Simulation and Experiment Reveal a Complex Scenario for the Adsorption of an Antifungal Drug in Ordered Mesoporous Silica

Ordered mesoporous silicas have been widely investigated as drug carriers in several fields, from tissue engineering to cancer therapy. The knowledge of the specific interactions between the surface of mesoporous silicas and drugs is necessary to guide development of new and improved drug delivery systems. However, such knowledge is still scarce, due to the arduous interpretation of experimental results. In this work, we characterize the incorporation of clotrimazole, a common antifungal drug, inside ordered mesoporous silica by means of a joint computational and experimental approach. Experimentally the drug was loaded through supercritical CO2 and its adsorption investigated through infrared spectroscopy, N-2 adsorption isotherms, and thermogravimetric analysis. Modeling involved static and dynamic Density Functional Theory simulations of clotrimazole adsorbed on realistic models of amorphous silica surfaces. A good agreement between the computational and the experimental results was obtained, concerning the energies of adsorption, the infrared spectra, and the distribution of drug inside the mesopores. However, a complete interpretation of the experimental results was possible only when simultaneously considering all the complex aspects of the drug-silica interaction. Indeed, the combination of both approaches allowed us to describe the drug-silica interface as a mix of multiple interaction configurations, based on a subtle balance of hydrogen bonding and dispersion interactions. Furthermore, at high drug loading, clotrimazole molecules are statistically distributed on the pore walls, forming an adsorbed molecular layer. Finally, notwithstanding the stable interactions, the drug still exhibits a significant mobility at room temperature, moving on a complex potential energy surface, as revealed by molecular dynamics simulations.