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.