Abstract
Cyclophosphamide (CP) adsorption in FAU zeolites with Si/Al ratios of 1, 5, and 25 was investigated using Grand Canonical Monte Carlo (GCMC) and Molecular Dynamics (MD) simulations, providing a comprehensive computational framework for understanding host-guest interactions in this drug delivery system. CP exhibits remarkably strong adsorption energies (-320 to −328 kcal/mol), yet achieves loading capacities of 45–78 molecules per unit cell, revealing a classic strength-capacity trade-off governed by molecular size and framework aluminum density. The deformation energy contribution (∼22.2–22.5%) indicates significant framework strain from the bulky CP molecule, a critical consideration for long-term carrier stability. The isosteric heat of adsorption increases with Si/Al ratio (26.4–28.9 kcal/mol). In contrast, the CP-to-water isosteric heat ratio (3.86–4.56) demonstrates CP's superior thermodynamic stability in aqueous environments-a desirable feature for physiological drug delivery. MD simulations reveal distinct diffusion regimes: CP diffusion is highest in FAU1 (2.72 × 10⁻¹⁰ m²/s) through surface-assisted diffusion, lowest in FAU5 (1.35 × 10⁻¹⁰ m²/s) due to barrier-dominated diffusion, with FAU25 showing unexpectedly high mobility (2.53 × 10⁻¹⁰ m²/s) as hydrophobic interactions do not restrict diffusion pathways. The anomalous diffusion exponent (α = 0.843–0.872) confirms subdiffusive behavior, with FAU1 closest to Fickian diffusion (α = 0.872), enabling predictable release kinetics. Langmuir isotherm modeling provides excellent fits (R² > 0.979), confirming monolayer adsorption on homogeneous sites, while the Dubinin-Radushkevich mean adsorption energy (8.33–10.91 kJ/mol) confirms physisorption with strong polar contributions. Thermodynamic parameters (ΔG° = −7.23 to −6.52 kJ/mol, ΔH° = −12.5 to −7.5 kJ/mol) confirm spontaneous, exothermic adsorption with decreasing entropy upon confinement. RDF analysis reveals preferential CP positioning within supercages (r ≈ 0.95 Å for P = O···Na⁺ interactions, r ≈ 1.57–1.59 Å for main structural ordering), with structural order (S = 0.912–0.965) increasing with Si/Al ratio. An inverse trend between structural order and adsorption capacity is observed across the three zeolite samples, suggesting that heterogeneous, less-ordered sites in Al-rich frameworks may be associated with superior loading performance. FAU1 emerges as optimal for maximum loading (78.4 molecules/unit cell), FAU5 for sustained long-term release, and FAU25 for controlled release with enhanced per-molecule stability. This work provides a comprehensive computational framework for the rational design of zeolite-based CP delivery systems, offering design principles for next-generation inorganic drug carriers, with potential relevance to environmental adsorption applications.