Proline has been
widely used for various cocrystallization applications,
including pharmaceutical cocrystals. Combining enantiopure and racemic
flurbiprofen and proline, we discovered 18 new crystal structures.
Liquid-assisted grinding proved highly efficient to explore all the
variety of crystal forms. A unique combination of state-of-the-art
characterization techniques, comprising variable temperature in situ X-ray diffraction and in situ ball-milling,
along with other physicochemical methods and density functional theory
calculations, was indispensable for identifying all the phases. Analyzing
the results of in situ ball-milling, we established
a stepwise mechanism for the formation of several 1:1 cocrystals via
an intermediate 2:1 phase. The nature of the solvent in liquid-assisted
grinding was found to significantly affect the reaction rate and,
in some cases, the reaction pathway.