Abstract
In pursuit of accessible and interpretable methods for direct and real-time observation of mechanochemical reactions, we demonstrate a tandem spectroscopic method for monitoring of ball-milling transformations combining fluorescence emission and Raman spectroscopy, accompanied by high-level molecular and periodic density-functional theory (DFT) calculations, including periodic time-dependent (TD-DFT) modelling of solid-state fluorescence spectra. This proof-of-principle report presents this readily accessible dual-spectroscopy technique as capable of observing changes to the supramolecular structure of the model pharmaceutical system indometacin during mechanochemical polymorph transformation and cocrystallisation. The observed time-resolved in situ spectroscopic and kinetic data are supported by ex situ X-ray diffraction and solid-state nuclear magnetic resonance spectroscopy measurements. The application of first principles (ab initio) calculations enabled the elucidation of how changes in crystalline environment, that result from mechanochemical reactions, affect vibrational and electronic excited states of molecules. The herein explored interpretation of both real-time and ex situ spectroscopic data through ab initio calculations provides an entry into developing a detailed mechanistic understanding of mechanochemical milling processes and highlights the challenges of using real-time spectroscopy.