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

166 M.R. Caira
stabilities, and temperatures and rates of interconversion are essential for ensuring
drug preparations with reproducible behaviour [24]. Already, legislation
requiring drug manufacturers to provide information relating to the occurrence
(or apparent absence) of polymorphism in their products has been introduced
[41]. Demonstrating the absence of a tendency to polymorphism is not easy;
most substances when investigated for a sufficiently long time will reveal more
than one polymorph [42].
Successful preparation of crystals of organic compounds having special properties
(e.g. second-harmonic generation, metallic conductivity) may hinge on
polymorphism, only one polymorph of the compound in question displaying
the desired property. Bernstein has recently described representative systems
which clearly illustrate the relationship between a polymorphic structure
(a crystal architecture characterised by well-defined molecular interactions)
and the unique physical properties which that structure confers on the solid
material [13].
These remarks serve to emphasise some of the more important practical
implications and consequences of polymorphism. Overcoming the problems
encountered requires a deeper understanding of the processes of nucleation,
crystal growth and polymorphic transformation. Several recent studies relating
to these topics are reviewed in the next section.
2.2
Crystallization and Polymorphic Transformations – Thermodynamic
and Kinetic Considerations
Crystallization of a specific polymorph from a melt, solution or vapour, commences
with nucleation, i.e. the formation of a critical “embryonic” nucleus
which is the structural blueprint for subsequent development and growth of the
macroscopic crystal. The factors determining nucleation rate (e.g. the associated
Gibbs free energy of activation, molecular volume, interfacial energy) generally
differ for polymorphs of the same substance [4]. Since, in a supersaturated
solution, nuclei of all possible polymorphs of the dissolved substance may be
imagined to exist [36], the outcome of crystallization is kinetically complicated
by competitive nucleation processes. Thermodynamic considerations of polymorphic
crystallization include Ostwald’s law of stages [4, 43], according to
which, at high supersaturation, the first form which crystallizes is the thermodynamically
least stable (most soluble) form. This form subsequently dissolves
and transforms into a more stable one. The cycle continues until only the
thermodynamically stable (least soluble) polymorph remains. The practical
implication is that it should be possible to isolate the different polymorphs of
a given compound at different levels of solution supersaturation and hence
exercise some control over the crystallization process.
As regards polymorphic transformations in general, two types are distinguished,
namely enantiotropic and monotropic [23]. These can be described in
terms of the Gibbs free energy G, which has a minimum value for the thermodynamically
stable phase of a polymorphic system and larger values for metastable
phases and is such that the polymorph with the higher entropy will tend