Molecular Modeling of Montmorillonite as a Delivery Carrier for Zoledronic Compounds

Zoledronic compounds are widely used as antiresorptive and antitumor agents to prevent bone loss and treat multiple myeloma; however, their pharmacokinetic limitations motivate the search for alternative delivery systems capable of improving their controlled release and bioavailability. In this work, we investigate the stability, structural behavior, and adsorption properties of zoledronic acid (ZOL) and its Ca2+ and Zn2+ salts confined within the interlayer space of the smectite clay mineral montmorillonite by combining empirical force field (FF), density functional theory (DFT), and molecular dynamics (MD) simulations. The main objective of this study is to evaluate the suitability of montmorillonite as a potential drug delivery system (DDS). Specifically, crystal polymorph structures of zoledronic acid [1-(2-hydroxy-2-phosphonate-2-phosphonoethyl)-1H-imidazol-3-ium)] (ZOL) and its Ca2+ and Zn2+ salts were analyzed. Our calculated crystal structures obtained by both methods (FF and DFT) agree well with the known experimental data. Furthermore, the intercalation of ZOL into the confined interlayer space of montmorillonite is energetically favorable. Several interlayer cations (Na+, Ca2+, and Zn2+) were also evaluated. MD simulations showed that ZOL adopts stable confined configurations within the interlayer space of montmorillonite, exhibiting small torsions of the imidazole group. Additionally, the desorption of ZOL in a modelized acidic medium is energetically favorable. Our calculations predict that this clay mineral holds strong potential for the controlled delivery of zoledronic compounds.