Application of Density Functional Theory to Molecular Engineering of Pharmaceutical Formulations

This review systematically examines the pivotal applications of the Density Functional Theory (DFT) in drug formulation design, emphasizing its capability to elucidate molecular interaction mechanisms through quantum mechanical calculations. By solving the Kohn-Sham equations with precision up to 0.1 kcal/mol, DFT enables accurate electronic structure reconstruction, providing theoretical guidance for optimizing drug-excipient composite systems. In solid dosage forms, DFT clarifies the electronic driving forces governing active pharmaceutical ingredient (API)-excipient co-crystallization, predicting reactive sites and guiding stability-oriented co-crystal design. For nanodelivery systems, DFT optimizes carrier surface charge distribution through van der Waals interactions and π-π stacking energy calculations, thereby enhancing targeting efficiency. Furthermore, DFT combined with solvation models (e.g., COSMO) quantitatively evaluates polar environmental effects on drug release kinetics, delivering critical thermodynamic parameters (e.g., ΔG) for controlled-release formulation development. Notably, DFT-driven co-crystal thermodynamic analysis and pH-responsive release mechanism modeling substantially reduce experimental validation cycles. While DFT faces challenges in dynamic simulations of complex solvent environments, its integration with molecular mechanics and multiscale frameworks has achieved computational breakthroughs. This work offers interdisciplinary methodology support for accelerating data-driven formulation design.