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Cocrystallization is an attractive approach to improving the physicochemical properties of active pharmaceutical ingredients (APIs), which have great potential in drug development. Accordingly, there is a growing need to understand the physicochemical changes that occur upon co-crystallisation. This work focuses on the combined use of spectroscopy and density functional theory (DFT) calculations to understand the molecular structure, hydrogen bond interactions and physicochemical properties of a pharmaceutical cocrystal. Solid-state NMR (ssNMR) spectroscopy can provide detailed molecular structure information on pharmaceutical cocrystals and complexes. It is non-destructive and usually provides deep structural insights that complement well with vibrational spectroscopy. In this work, a cocrystal of an antibiotic drug, nitrofurantoin (NF), with 4-hydroxybenzoic acid (4HBA) is examined to understand the capability of multiple spectroscopic techniques such as infrared (IR), Raman and solid-state NMR spectroscopies, and to confirm the molecular structure and hydrogen bonding of cocrystal systems. The results of IR and Raman spectroscopy showed that for the cocrystal formation, NF and 4HBA molecules interact through N–H…O–H interactions between the imide N–H of nitrofurantoin and the phenolic –OH of 4-hydroxybenzoic acid, and these interactions are also confirmed by natural bond orbital (NBO) and quantum theory of atoms in molecules (QTAIM) analyses. It is critical to understand whether a given cocrystal, upon conceiving a modified crystalline structure compared to that of its API, shows enhanced physical and chemical properties or not. Computationally, it is found that the NF–4HBA cocrystal shows softer (more reactive) behaviour in comparison to NF as its cocrystal, NF–4HBA, has a low band gap in comparison to the API, NF. These results demonstrate that the quantum chemical approach predicts accurately how to relate cocrystal with its physical and chemical properties. [ABSTRACT FROM AUTHOR]

[Display omitted] • Computational and experimental work has been performed on HCTZ as well as HCTZ- 4ABA. • Two functionals B3LYP and wB97X-D have been used to study hydrogen bonding interactions. • NH, NH 2 and O=S=O groups were involved in neighboring interactions. • NBO analysis and QTAIM are used to analyze the nature and the strength of hydrogen bonding. In this study, the molecular, electronic, and chemical properties of the drug hydrochlorothiazide (HCTZ) are determined after cocrystallization with 4-aminobenzoic acid (4-ABA). Analysis has been performed to understand how those variations lead to alteration of physical properties and chemical reactivity in the cocrystal HCTZ-4ABA. IR and Raman characterizations were performed along with quantum chemical calculations. A theoretical investigation of hydrogen bonding interactions in HCTZ-4ABA has been conducted using two functionals: B3LYP and wB97X-D. The results obtained by B3LYP and wB97X-D are compared which leads to the conclusion that B3LYP is the best applied function (density functional theory) to obtain suitable results for spectroscopy. The chemical reactivity descriptors are used to understand various aspects of pharmaceutical properties. Natural bond orbital (NBO) analysis and quantum theory of atoms (QTAIM) are used to analyze nature and strength of hydrogen bonding in HCTZ-4ABA. QTAIM analyzed moderate role of hydrogen bonding interactions in HCTZ-4ABA. The calculated HOMO-LUMO energy gap shows that HCTZ-4ABA is chemically more active than HCTZ drug. These chemical parameters suggest that HCTZ-4ABA is chemically more reactive and softer than HCTZ. The results of this study suggest that cocrystals can be a good alternative for enhancing physicochemical properties of a drug without altering its therapeutic properties. [ABSTRACT FROM AUTHOR]

• 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]

