Solvatochromic Effects and Photophysical Properties of Metformin Hydrochloride and Its Interaction with Caffeine: Spectroscopic and Computational Approaches

Abstract

This dissertation provides an investigation of the solvatochromic effect and photophysical properties of metformin hydrochloride (MF-HCl) as well as its interaction with caffeine (CAF), utilizing the integrated spectroscopic and computational approaches. Absorption and fluorescence spectra of MF-HCl were analyzed in solvents of differing polarity, revealing the influence of solvent environment on spectral behavior. For the Solvatochromic effect, Lippert-Mataga, Bakhshiev, Kawski-Chamma-Viallet, and Reichardt models were employed to estimate the ground and excited state dipole moments, with the excited state dipole moment higher than the ground state, suggesting that enhancement might be by intramolecular charge transfer in the excited state. These results were also supported by Density Functional Theory (DFT) using various basis sets. Photophysical properties such as fluorescence quantum yield, lifetime, radiative and non-radiative decay transition dipole moment, and integrated absorption coefficient were found to vary with solvent polarity and MF-HCl concentration. Fluorescence quenching with CAF indicated a predominant static quenching mechanism, forming a ground-state complex. The binding constants, quenching rates, and thermodynamic parameters results obtained indicate the spontaneous, enthalpy-driven interaction, likely mediated by hydrogen bonding and van der Waals forces. The spectral overlap between MF-HCl emission and CAF absorption yields an energy transfer efficiency of 0.72, indicative of Förster resonance energy transfer (FRET). This is substantiated by a Förster radius (R₀) of 1.81 nm and a binding distance (r) of 1.55 nm, consistent with efficient FRET. Molecular docking simulations revealed a notable enhancement in the binding profile of MF-HCl to the AMPK receptor in the presence of caffeine. The binding affinity improved from 5.0 kcal/mol (MF-HCl alone) to -5.9 kcal/mol (MF-HCl + CAF), suggesting a synergistic stabilization of the protein-ligand complex. These computational results complement spectroscopic quenching data, providing molecular-level evidence that caffeine may modulate the pharmacodynamic interaction of metformin with its primary metabolic target. Overall, this work elucidates the solvent-dependent photo physics of MF-HCl and its molecular interaction with CAF, providing valuable implications for understanding drug behavior, potential drug-drug interactions, and pharmacokinetics.