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

Crystalline Polymorphism of Organic Compounds 169
their relative growth rates could be determined. The thermodynamics and
kinetics of crystallization of large molecules from solution have been discussed
[49]. Modelling of the crystallization of protein molecules indicated that the
concepts and numerics of colloid stability theory are appropriate.
Recent studies of polymorphic transformations in organic crystals mediated
by melt, solution and interface have been reviewed [4]. Interface-mediated
transformation has only recently been recognized as a distinct mode of polymorphic
transformation. It involves nucleation and growth of a new polymorph
through mass transfer across the interface connecting single crystals of two
different polymorphs and it differs from solid-solid transformations in that a
microscopic solution layer is required as an interface. Transformations mediated
by melt, solution and interface are usually more rapid than solid-solid
transitions; for the latter, the activation energy is larger due to the fact that
nucleation and growth of the new phase within a second phase involve diffusion
and structural rearrangement at the reaction interface. The fundamental
thermodynamic relationships governing polymorphic solid state transitions
have been reviewed [6]. It has also been pointed out that the mechanisms of
polymorphic transitions in molecular crystals are largely unknown, though
order-disorder transitions are understood in reasonable detail [5]. An important
technique for studying solid-solid transformations is thermal analysis and
a review of the basic thermodynamic principles for interpreting thermal analysis
data for both polymorphic and pseudopolymorphic systems has appeared
[23]. Kinetic and thermodynamic aspects of the thermal decomposition of
inclusion compounds (a special class of pseudopolymorphs) have also recently
been discussed [50].
Theoretical and experimental studies of the role of solvent on polymorphic
crystallization and phase transformations abound in the literature of the last few
years and some pertinent examples are described here. For solvent-mediated
transformations, the driving force is the difference in solubility between different
polymorphs. An important earlier paper on the kinetics of such phase
transformations [51] described a model featuring two kinetic processes in solid
to solid phase changes via a solution phase, namely dissolution of the metastable
phase and growth of the stable one.
The effect of solvent on the crystallization of polymorphs has recently been
investigated [43] using as a model compound the antibacterial sulphathiazole
whose four known polymorphs are well characterised. The study, whose express
intention was to test the Ostwald law, involved crystallization of the pure polymorphic
forms of the drug, solubility measurements and crystallizations from
various solvent systems. Systematic variation of supersaturation was employed
in an attempt to crystallize each of the four forms of sulphathiazole, as predicted
by the Ostwald law. Solubility studies showed Form I to be the most soluble
form, followed in order by Forms II, IV and III. The supersaturation crystallizations
using acetone, acetone-CHCl 3 (3:2), n-propanol and water, revealed that
only the acetone-CHCl 3 system yielded results in accord with theory, Forms I, III
and IV being isolated from it by varying the supersaturation. Crystallization
from n-propanol, for example, yielded only Form I at all supersaturation levels.
Thus, the finding that some solvents selectively favour the crystallization of a