Experimental and Theoretical Charge Density Study of Isonicotinamide Polymorphs

Abstract Isonicotinamide is widely studied for its strong and directional hydrogen bonds, which play a critical role in crystal engineering and polymorphism. To address the absence of a quantitative charge density comparison for the two most studied isonicotinamide polymorphs (denoted 1a and 1b), this study maps the electron density distribution and topological properties of 1a and 1b, which differ in intermolecular connectivity, linking their respective H-bonding networks, intermolecular interaction strengths and lattice energetics within a single experimental and theoretical framework. High-resolution X-ray diffraction data were analyzed using the Hansen–Coppens multipole model. Topological parameters at bond critical points were evaluated to quantify hydrogen bonding, weak interactions, and electron density redistribution across the molecule. Both polymorphs exhibit well-defined hydrogen bonding networks dominated by N–H···N interactions, with bond strengths ranging from 6.48 to 35.5 kJ mol–1. Topological analysis revealed high electron densities and negative Laplacian values for covalent bonds, whereas the hydrogen-bond critical points exhibited positive Laplacian values consistent with closed-shell interactions. Notably, 1a shows stronger lattice stabilization (−114 kJ mol–1) compared to 1b (−82 kJ mol–1), indicating more efficient packing. By mapping the electron density topology and energy framework partitioning that distinguish the more stable P21/c form 1a from its less efficiently packed polymorph 1b (also P21/c), at the atomic level, this study provides a quantitative reference framework that can be used to predict and rationalize stability and solubility differences among the growing family of isonicotinamide-based pharmaceutical cocrystals.