Structure–Polymorphism Study of Fenamates: Toward Developing an Understanding of the Polymorphophore

The ability of molecules to adopt
more than one unique crystalline
structure, polymorphism, is a phenomenon of considerable scientific
interest because it challenges the notion that molecules arrange themselves
exclusively in the thermodynamically most stable crystal form. The
factors influencing this behavior are manifold and have defied simple
prediction. To illustrate an approach to elucidating these factors,
the solid-state behavior of a series of molecules that are derivatives
of tolfenamic acid (TA), a pentamorphic system, was explored. In analogy
to the manner in which drugs are discovered through structure–activity
relationships and the identification of a pharmacophore, we test here
the notion that when a collective ensemble structural motifs, a “polymorphophore,”
is incorporated into a molecule it renders the compound polymorphic.
The structure–polymorphism relationship in six TA analogues,
both commercial and newly synthesized, was undertaken with the intention
of systematically understanding the factors that influence the polymorphism
in the fenamic acid class through a combined computational as well
as experimental approach. Ultimately, such studies may be used to
experimentally derive the propensity for polymorphic behavior of a
given molecular motif and perhaps provide a pathway to engineer molecular
compounds with controlled properties in the solid state.