Cocrystal screening of benznidazole based on electronic transition, molecular reactivity, hydrogen bonding, and stability 

Abstract

A computational evaluation for the cocrystal screening of benznidazole (BZN) API through hydrogen bonding with four coformers (maleic acid, malonic acid, oxalic acid, and salicylic acid) containing carboxylic groups has been done using density functional theory. The nitrogen of the imidazole in benznidazole and the carboxylic group in the coformer form a hetero-synthon, forming a strong hydrogen bond between the molecules. The strength of hydrogen bonding O-H…N in all mentioned cocrystals was evaluated using QTAIM analysis, and the pairing energy of interaction is measured by determining donor and acceptor parameters for hydrogen bonds from maxima and minima on the MEP surface. When compared to BZN-malonic acid, BZN-oxalic acid, and BZN-salicylic acid cocrystals, the interaction energy for the BZN-maleic acid cocrystal for O-H...N bonding was found to be higher and it forms a strong interaction. The RDG plot and natural bond orbital analyses were also used to confirm the intermolecular hydrogen bonding of the OH group with the nitrogen of the imidazole ring of benznidazole in the cocrystal. The strength of hydrogen bond O-H…N was found to be more beneficial as compared to C-H...O interaction which was verified from ESP analysis. Based on frontier molecular orbital theory, it was found that the reactivity of BZN-salicylic acid cocrystal is more and is polarizable as compared to BZN-maleic acid, BZN-malonic acid, and BZN-oxalic acid cocrystals. Using the TD-DFT/6-311++G(d,p) method, the UV-Vis absorption spectrum was analyzed in the solvent water to determine the influence of solvent in cocrystals with a polarizable continuum model. Cocrystals of benznidazole were found to have better physicochemical characteristics than API benznidazole.