• Geometry optimization of NF-PHEN (cocrystal) has been done using B3LYP functional. • Spectroscopic (FT-IR and FT-Raman) study of NF-PHEN has been done. • NBO and AIM analysis have been done for the understanding of charge transfer within the cocrystal. • Global and local reactivity descriptors are used to determine chemical reactivity and site selectivity. • The global reactivity parameters of NF-PHEN have been compared with that of other two cocrystals of NF (nitrofurantoin-melamine monohydrate (NF-MELA-H 2 O) and nitrofurantoin-urea (NF-urea)). • Amongst all the cocrystals (NF-MELA-H 2 O, NF-urea and NF-PHEN), NF-PHEN is chemically most reactive. This work gives the unified insight of vibrational spectroscopy (FT-IR and FT-Raman) and density functional theory (DFT) calculations to get an understanding of the hydrogen bonding pattern and chemical reactivity of a cocrystal of nitrofurantoin (NF, an antibacterial drug) with phenazine (PHEN). FT-Raman (100-3700 cm−1) and infrared (400-4000 cm−1) spectroscopic techniques were used for the characterization of the NF-PHEN cocrystal and NF drug itself in the solid state. The intermolecular H-bonding is affirmed by natural bond orbital (NBO) and quantum theory of atoms in molecules (QTAIM) studies. The reactivity studies of NF-PHEN through global and local reactivity descriptors have also been performed. The global reactivity parameters of NF-PHEN have been compared with that of NF itself and two other cocrystals of NF [nitrofurantoin-melamine monohydrate (NF-MELA-H 2 O) and nitrofurantoin-urea (NF-urea)] where hetero-atom (nitrogen) rich coformers have been used. It is established that all the three cocrystals show more chemical reactivity than NF itself. And amongst three NF cocrystals, NF-MELA-H 2 O is most stable while NF-PHEN is chemically most reactive. In other words, NF-PHEN is chemically softer than other two cocrystals. Molecular electrostatic potential (MEP) map has also been studied as it is correlated to the electronic density and is advantageous in considering sites for electrophilic and nucleophilic strikes together with hydrogen bonding interactions. Molar refractivity (MR) value of NF-PHEN falls within the range set by Lipinski's modified rule and suggests that the studied cocrystal may show drug likeness. Accordingly, structural and reactivity studies could be successfully employed to a pharmaceutical cocrystal, NF-PHEN, considered in this study and for various other multicomponent crystals in gaining insights into their hydrogen bond interactions and physicochemical properties. [Display omitted] [ABSTRACT FROM AUTHOR]

Cocrystal monohydrate of nitrofurantoin (NF) with melamine (MELA) has been studied as NF is an antibacterial drug used for the treatment of urinary tract infections. The structure of nitrofurantoin-melamine-monohydrate (NF-MELA-H 2 O) is characterized by FT-IR and FT-Raman spectroscopy. The energies and vibrational frequencies of the optimized structures calculated using quantum chemical calculations. Supported by normal coordinate analyses and potential energy distributions (PEDs), the complete vibrational assignments recommended for the observed fundamentals of cocrystal hydrate. With the aim of inclusion of all the H-bond interactions, dimer of NF-MELA-H 2 O has been studied as only two molecules of cocrystal hydrate are present in the unit cell. By the study of dimeric model consistent assignment of the FT-IR and FT-Raman spectrum obtained. H-bonds are of essential importance in an extensive range of molecular sciences. The vibrational analyses depict existence of H-bonding (O-H⋯N) between water O-H and pyridyl N atom of MELA in both monomer and dimer. To probe the strength and nature of H-bonding in monomer and dimer, topological parameters such as electron density (ρ BCP), Laplacian of electron density (∇2ρ BCP), total electron energy density (H BCP) and H-bond energy (E HB) at bond critical points (BCP) are evaluated by quantum theory of atoms in molecules (QTAIM). Natural bond orbitals (NBOs) analyses are carried out to study especially the intra and intermolecular H-bonding and their second order stabilization energy (E(2)). The value of HOMO-LUMO energy band gap for NF-MELA-H 2 O (monomer and dimer both) is less than NF, showing more chemical reactivity for NF-MELA-H 2 O. Chemical reactivity has been described with the assistance of electronic descriptors. Global electrophilicity index (ω = 7.3992 eV) shows that NF-MELA-H 2 O behaves as a strong electrophile than NF. The local reactivity descriptors analyses such as Fukui functions, local softnesses and electrophilicity indices performed to determine the reactive sites within NF-MELA-H 2 O. In MEP map of NF-MELA (monomer and dimer) electronegative regions are about NO 2 and C=O group of NF, although the electropositive regions are around NH 2 , N-H group and H 2 O molecule. Molar refractivity (MR) value of NF-MELA-H 2 O (monomer and dimer) lies within the range set by Lipinski's modified rules. This study could set as an example to study the H-bond interactions in pharmaceutical cocrystals. Unlabelled Image • Geometry optimization of NF-MELA-H 2 O (cocrystal hydrate) has been done using B3LYP functional. • Spectroscopic (FT-IR and FT-Raman) study of NF-MELA-H 2 O has been done. • NBO and AIM analysis have been done for the understanding of charge transfer within the cocrystal hydrate. • Global and local reactivity descriptors are used to determine chemical reactivity and site selectivity. [ABSTRACT FROM AUTHOR]