Physical Properties of Crystalline and Amorphous Solids - Freeze-drying of Pharmaceuticals and Biopharmaceuticals - page 71

Another type of crystal diversity, somewhat related to polymorphism,
is brought about by the effects of temperature and/or pressure on
chemical composition. The phenomenon is common with solvates, and
particularly hydrates, that are formed by many ionic and molecular
compounds, when they are crystallised from aqueous solution. Common
examples include Na 2 SO 4 ,Na 2 CO 3 and alkali metal phosphates, most of
which can exist in a variety of hydrated crystalline forms. Organic
hydrate formers, of high relevance to freezing include glucose.H 2 O,
maltose.H 2 O, lactose.H 2 O, a,a-trehalose.2H 2 O, b,b-trehalose.4H 2 O
and ranose.5H 2 O. It should be clearly understood that any statement
in the literature that a particular carbohydrate does not form hydrates
must be viewed with scepticism. It can only mean that no such hydrate
has yet been detected. It is likely that many ''hidden'' sugar hydrates
could exist under appropriate, perhaps extreme, conditions. The recent
discovery of a previously unknown hydrate of mannitol, a favourite
pharmaceutical excipient, gave rise to freeze-drying problems, until the
nature of the problem was recognised: water was released into the freeze-
dried product during the decomposition of the mannitol hydrate into
one of its well-known anhydrous polymorphs. 57
Other materials that also appear to be solid may, however, be devoid of
such long-range atomic/molecular order. Although some short-range
order is likely to exist, such materials are classified as ''amorphous''.
There is no general agreement about the dividing line between crystal-
linity and amorphism, i.e. between long- and short-range order, or how
many unit cells are required for a material to display the physical
characteristics of crystallinity. 173 In principle, most materials can exist
in both forms, depending on the method of preparation, processing and
storage conditions. Sucrose, for example, is commercially supplied as an
anhydrous crystalline solid at ambient temperature. If, however, crystal-
line sucrose is melted and then rapidly cooled, crystal nucleation does not
occur spontaneously at the equilibrium melting point. Instead, the under-
cooled liquid sucrose becomes increasingly viscous until, over a particular
range of temperature, the viscosity suddenly increases by several orders of
magnitudeandthesucrosesolidifiesintoaglass (i.e. an amorphous solid).
An amorphous ''solid'' is therefore characterised by its lack of a long-
range ionic, atomic or molecular order. It is thus an undercooled liquid
that is thermodynamically unstable with respect to the crystal form, but
the energy barrier to viscous flow is high enough to prevent its reversion
to the stable, crystalline state, at least within the normal time scale of
observation. In a similar manner, other kinetic rate processes, e.g.
chemical reactions, are severely inhibited in the glassy state. This makes
the glass a valuable stabilising matrix for chemically labile materials.