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

Crystalline Polymorphism of Organic Compounds 177
correlate with higher packing energy. Finally, from the observation that 24 % of
the polymorphic pairs analysed comprised both a centrosymmetric and a noncentrosymmetric
partner, it was concluded that the link between molecular
properties and centrosymmetry of crystals is evidently weak. The reader is
referred to this seminal study [79] for the full exposition of the above conclusions
and their justification, as well as further perceptive observations on the
phenomenon of polymorphism.
3
Methodology for the Study of Crystal Polymorphism
3.1
Review of Preparative Methods
Research on the polymorphism of a new molecular entity normally commences
with experimental screening which can indicate the occurrence of more than
one crystalline form of the substance. An inexpensive method of such testing is
hot stage microscopy (HSM), which has been used very extensively and effectively
by a leading proponent [80] for many years to provide preliminary indications
of the presence of crystalline polymorphic and pseudopolymorphic
(solvated), as well as glassy (amorphous) forms, all of which may have practical
utility. Pseudopolymorphic forms are molecular adducts containing solvent of
crystallization and have been classified [37] as stoichiometric solvates and nonstoichiometric
inclusion compounds possessing channel, layer or cage (clathrate)
structures. Procedures for detecting the existence of multiple forms by HSM
have been outlined [37, 81]. These include, for example, the observation of solidsolid
transformation upon heating the substance,observation of transformation
(spontaneous or mechanically induced) following the freezing of a melt, and
detection of gas evolution as bubbles from pseudopolymorphs immersed in
silicone oil during heating (indicative of a solidÆ gas +solid transformation).
Once the existence of multiple forms is established, practical methods for the
preparation of specific forms on a larger scale may be explored. Frequently,
recrystallization of the compound from solvents or solvent mixtures spanning a
wide polarity range is effective in producing several of the different forms in sufficient
quantity for complete characterisation by the analytical methods to be
discussed.Most pseudopolymorphs are prepared by crystallization of the parent
organic compound from the respective solvent, whereupon the latter becomes
incorporated in the new crystal. Recrystallization from a mixed solvent system
may yield a pseudopolymorph containing either or both solvents. Exposure of
the parent organic compound to vapours may also result in the formation of
pseudopolymorphs (as occurs e.g. when anhydrous drugs react with atmospheric
water to form hydrates). This is exemplified by the drug indomethacin,
for which four polymorphic forms (I–IV) have been identified [82]. Crystallization
of the commercially available Form I from over fifty solvents yielded Forms
I, II, IV and mixtures of these, as well as a number of pseudopolymorphs [83]. To
ensure subsequent reproducibility in the preparation of specific forms by
crystallization, careful attention to the details of solvent purity, degree of solu-