Mapping the Intermolecular Interaction Landscape in a New Nicotinamide–Undecanoic Acid Cocrystal: Supramolecular Structure, Spectroscopic Analyses, and Computational Studies

Abstract

A novel cocrystal composed of nicotinamide (NA) and undecanoic acid (UA) in a 1:1 stoichiometry has been successfully synthesized via slow evaporation and comprehensively characterized through a multidisciplinary approach combining experimental and computational methods. Single-crystal X-ray diffraction revealed that the NA–UA cocrystal crystallizes in the triclinic symmetry (P̅1) with two NA-UA formulas per unit cell (Z = 2). The supramolecular assembly is primarily stabilized by classical O–H···N hydrogen bonding between the carboxylic acid group of UA and the pyridine nitrogen of NA, complemented by N–H···O interactions involving the amide function. Hirshfeld surface analysis and 2D fingerprint plots quantitatively mapped the intermolecular interaction landscape, revealing that H···H (67.8%), H···O/O···H (17.2%), and H···C/C···H (6.5%) contacts dominate the crystal packing, with significant contributions from dispersive interactions along the aliphatic chain. Crystal void analysis demonstrated efficient molecular packing with a void volume of 108.27 Å (≈12% of the total unit cell volume). Vibrational analyses (Raman and Fourier transform infrared spectroscopy) confirmed the presence of both molecular components and identified characteristic shifts in hydrogen-bond functional groups. Density functional theory calculations confirmed the excellent agreement with experimental vibrational modes and validated the optimized crystal structure. In silico pharmacokinetics predictions indicated favorable pharmacokinetic properties, including high gastrointestinal absorption, compliance with Lipinski’s rule of five, and absence of cytochrome P450 inhibition, although the cocrystal exhibited nonpermeability across the blood–brain barrier. This work establishes the structural framework and physicochemical characteristics of a new NA–UA cocrystal, providing fundamental insights into the interplay between hydrogen bonding and dispersive forces in drug-coformer assemblies and contributing to the rational design of pharmaceutical cocrystals with tailored properties.