Revealing new non-covalent interactions in polymorphs and hydrates of Acyclovir: Hirshfeld surface analysis, NCI plots and energetic calculations

Abstract

An exhaustive evaluation of intermolecular interactions in the four known stable Forms of Acyclovir (ACV), namely, two polymorphs (Forms I and II) and two hydrates (Forms V and VI), is presented completing the descriptions of crystal packing previously reported, which were based only on conventional H-bonds. Non-classical C[sbnd]H···O H-bonds, as well as π…π and lone-pair…π interactions, are here geometrically and energetically revealed for all the four Forms. The lattice energies and the intermolecular interaction energies are quantified using PIXEL method. The Hirshfeld surfaces have been performed to visualize and quantify the interactions and their quantitative contributions. The nature attractive in the dimers involving hydrogen bonds, and π-stacking interactions has been assessed by non-covalent interaction (NCI) plots. Further, the prediction of the new interactions has been analyzed using the quantum theory of “atoms-in-molecules” (QTAIM) and molecular electrostatic potential (MEP) surface calculations, showing a closer insight on the crystal stability of ACV.