Driving Forces in the Formation of Paracetamol Cocrystals and Solvate with Naphthalene, Quinoline and Acridine.

Paracetamol is an important analgesic and antipyretic drug showing poor tabletability. Among the various approaches used to improve this property, understanding the forces that govern the crystal packing is revealed to be crucial. We prepared three stable compounds: (par)∙(nap) (), (par)∙(quin) (), and (par)∙(acr) () (nap-naphthalene, quin-quinoline, acr-acridine) being cocrystals or solvate. The structural studies showed that all the reported compounds are composed of alternately arranged layers of paracetamol and coformer. Several supramolecular motifs in the paracetamol layer were identified: R44(22) in (); R64(20) and R22(8) in (); and R22(8), R42(12), and R44(26) rings in (). The stability of the crystal network was studied by interactions analysis performed by Hirshfeld surface and fingerprint approaches and the energy between the closest units in the crystal network was calculated. It showed that the strongest interactions were found between blocks connected by N-H⋯O=C and O-H⋯O/N hydrogen bonds due to an important coulombic factor. The dispersive energy becomes important for tail-to-tail (and head-to-tail) arranged paracetamol units, and it prevails in the case of stacking interactions between coformer molecules. The importance of dispersive forces increases with the size of the aromatic system of the coformer. XAS studies confirmed the successful preparation of compounds and provided some details about electron structure.