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

Crystalline Polymorphism of Organic Compounds 201
altering the rheological properties of drug polymorphs in particular. However,
thermal treatment or vacuum drying has also been applied to more general
inclusion compounds containing both natural and synthetic host molecules in
order to prepare pure polymorphic forms of the host. Of the seven polymorphic
forms of gossypol (5) identified thus far [162], only two were obtained by appropriate
recrystallizations from solution, while the remainder resulted from desolvation
of various gossypol clathrates. The latter could be divided into isostructural
groups and it was found that all members of a given group yielded the same
polymorph on desolvation. These unusual and intriguing results imply the
existence of a “template” effect in this system. Similar experiments with pseudopolymorphs
of indomethacin (6) also yielded a series of isostructural pseudopolymorphs
[83], but in this case there was virtually no correlation between a
given series and the identity of the polymorph resulting from desolvation. A
systematic study of such systems to elucidate the mechanisms of desolvation is
desirable if this process is to be exploited in a predictive way for the control of
polymorphism.
Polymorphic inclusion compounds of a host molecule with the same guest
can occur if the host-guest interactions are flexible enough to allow nearly equienergetic,
but crystallographically distinct host-guest packing arrangements.
Reports of the preparations of such polymorphs are rare [163], but would probably
increase in frequency if a variety of preparative conditions were to be
employed.
As with most organic compounds, inclusion complexes are usually prepared
only once and the chances of detecting polymorphism are correspondingly
small. The well known host molecule cholic acid (7) has been shown to form
different polymorphic inclusion complexes with the same guest [164]. The polymorph
which crystallizes is determined by the absence or presence of a third
chemical species. Crystallization of cholic acid from, e.g., acrylonitrile yielded
the 1:1 host-guest complex with space group P2 12 12 1, while addition of acrylonitrile
to a saturated solution of the host in butan-1-ol yielded a 1:1 cholic
acid ◊ acrylonitrile complex with space group P2 1. X-ray analyses confirmed that
the polymorphs contained different packing arrangements as well as different
hydrogen bonding networks. The controlling role of the third component in
effecting precipitation of a specific polymorph was not clarified in the report
but selective adsorption of solvent molecules on the surfaces of growing crystals
may be involved.
During the last ten years, considerable progress has been made in the control
and modification of crystal properties using “tailor-made auxiliaries” [35, 36].
These auxiliaries may act either as promoters of crystal growth (making them
useful for the study of nucleation processes) or as inhibitors (for use in the control
of, e. g., morphology, enantiomeric resolution and polymorphism). The
strategy for effecting kinetic resolution of a conglomerate involves the design of
chiral-resolved polymeric inhibitors which will, in solution, bind selectively to
only one of the growing enantiomeric crystalline phases, thus preventing its
growth and permitting unhindered growth of the other enantiomeric phase.
Where simultaneous crystallization of the racemic phase might occur, design of
the inhibitor would have to take this into account. It must be emphasised that