Novel pK_a/DFT-Based Theoretical Model for Predicting the Drug Loading and Release of a pH-Responsive Drug Delivery System

Abstract

Herein, we present a theoretical model that combines classical pK a theory with quantum mechanical calculations to predict the extent of interaction between acid-/base-dependent species over a full range of pH conditions. To demonstrate the theoretical model, we have predicted the drug loading and release of a pH-responsive drug delivery system consisting of sulfasalazine, an anionic anti-inflammatory drug molecule, loaded onto the positively charged trimethylammonium (TA)-functionalized mesoporous silica nanoparticle surface. The model relies on the possible combinations of pH-dependent states of the surface (S) and drug (D) molecules as neutral (0) and deprotonated (−1) states, whose relative probabilities depend on their pK a value and the desired pH. The four possible combinations were identified as S0D0, S0D–1, S–1D0, and S–1D–1, and periodic density functional theory calculations were performed for systems comprising drug fragments adsorbed onto a model TA-functionalized quartz surface to calculate the pH-dependent interaction energy (E int pH). The E int pH value was attractive at the acidic environment of stomach (pH 2–5), where a drug is loaded and repulsive at neutral or slightly basic pH in the small intestine where it is released; the behavior is in accordance with the experimentally reported data. We also validated the experimental necessity of surface functionalization.

Interplay between Electrostatic and Hydrophobic Interactions in the pH-Dependent Adsorption of Ibuprofen onto Acid-Functionalized Multiwalled Carbon Nanotubes

“…At a specific pH, the binding energy ( E BE pH ) is calculated by adding all the contributions of the different protonation possibilities as illustrated in eq …”

“…The concentrations of the deprotonated and neutral states at a given pH depend on the p K a values of both species. The fractions of these species present at a particular pH are calculated by using the rearranged Henderson–Hasselbalch equation illustrated in eq …”

“…Both QM and MM simulations of the drug, adsorbent, and IBP/CNT complexes were conducted in the gas phase at different pH combinations. This task was undertaken by employing a newly developed method previously described by our research group . In this method, four possible pH combinations were explored based on the deprotonation of the two molecular species [i.e., CNT-COOH (T) and IBP (D)] involved during adsorption.…”

“…This task was undertaken by employing a newly developed method previously described by our research group. 33 In this method, four possible pH combinations were explored based on the deprotonation of the two molecular species [i.e., CNT-COOH (T) and IBP (D)] involved during adsorption. These possibilities include a system where (i) both species are neutral (T 0 D 0 ), (ii) T is neutral, and D is deprotonated (T 0 D −1 ), (iii) the surface of T is deprotonated, and D is neutral (T −1 D 0 ), and (iv) both species are deprotonated (T −1 D −1 ).…”

Periodic DFT Calculations—Review of Applications in the Pharmaceutical Sciences

“…One of their application areas is the surface modelling. The research in this topic refers to various surface utilization possibilities in drug development-related sciences, as drug's adsorption and release from a drug delivery medium [104][105][106], tableting process (slip agents, optimization of tableting process parameters) [107], elucidation of contaminants, or surface-induced polymorphism [108].…”