Exploring the Structure-Polymorphism Relationship of the ROY Polymorphophore via the use of Solid-Form Informatics

Polymorphism is a phenomenon by which a single chemical entity can crystallise
in multiple distinct crystalline forms, each displaying unique physicochemical
properties. As such, polymorphism is a relevant issue across any field which
utilises crystalline forms, in particular the pharmaceutical industry. Significant
time and money is spent industrially to explore the polymorphic landscape of
candidate molecules, using methods such as High-Throughput Screening and
Crystal Structure Prediction. Despite its relevance, little progress has been made
towards any understanding of links between chemical structure and
polymorphism.
A polymorphophore is a class of compounds which, analogous to the concept of
a pharmacophore, has the ability to impart structures with polymorphism when
incorporated into a new chemical structure. These structures could provide a link
between chemical structure and the phenomenon of polymorphism, but to date
only two polymorphophore structures have been confirmed and investigated
experimentally
(N-phenylbenzamide and Fenamates). 5-methyl-2-[(2
nitropphenyl)amino]-3-thiophenecarbonitrile (aka ROY) is a compound for which
12 unique single component crystal forms have been discovered, which has also
been suspected of being a polymorphophore but has yet to be confirmed as such.
In this work the ROY structure was investigated using Solid Form Informatics
(SFI), an informatics workflow which utilises the Cambridge Structural Database
(CSD), a public library of crystal information containing over 1.25 million
structures. SFI utilises informatics tools developed from the data within the CSD
to explore the intra-, inter- and supramolecular environments of the 12 ROY
polymorphs, in order to find structural features which may influence the
polymorphism of ROY. These structural features were used to design and
synthesise a set of 12 structural analogues of ROY, which were then crystallised
and analysed using SFI to track the changes in intra-, inter- and supramolecular
environment introduced by changes in structure.
Finally, these 12 structural analogues were subject a low-/medium throughput
polymorph screen, during which nine analogues were confirmed to display at
least two polymorphic forms. These data confirm the classification of ROY as a
polymorphophore. However, the lack of data regarding the properties, behaviour
and influence of polymorphophores in general make it difficult to provide a full
evaluation of the implications of this classification.