Synchrotron X-ray powder diffraction validation of real-time in situ terahertz-Raman monitoring of resonant acoustic mixing cocrystallization.

While synchrotron-based X-ray powder diffraction (XRPD) is often seen as the "gold standard" for real-time in situ monitoring of transformations of crystalline phases under mechanochemical conditions, an exciting opportunity to perform such studies using laboratory benchtop instrumentation is offered by terahertz-Raman (THz-Raman) spectroscopy, capable of detecting changes in lattice phonon bands. Here, we integrate synchrotron XRPD and THz-Raman into a tandem methodology that enabled the qualitative, as well as quantitative validation of the potential of THz-Raman spectroscopic monitoring of cocrystallization under Resonant Acoustic Mixing (RAM) conditions. By using halogen-bonded cocrystals that are difficult to differentiate using conventional Raman spectroscopy as model systems, this work reports strong agreement between the measured rate constants, as well as the ability to detect new crystalline phases by both THz-Raman spectroscopy and synchrotron XRPD. These results are an important first step in validating THz-Raman spectroscopy as a versatile, laboratory-based alternative to using synchrotron radiation for materials discovery and real-time in situ tracking of changes in materials structure, in both neat and liquid-assisted mechanically agitated processes.