Polymorphic behavior in isoniazid-4-hydroxybenzoic acid hydrated cocrystals: A combined terahertz, Raman vibrational spectroscopy, and DFT analysis

Isoniazid (INH), a frontline anti-tuberculosis drug, faces rising resistance and hepatotoxicity, motivating crystal-engineering approaches. The INH-4-hydroxybenzoic acid (INH-HBA) cocrystal shows multiple polymorphs, its hydrate exists in two forms whose lattice water markedly alters hydrogen-bond topology and molecular packing. We combined terahertz time-domain spectroscopy (THz-TDS) and FT-Raman spectroscopy with periodic solid-state DFT and potential energy distribution (PED) analysis to assign vibrational modes and link spectral features to structural motifs. Hirshfeld surface analysis indicates form I is dominated by multi-directional O H...N contacts and an R 2 2 ( 8 ) N H...O synthon that yields parallel layered packing. By contrast, form II uses lattice water to bridge O H...O/N H...O interactions and weak C H...O contacts, producing a cross-stacked three-dimensional network lacking R 2 2 ( 8 ) dimers. Observed spectral differences are attributed to these distinct intermolecular interactions and associated vibrations. By integrating experimental and theoretical data, this study provides spectroscopic-structural insights into INH-HBA hydrate polymorphism, offering a foundation for pharmaceutical cocrystal identification and design.