Listening to the formation of cocrystals and transformation of polymorphs in mechanochemistry through advanced operando acoustic analysis and real-time methods

In this contribution, we apply our newly developed ball-milling operando platform, which combines Raman spectroscopy, thermal (IR) imaging, as well as acoustic and high-speed optical video recordings, to the synthesis and transformation of citric acid – isonicotinamide (1 : 2) cocrystal polymorphs. Particularly, we demonstrate how Raman, temperature, acoustic and video data are complementary and enable to detect and connect together chemical and physical events happening during the ball-milling in a time-resolved manner. Importantly, we show that the formation of the three polymorphs can be detected through the acoustic analyses solely. Even more impressively, the meticulous analyses of the sound data allowed the subtle polymorphic transitions to be perceived in operando mode when the Raman spectroscopy was not conclusive enough. Such changes in sound signatures are greatly linked to the beads’ motions in the milling jar. A new data analysis methodology of acoustic recordings is proposed through a combination of energetical and statistical approaches, which simplifies the data analyses for potential users. The interpretation of the detected sound signals was further validated thanks to the high-speed videos recorded in synchronization with all other operando techniques. Finally, we broaden this acoustic methodology to opaque stainless-steel jars, showing the relevance of the acoustic analysis method for any type of milling jars.