Listening to the Formation of Polymorphs in a Ball Mill

In this contribution, we apply our newly developed ball-milling operando platform, which combines Raman spectroscopy and 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 in transparent PMMA jars. Particularly, we demonstrate how Raman, temperature, acoustic, and video data are complementary and enable detection and connection of chemical and physical events happening during ball-milling in a time-resolved manner. Importantly, we show that the formation of the three cocrystal polymorphs can be detected through acoustic analyses solely. Even more impressively, the meticulous analyses of the sound data allowed 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 energetic and statistical approaches that 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 following polymorphic transformations of cocrystals, as well as pure substances, in any type of milling jar.