Exploring polymorphism, stoichiometric diversity and simultaneous existence of salt and cocrystal during cocrystallization using mechanochemistry

We demonstrate here the mechanochemical cocrystallization of trans -aconitic acid (TACA) with nicotinamide (NA) that leads to the formation of multi-component crystal forms with stoichiometric diversity, polymorphism with high Z ′′ and the simultaneous existence of salt and cocrystal. During cocrystallization, we obtained a 1 : 1 molecular salt hydrate of TACA with NA and two polymorphic cocrystal hydrates of the same in 1 : 2 ratios, with a Z ′′ value of seven, respectively. Manual grinding shows that 1 : 1 molecular salt and 1 : 2 cocrystal polymorphs are interconvertible under appropriate conditions. Moreover, cocrystal dissociation was observed upon heating the 1 : 2 cocrystal and in the presence of excess TACA during the preparation of the form I cocrystal using LAG. Thermal analysis, powder XRD, and DFT calculations establish the relative stability of the multi-component solids. Three-component polymorphic systems with high Z ′′ are quite unusual; however, based on mechanochemistry, we have successfully synthesized and characterized them.