Correlating the melting point alteration with the supramolecular structure in aripiprazole drug cocrystals

Abstract

Five novel cocrystals of antipsychotic drug aripiprazole are reported with dihydroxy- and trihydroxybenzene coformers. The cocrystals are designed by exploiting the piperazine N acceptor of aripiprazole to participate in O–H⋯N hydrogen bonding with the hydroxyl functional group of the coformers. Powder X-ray diffraction, IR spectroscopy, single crystal X-ray diffraction, differential scanning calorimetry and thermogravimetric analysis are employed for the characterization of the new solid forms. Significant changes are noted in the melting points of the cocrystals even though the coformers are similar in size and adopt isostructural crystal packing with aripiprazole. For example, the aripiprazole–catechol cocrystal melts at 121.2 °C, whereas its isostructural aripiprazole–resorcinol partner melts at 175.6 °C. Plausible reasons accounting for the thermal differences are inferred from a combined single crystal and spectroscopic study. Our results indicate that higher melting cocrystals are noticed in structures sustained by strong helical networks of O–H⋯N and O–H⋯O hydrogen bonds along the three-dimensional space in the crystal. Lower melting cocrystals are noticed when strong hydrogen bonds are restricted to two-dimensional layers, leaving their three-dimensional interlayer packing achieved by weaker interactions. The presence of stronger hydrogen bonds in higher melting cocrystals is also evidenced by amide spectral shifts. The isostructurality of the cocrystals is an advantage in this study for it allowed a direct structural comparison of different cocrystals and accounted for their thermal behaviour.