Synthesis, Structure, Vibrational Spectra and Thermal Analysis of Isoniazid-Succinic Acid Cocrystal

Neris Inci Inan; Ainur Syeitkhajy; Ayberk Yilmaz; Nihal Sarier; Gulce O. Ildiz; Rui Fausto

doi:10.53941/ps.2026.100027

Abstract

Cocrystals have gained increasing attention as an effective solid-state strategy to modify physicochemical properties through noncovalent intermolecular interactions in keeping or improving pharmacological activity. In this study, a 2:1 isoniazid (INH): succinic acid (SUC) cocrystal, where the coformers are linked through interactions between the carboxylic acid groups of SUC and the pyridine nitrogen and hydrazide moieties of INH, was synthesized and comprehensively analyzed using a combination of crystallographic, thermal, spectroscopic, and computational methods. Single crystal X-ray diffraction (SC-XRD) confirmed the structure of the synthesized material, highlighting the relevance of intermolecular O–H···N, N–H···O and N–H···N interactions to stabilize the cocrystal. Differential scanning calorimetry (DSC) was used to evaluate the thermal behavior of the cocrystal, in a comparative basis with crystals of the pure components. The cocrystal melts at T_m (onset) = 141.3 ± 0.5 °C, with ΔH_fus = 27.4 ± 0.5 kJ mol⁻¹ per molecule, i.e., at a significant lower temperature and with a lower enthalpy of fusion compared to the stable polymorphic variations of the pure components (INH (polymorph 1): T_m (onset) = 170.1 ± 0.5 °C, ΔH_fus of 29.5 ± 0.5 kJ mol⁻¹; SUC (polymorph β): T_m (onset) = 188.4 ± 0.5 °C, ΔH_fus = 31.4 kJ mol⁻¹), but at a considerably higher temperature than that corresponding to the melting of the eutectics (126.0 ± 0.5 °C). Infrared and Raman spectroscopies were employed to characterize vibrationally the cocrystal and to evaluate changes associated with changes in intermolecular interactions in going from the crystals of the pure components to the cocrystal. The experimental results were complemented by density functional theory (DFT) calculations performed on the isolated INH-SUC-INH, SUC-INH-INH-SUC and INH-INH structural units present in the cocrystal as well as on the cocrystal itself using fully-periodic calculations. A detailed investigation of the major intermolecular interactions present in the cocrystal was also undertaken using the Hirshfeld surface analysis approach. The CE-energy decomposition method of Spackman and coworkers was applied to obtain a detailed picture of the cocrystal lattice energetics, also in comparison with those of the crystals of the pure components.

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