Illuminating milling mechanochemistry by tandem real-time fluorescence emission and Raman spectroscopy monitoring.

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 spectroscopic and kinetic data are supported by X-ray diffraction and solid-state nuclear magnetic resonance spectroscopy measurements.

Computational evaluation of halogen-bonded cocrystals enables prediction of their mechanochemical interconversion reactions.

Periodic density-functional theory (DFT) calculations were used to predict the thermodynamic stability and the likelihood of interconversion between a series of halogen-bonded cocrystals. The outcomes of mechanochemical transformations were in excellent agreement with the theoretical predictions, demonstrating the power of periodic DFT as a method for designing solid-state mechanochemical reactions prior to experimental work. Furthermore, the calculated DFT energies were compared with experimental dissolution calorimetry measurements, marking the first such benchmark for the accuracy of periodic DFT calculations in modelling transformations of halogen-bonded molecular crystals.