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

It is difficult to accurately distinguishthe amount of a druginside versus outside of a carrier during drug loading, which limitsthe ability to determine the kinetic data (the drug diffusion coefficient,energy barrier, etc.). Here, we demonstrated the feasibility of determiningthe drug diffusion coefficient and content without distinguishingwhether it is inside or outside of a carrier. Specifically, the sampleof gamma-cyclodextrin metal-organic frameworks (CD-MOF) loadedwith unstable and viscous alpha-lipoic acid (LA) was examined. Furthermore,the LA stability was enhanced by the CD-MOF via a straightforwardand unambiguous solvent-free method, and the mechanism behind it wasthoroughly explored based on the diffusion coefficient. For the firsttime, a combination of mathematical modeling and new experimentalmeasurements was used to determine the diffusion coefficient of LAin CD-MOF crystals. Accordingly, the strong adhesion free energy (-8.64 +/- 0.56 kcal center dot mol(-1)) between LA and thedicyclodextrin cavity in the CD-MOF was determined. Furthermore, thenature of the adhesion force was identified to be the chemisorptiondominated by hydrogen binding employing a combination of molecularmodeling (docking and density functional theory, DFT) and experimentalmethods (solid-state nuclear magnetic resonance, ssNMR). Finally,this study revealed that the stability enhancement of LA in the CD-MOFis due to the combined actions of the high binding free energy ofLA with the dicyclodextrin cavity and its steric hindrance, togetherwith the accelerating roles of the CD-MOF cage environment.