Application of Density Functional Theory to Molecular Engineering of Pharmaceutical Formulations

Abstract

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.

Keywords: density functional theory; drug release; molecular interactions; pharmaceutical formulations.

Figure 1

TOC (Reprinted with permission from Ref. [3], Copyright © 2021 by Deghady, A.M.; Hussein, R.K.; Alhamzani, A.G.; Mera, A.; Ref. [4]. Copyright © 2016 by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. Ref. [5]. Copyright © 2016 by Kawai, S.; Foster, A.S.; Björkman, T.; Nowakowska, S.; Björk, J.; Canova, F.F.; Gade, L.H.; Jung, T.A.; Meyer, E; Ref. [6]. Copyright © 2015 by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim; Ref. [7]. Copyright © 2023 by Elsevier Ltd; Ref. [8]. Copyright © 2022 by American Chemical Society; Ref. [9]. Copyright © 2021 by Ran Friedman; Ref. [10]. Copyright © 2021 by American Chemical Society; Ref. [11]. Copyright © 2021 by American Chemical Society. Ref. [12] Copyright © 2023 Elsevier Inc.)

Figure 2

MEP and ALIE surfaces of PIDAA. Reproduced from ref. [41]. This is an open-access publication.

Figure 3

A schematic workflow for employing DFT calculations in polymer-based drug delivery systems. Reproduced from ref. [65]. This is an open-access publication.

Figure 4

HS, FP, and MEPS analysis of NPX–CPL and NPX–OMT. (a) HS and FP of NPX–CPL; (b) HS and FP of NPX–OMT; (c) MEPS of NPX–CPL; (d) MEPS of NPX–OMT. Reproduced from ref. [80]. This is an open-access publication.