One such study for glucose, based on neutron scattering, led to the
conclusion that structurally, the glass can be best modelled as a deformed
crystal, in which the unique atomic separations and hydrogen-bond
angles have become somewhat distorted during fusion and quenching
into the glassy state, i.e. partially arrested crystallisation. 79 Despite the
structural similarities of the crystal and the glass, their thermomechanical
properties are dramatically different.
It was earlier mentioned that in an amorphous material, cooled to
within its narrow vitrification temperature range, molecular relaxation
rates decrease by several orders of magnitude, so that physical and
chemical changes become very slow, hardly accessible within the time
scales that govern ordinary experimentation. It is nevertheless important
to be aware that such changes do occur, even though relaxation times
may increase to weeks, months, years or centuries. In practice, below T g ,
molecular relaxation times become too long for equilibrium to be
established on an experimental time scale. This is related to a drastic
reduction in the number of accessible configurations, which a system can
adopt as the temperature is lowered. If W(T) is the probability of a