Diffusion Kinetics-Based Loading of Lipoic Acid into Cyclodextrin Metal–Organic Frameworks via a Solvent-Free Method and Mechanism of Stability Enhancement

Abstract

It is difficult to accurately distinguish the amount of a drug inside versus outside of a carrier during drug loading, which limits the ability to determine the kinetic data (the drug diffusion coefficient, energy barrier, etc.). Here, we demonstrated the feasibility of determining the drug diffusion coefficient and content without distinguishing whether it is inside or outside of a carrier. Specifically, the sample of gamma-cyclodextrin metal−organic frameworks (CD-MOF) loaded with unstable and viscous alphalipoic acid (LA) was examined. Furthermore, the LA stability was enhanced by the CD-MOF via a straightforward and unambiguous solvent-free method, and the mechanism behind it was thoroughly explored based on the diffusion coefficient. For the first time, a combination of mathematical modeling and new experimental measurements was used to determine the diffusion coefficient of LA in CD-MOF crystals. Accordingly, the strong adhesion free energy (−8.64 ± 0.56 kcal•mol −1 ) between LA and the dicyclodextrin cavity in the CD-MOF was determined. Furthermore, the nature of the adhesion force was identified to be the chemisorption dominated by hydrogen binding employing a combination of molecular modeling (docking and density functional theory, DFT) and experimental methods (solid-state nuclear magnetic resonance, ssNMR). Finally, this study revealed that the stability enhancement of LA in the CD-MOF is due to the combined actions of the high binding free energy of LA with the dicyclodextrin cavity and its steric hindrance, together with the accelerating roles of the CD-MOF cage environment.