Insight into the Influential Mechanism of Polymorphic Parent Molecule with High Z’ on the Cocrystal Formation

A crystal structure with Z’ > 1 involves two or more molecules that occupy crystallographically distinct sites and thus has a unique nature. This structure feature has a clear conceptual analogy with the formation of cocrystals. In addition, due to the unique structural features of high Z’ crystals, they have also been proposed as candidates for cocrystal formation. Here, we make an attempt to unmask the relationship between high Z’ structures and the formation of cocrystals. m-Hydroxyacetophenone (mHAP) has two anhydrous forms (form I and form II), and form II was crystallized with Z’ = 2. Three cocrystals of mHAP with hexamethylenetetramine, piperazine, and 2-methylpiperazine were obtained using slow evaporation methods, and the new structures were confirmed by single-crystal X-ray diffraction. mHAP molecules in cocrystal structures adopt a conformation consistent with that in the form I of mHAP (Z’ = 1 structures). No relationships were found between the internal molecular arrangement of cocrystals and the crystal structure of Z’ = 1 structures according to Xpac analysis, but the 1D chain of cocrystals is similar to that of Z’ = 2. Taken together, the mHAP molecules in the similar 1D chain are arranged in staggered and reversed ways, and all are connected through C-H···π bonds. For the Z’ = 2 structure of mHAP, there are two kinds of molecules existing in the asymmetric unit, which is similar to that in cocrystals and can be considered as a self-host-guest structure. In the cocrystal structures, co-formers replace the host molecule and they retain the structure of the guest molecule. This Z’ = 2 crystal structure of mHAP has a possible structure-oriented effect in the formation of cocrystals.