Influence of Liquid on Crystallite Size Evolution During Ball Milling

Liquid-assisted grinding (LAG) is a commonly used mechanochemical procedure, especially for polymorphic conversions. However, it is not understood what effect liquid additives actually have in driving mechanochemical polymorphic conversions, precluding our ability to control solid form transformations under mechanochemical conditions. We here present a time-resolved in situ (TRIS) synchrotron powder X-ray diffraction (PXRD) monitoring strategy that can track, with few-nanometer resolution, the evolution of crystallite size under liquid-assisted ball milling conditions. We apply this method to investigate the influence of liquid additives on the polymorphic conversion of the 1:1 cocrystal of theophylline and benzamide, with particular focus on the role that crystallite size plays in driving ball milling-induced polymorphic transformations. We found that the crystallite sizes achieved by ball milling are highly sensitive to the amount of liquid added to the reaction mixture. Liquid additives generally lead to larger crystallite sizes as compared with the neat grinding (NG) protocol, with our findings indicating that crystallite size reduction is not the main factor that causes polymorph conversion under liquid-assisted grinding conditions. The data presented clearly suggest the presence of an induction period before phase transformation begins with a minimum value in the crystallite size of the starting polymorph, marking the end of that induction period.