Structural, Electronic, and Optical Properties of Monoclinic Pharmaceutical Crystals: A DFT Study of Salicylic Acid, Acetylsalicylic Acid, Acetaminophen, and Ibuprofen.

The solid-state properties of pharmaceutical compounds play a critical role in their therapeutic efficacy, influencing their solubility, bioavailability, and stability. In this study, we investigate the monoclinic crystalline forms of four widely used anti-inflammatory drugssalicylic acid, acetylsalicylic acid (aspirin), acetaminophen (paracetamol), and ibuprofenusing density functional theory (DFT). Employing the Perdew, Burke, and Ernzerhof (PBE) functional with Tkatchenko-Scheffler dispersion correction, we performed geometry optimizations of the unit cells, achieving lattice parameters within 1-2% of experimental values. Time-dependent DFT (TD-DFT) calculations revealed molecular UV-vis absorption spectra consistent with experimental data, elucidating key electronic transitions. Kohn-Sham band structure analyses using the HLE17 functional identified indirect band gaps ranging from 2.99 eV (salicylic acid) to 4.02 eV (ibuprofen) with near-direct transitions suggesting potential optical activity. For the acetylsalicylic acid crystal, the calculated optical absorption spectrum reproduces the main experimental features after a rigid energy shift, highlighting the effectiveness and limitations of the DFT-PBE + TS approach for describing its optical properties. Optical absorption and dielectric function calculations for light polarized along the (100), (010), and (001) crystal directions highlighted anisotropic responses tied to crystal packing and hydrogen-bonding networks. These findings provide a comprehensive understanding of the interplay among the molecular structure, crystal lattice, and optoelectronic properties, offering insights and providing a theoretical foundation for the rational design of pharmaceutical formulations with enhanced performance.