A DFT/TD-DFT investigation of clozapine adsorption on B12Y12 (Y = N, P) nanocages as vehicles for applications in schizophrenia treatment†

Clozapine (Clo) is a highly effective antipsychotic for treatment-resistant schizophrenia, but its clinical use is hampered by poor delivery due to its lipophilic nature. In this study, density functional theory (DFT) and time-dependent DFT (TD-DFT) were used to investigate B₁₂N₁₂ and B₁₂P₁₂ nanocages as potential carriers for Clo delivery. Molecular electrostatic potential (MEP) analysis revealed three electron-rich adsorption sites on Clo (N13, Cl16, and N32), which served as anchoring points for nanocage attachment. Clo/B₁₂N₁₂ configurations (A–C) and Clo/B₁₂P₁₂ complexes (D–F) were labelled as Sites 1–3. The findings reveal that the adsorption energies for Clo on both nanocages fall between −20 and −40 kcal mol⁻¹ (i.e. −39.96 to −22.05 kcal mol⁻¹), indicating strong and stable chemisorption. These interactions are both spontaneous and exothermic, as supported by negative values of ΔG_ad and ΔH_ad. NBO analysis demonstrates greater charge transfer from Clo to B₁₂N₁₂ (up to 1.240e) compared to B₁₂P₁₂ (up to 0.589e). Both nanocages significantly reduce the HOMO–LUMO gap of the system (by 42.66% for B₁₂N₁₂ and 29.52% for B₁₂P₁₂), which enhances conductivity and could facilitate drug detection. QTAIM analysis indicates that complexes A, C, D and F feature partially covalent interactions, while B and E are more ionic, suggesting a balance between strong binding and the potential for controlled release. Recovery time calculations further show that complexes B and E allow for faster drug release. Overall, these findings highlight B₁₂N₁₂ and B₁₂P₁₂ nanocages as promising nanocarriers for targeted clozapine delivery, combining stable binding with the potential for efficient and controlled drug release and, however, warranting experimental validation for addressing current challenges in schizophrenia therapy.