The Role of Weak Interactions in the Phase Transition and Distinct Mechanical Behavior of Two Structurally Similar Caffeine Co-crystal Polymorphs Studied by Nanoindentation

Although weak interactions, such
as C–H···O
and π-stacking, are generally considered to be insignificant,
it is their reorganization that holds the key for many a solid-state
phenomenon, such as phase transitions, plastic deformation, elastic
flexibility, and mechanochromic luminescence in solid-state fluorophores.
Despite this, the role of weak interactions in these dynamic phenomena
is poorly understood. In this study, we investigate two co-crystal
polymorphs of caffeine:4-chloro-3-nitrobenzoic acid, which have close
structural similarity (2D layered structures), but surprisingly show
distinct mechanical behavior. Form I is brittle, but
shows shear-induced phase instability and, upon grinding, converts
to Form II, which is soft and plastically shearable.
This observation is in contrast to those reported in earlier studies
on aspirin, wherein the metastable drug forms are softer and convert
to stable and harder forms upon stressing. To establish a molecular-level
understanding, we have investigated the two co-crystal polymorphs I and II by single-crystal X-ray diffraction,
nanoindentation to quantify mechanical properties, and theoretical
calculations. The lower hardness (from nanoindentation) and smooth
potential surfaces (from theoretical studies) for shearing of layers
in Form II allowed us to rationalize the role of stronger intralayer (sp2)­C–H···O
and nonspecific interlayer π-stacking
interactions in the structure of II. Although the Form I also possesses the same type of interactions, its strength
is clearly opposite, that is, weaker intralayer (sp3)­C–H···O and specific interlayer π-stacking interactions. Hence,
Form I is harder than Form II. Theoretical
calculations and indentation on (111) of Form I suggested
the low resistance of this face to mechanical stress; thus, Form I converts to II upon mechanical action. Hence,
our approach demonstrates the usefulness of multiple techniques for
establishing the role of weak noncovalent interactions in solid-state
dynamic phenomena, such as stress-induced phase transformation, and
hence is important in the context of solid-state pharmaceutical chemistry
and crystal engineering.