Structural and Energetic Aspects of Entacapone-Theophylline-Water Cocrystal

Abstract

Pharmaceutical cocrystals are currently gaining interest among the scientific community, due to their great potential for providing novel crystalline forms with superior properties such as solubility, dissolution rate, bioavailability, and stability. Robust computational tools are valuable tools in the rationalization of cocrystal formation, by providing insight into the intermolecular interactions of multicomponent molecular solids. In this study, various computational techniques based on charge density analysis were implemented to assess structural and energetical perspectives of the interactions responsible for the formation and stability of entacapone-theophylline-water (ETP-THP-water, 1:1:1). Significant non-covalent interactions (NCIs) were identified and evaluated by Hirshfeld surface analysis and density functional theory (DFT) computations, and three-dimensional networks (energy vector diagrams, lattice energy frameworks) were constructed, outlining the crucial stabilizing role of water and the dominance of π-π stacking interactions in the cocrystal. Furthermore, thermal dehydration studies confirmed the strong binding of water molecules in the crystal lattice, as expressed by the high activation energy.

Nano- and Crystal Engineering Approaches in the Development of Therapeutic Agents for Neoplastic Diseases

“…Quantum chemistry calculations are also used as an approach in estimating interaction energies between molecules, thereby generating more information regarding their supramolecular architecture [118]. Quantum chemistry-based investigations aid in revealing important information about the nature and strength of non-covalent bonds involved in co-crystals [119]. The single-crystal XRD (scXRD) characterization technique gives a detailed structure of the crystal.…”

“…Quantum chemistry investigations use computational approaches to provide an indepth understanding of co-crystal structures, molecular packing motifs, and corresponding intermolecular interactions [119]. Computational work is also used to determine the optimized geometry of the molecules using different methods [124].…”

“…Density functional theory (DFT) and coupled cluster (CC) or quantum Monte Carlo methods are used as standard methods for the quantitative study of large weakly correlated systems [125]. DFT computations are essential in the identification and interpretation of the relationship between the structure and stability or other physicochemical properties of a co-crystal [119]. The Hartree-Fock (HF) method uses spatial coordinate positions of crystals from X-ray structural analysis as its initial coordinates to optimize the geometry of the molecules [124].…”