198 Topics in Current Chemistry Editorial Board: A. de Meijere KN ...

Crystalline Polymorphism of Organic Compounds 167
a
b c
Fig. 1a–c. Gibbs free energy vs temperature for: a a dimorphic system, exhibiting; b enantiotropy;
c monotropy
to become the stable form at higher temperature (species B in Fig. 1a). Above T t
(the transition temperature), B is the stable polymorph while A is metastable
and vice versa at temperatures below T t.In an enantiotropic system (Fig. 1b),the
free energy curve for the common liquid phase L intersects the A and B curves
at T > T t. In this case, the lower melting form (A) is stable at T < T t, the higher
melting form is stable at T > T t, and the transition between the two forms is in
principle reversible. Since transition temperatures in practice are often in the
range 20–200°C, one practical implication of enantiotropy is that conversion of
one polymorph into another may be favoured during routine manufacturing
processes [24]. On the other hand, for a system displaying monotropy (Fig. 1c),
curve L intersects those for A and B below T t and the higher melting form (A) is
always the thermodynamically stable one. Thus, below the melting point, only
one form is stable and the other metastable. In practice, if a desired metastable
polymorph is obtained during manufacture, it can revert to the stable polymorph
under suitable conditions (e.g. in suspension, via solvent-mediation, or
during compression). It follows that to prepare a specific polymorph and be
aware of its possible fate during handling, it is advantageous to know the transition
temperatures and thermodynamic stabilities of all the forms that may
appear in the system [24].
The general considerations above highlight the importance of nucleation and
the role of environmental conditions (e.g. solvent, temperature) in the crystallization
of polymorphs as well as their interconversions. These areas continue to
be the subject of intense interest especially in the context of polymorphic
control in crystallization.
Some fundamental aspects of the nucleation process have been investigated
by molecular dynamics (MD) methods. In a recent review [44] the advantages
and limitations of molecular cluster models in simulating the dynamics of
nucleation and phase changes have been discussed. In this approach, molecular
dynamic simulations are correlated with experimental nucleation rates extracted
from electron diffraction patterns of molecular supersonic jets. The dynamics
of freezing of ammonia, CCl 4 and water, and the phase transformations of
t-butyl chloride have been analysed. A useful feature of the MD computational