Elucidation of the spectral and structural characteristics of nitrofurantoin-4-hydroxybenzamide cocrystal

Cocrystallization has emerged as an important strategy in supramolecular chemistry for tuning the physicochemical properties of active pharmaceutical ingredients (APIs). In this study, a cocrystal composed of nitrofurantoin (NF) and 4-hydroxybenzamide (4HBAM) is systematically investigated using combined experimental and computational approaches. Fourier-transform infrared (FT-IR) and Raman spectroscopy were employed to probe vibrational characteristics, while density functional theory (DFT) calculations were performed to optimize the molecular structure and evaluate interaction energies, thermodynamic parameters, and electronic properties. The calculated thermodynamic parameters yielded negative values of enthalpy (ΔH) and Gibbs free energy (ΔG), indicating that the formation of the NF-4HBAM (1,2) cocrystal is exothermic and thermodynamically favourable within the adopted DFT model, while the negative entropy change (ΔS) reflects the increased ordering accompanying cocrystal formation. The calculated interaction energy supports the stability of the hydrogen-bonded assembly. Spectroscopic results show pronounced red shifts in the vibrational frequencies of amide, phenolic OH, and carbonyl (CO) groups, suggesting the presence of strong intermolecular hydrogen bonds of the type NH···O and OH···OC. These interactions are further validated through atom-in-molecules (AIM) and natural bond orbital (NBO) analyses. Frontier molecular orbital analysis reveals a donor-acceptor electronic arrangement, with electron density localized primarily on 4HBAM (HOMO) and NF (LUMO), while global reactivity descriptors indicate increased polarizability and comparatively lower kinetic stability of the cocrystal relative to isolated components. Overall, the study provides a detailed molecular-level insight into the structural and spectroscopic behaviour of the NF-4HBAM system, highlighting its potential relevance in pharmaceutical applications.