Crystal engineering of a new pharmaceutical polymorph of gallic acid monohydrate: a structural comparative study and chemical computational quantum investigations

Abstract

Exploiting new polymorphs of active pharmaceutical ingredients (APIs) has a significant role in the development of new processes for the pharmaceutical industry. Within this context, we report in this work, the synthesis, crystal structure and Hirshfeld surface analyses and complementary computational quantum investigations of the seventh pharmaceutical polymorph of gallic acid monohydrate (GAM-VII). The structural properties have been determined from accurate single crystal data collected at 100 K and reveal that the formation and stability of this new polymorph are associated with the implementation of water molecules within the network of the moderate intermolecular interactions involving carboxyl groups. A detailed and systematic comparison of molecular conformations and packings, hydrogen bonding and intermolecular interactions of the studied polymorph (GAM-VII) was performed with the other six known GAM polymorphs. In this new polymorph, gallic acid molecules (GA) adopt syn COOH orientations leading to the formation of the common centrosymmetric (COOH)₂ dimer R²₂(8). This homo-synthon configuration was only observed in polymorphs I, III and V. Moreover, the analysis and quantification of the contributions of different intermolecular interactions within the supramolecular assemblies were conducted using the Hirshfeld surface (HS) method. This investigation allowed reflection of the offset stacking arrangement of GA molecules and the presence of π⋯π interactions between the benzene rings in the studied polymorph. Based on complementary theoretical calculations, we were able to determine and discuss many fundamental characteristics in the reactivity process of this new polymorph such as dipole moment, ionization, chemical potential, electronegativity and electrophilicity index.