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• Computational and experimental work has been performed on cocrystal of hydrochlorothiazide (HCTZ) and nicotinamide (NCT). • H-bonding interaction was studied by using monomeric, dimeric and trimeric models of HCTZ-NCT cocrystal. • NH 2 and C = O groups were involved in neighbouring hydrogen bonding interactions. • QTAIM and NBO analysis were done to explore inter and intramolecular H-bond interactions. • MEPS was performed to observe the reactive sites of the molecules. The present work focuses on the study of structural, vibrational, chemical properties and the effect of hydrogen bonding interaction in the formation of a cocrystal of hydrochlorothiazide (HCTZ, a diuretic drug) with nicotinamide (NCT) using vibrational spectroscopy (FT-IR and FT-Raman) and density functional theory. HCTZ being a BCS class IV drug, has low permeability and solubility; therefore, its cocrystal is studied. Monomer, dimer and trimer of HCTZ-NCT cocrystal were studied to understand hydrogen bonding interactions. The shifting in the wavenumber and the elongation in bond lengths of the amide (NH 2) group of HCTZ and carbonyl (C = O) group of NCT were observed in all the models of HCTZ-NCT cocrystal due to the hydrogen bonding interaction. The importance of hydrogen bonding were also explored by natural bond orbital (NBO) analysis in support of the quantum theory of atom in molecules (QTAIM). The chemical reactivity of HCTZ, NCT and HCTZ-NCT cocrystal was examined by MEPS map, FMOs, global electronic reactivity descriptor, ECT descriptors, and molar refractivity. The lesser value of the HOMO-LUMO energy gap in the cocrystal than API reflects that the chemical reactivity of the cocrystal was better than API itself. The comparison between API(HCTZ) and cocrystal (HCTZ-NCT) implies that pharmaceutical cocrystals may be a better option to improve and enhance the pharmacological properties of drugs. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • Computational and experimental work has been performed on hydrochlorothiazide (HCTZ). • H-bonding interaction was studied using monomeric, dimeric and trimeric models. • NH 2 and O S O groups were involved in neighboring interactions. • QTAIM and NBO analysis was done to explore inter and intramolecular H-bond interactions. Hydrochlorothiazide (HCTZ) being a diuretic drug widely used in anti-hypertensive therapy as it lowers the blood pressure by reducing the reabsorption of electrolytes in kidney resulting an increment of urine output and lowering the blood pressure. The purpose of the present work is to study the structural, vibrational and chemical properties of HCTZ based on its monomeric, dimeric and trimeric models by utilizing computational methods and experimental techniques. Density functional theory (DFT) with functional B3LYP and 6-311++G (d, p) basis set was used for a detailed computational study. Monomeric, dimeric and trimeric models of HCTZ have been studied for a better understanding of inter- and intramolecular hydrogen bonding. FT-IR (400–3800 cm−1) and FT-Raman (100–3600 cm−1) spectroscopy have been utilized for the characterization of HCTZ. The shifting in wavenumber of NH 2 and O S O group were observed in dimer and trimer due to the formation of intermolecular hydrogen bonding. Quantum theory of atoms in molecules (QTAIM) along with natural bond orbital (NBO) analysis were performed to examine the nature and strength of hydrogen bonding which showed that all the interactions were medium and partially covalent in nature; transition from LP(3)O15 → σ*(H46 → N32) and LP(3)O39 → σ*(H74 → N51) were responsible for the formation of O15•••H46 and O39•••H74 H-bonds, respectively. HOMO-LUMO energies predicted the chemical reactivity and stability of the molecule and the energy gap for dimer (4.6240 eV) and trimer (4.0493 eV) was found to be lesser than the monomer (5.0888 eV) which showed that the dimer and trimer have predicted more chemical reactivity in comparison to monomer. The most electronegative electrostatic potential was observed around the O S O group and the most electropositive potential around the amide group from MEPS analysis. Global as well as local reactivity descriptors have predicted the reactivity and hence, stability of the title molecule. [ABSTRACT FROM AUTHOR]