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

TL;DR

This paper uses computational methods to study the structural and optical properties of four common anti-inflammatory drugs in their monoclinic crystal forms.

Contribution

The study provides a detailed DFT-based analysis of the electronic and optical properties of monoclinic pharmaceutical crystals, revealing anisotropic optical responses.

Findings

DFT calculations reproduced lattice parameters within 1–2% of experimental values for monoclinic drug crystals.

TD-DFT calculations showed UV–vis absorption spectra consistent with experimental data, revealing electronic transitions.

Optical absorption and dielectric function calculations revealed anisotropic responses linked to crystal packing and hydrogen bonding.

Abstract

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.

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