Unveiling Solvent-Mediated Mechanochemical Cocrystallization Pathways by In Situ CLASSIC NMR Spectroscopy

Although mechanochemical synthesis offers a sustainable way to produce solid forms of pharmaceutical compounds, the molecular-level mechanisms that govern solvent-mediated transformations remain largely unexplored. In this study, we present an in situ solid-state nuclear magnetic resonance (NMR) approach to directly monitor the evolution of liquid-assisted grinding reactions under magic-angle spinning conditions. Using a modified CLASSIC NMR protocol, we tracked the cocrystallization of two model systems, theophylline–benzamide and metronidazole–gallic acid, in the presence of solvents with different levels of polarity. This method allows us to observe both the solid and liquid phases within the reaction environment simultaneously, revealing transient intermediates, hydrate formation, and solvent-dependent polymorphic outcomes. Comparisons with time-resolved in situ X-ray diffraction confirm the complementary nature of NMR in capturing mechanistic details that are otherwise inaccessible to a diffraction-based analysis. This work establishes solid-state NMR as a powerful and accessible in situ tool for investigating the effects of solvents in mechanochemical synthesis, thereby advancing our molecular understanding of polymorphic control and reaction pathways.