Polymorphs of 2-[2-[(2,6-dichlorophenyl)amino]phenyl]acetic acid (Diclofenac): Differences from crystallography, Hirshfeld surface, QTAIM and NCIPlots

Abstract

Differences from crystallography, Hirshfeld surface, QTAIM, and NCIPlots in two monoclinic polymorphs from Diclofenac were studied, in space groups, P 21/ c and C 2/ c , and we make a new refinement of the C 2/ c form. • A new refinement is reported for Diclofenac. • The non-covalent interactions are analyzed using a variety of computational methods. • This work provides a better understanding of the nature of non-covalent interactions on two Diclofenac polymorphs. • The strength of the intermolecular hydrogen bond is the main difference between Diclofenac polymorphs. In this work, an experimental and theoretical comparison of the crystal structure of both polymorphs of the title compound was achieved. Hirshfeld surface analysis ( d norm surface and two-dimensional fingerprint plots) which reveal the nature of intermolecular interactions for the title compounds were performed and discussed. The H∙∙∙H contacts were the major contributors to the Hirschfeld surface with 32.5% and 32.8% for Diclofenac (I) and Diclofenac (II), respectively. The contributions of the O∙∙∙H/H∙∙∙O (15.2%) and O∙∙∙H/H∙∙∙O (13.9%) interactions are smaller, but significant for the crystal architecture of Diclofenac (I) and Diclofenac (II), respectively. The quantum theory of atoms in molecules, reduced density gradient and natural bonds orbital studies was performed. The analysis showed the Cl∙∙∙π, H∙∙∙π, arene-CH∙∙∙Cl, and Cl∙∙∙Cl interactions as the main stabilizing forces of the crystal structure of polymorphs. The strength of the intermolecular hydrogen bond in Diclofenac (I) is greater than Diclofenac (II). The orbital origin of the hydrogen bond is attributed to the electron density transfer from the lone-pair of carbonyl oxygen in the carboxylic group to both, the intermolecular σ*(OH) from the carboxylic group and the intramolecular σ*(NH).