Molecular Docking Aided Study of Transient Metal Inclusion and Tertiary Complexation of Fenofibrate: Effect on Solubility

Background: Fenofibrate, a widely used lipid-lowering agent, exhibits limited bioavailability due to its BCS Class II status and poor aqueous solubility. Enhancing its solubility is crucial to improving therapeutic efficacy. Methods: This study explored solubility enhancement via molecular docking-guided screening of transition metal complexes and inclusion complexes with beta-cyclodextrin (β-CD). Transition complexes of fenofibrate with copper acetate were synthesized at a 1:1 molar ratio in a methanolwater mixture (2:1). Additionally, inclusion complexes of these metal complexes with β-CD were prepared in a 1:1 molar ratio and dried. Physicochemical characterization was performed using FTIR, XRD, and SEM analyses. Molecular docking identified potential interactions and conformational stability of the complexes. Results: The aqueous solubility of fenofibrate increased significantly, 17-fold in the transition metal complex and 25-fold in the β-CD inclusion complex compared to the pure drug. The complexes demonstrated structural changes, including amorphization, which likely contributed to enhanced solubility. Molecular docking revealed strong interactions between fenofibrate, copper acetate, and β-CD, supporting the formation of stable complexes. Conclusion: The results indicate that fenofibrate’s solubility can be markedly enhanced through complexation with transition metals and β-CD. These approaches, particularly the β-CD inclusion complexes, hold the potential for improving fenofibrate's bioavailability and therapeutic outcomes, offering a promising strategy for addressing solubility challenges in poorly water-soluble drugs.