Location of Solvated Probe Molecules Within Nonionic Surfactant Micelles Using Molecular Dynamics

Abstract

An iconic textbook that pharmaceutical scientists encounter in undergraduate courses is "Martin's Physical Pharmacy and Pharmaceutical Sciences." Within the chapter on Colloids, a figure indicates the location of solubilization of molecules within spherical, nonionic surfactant micelles. The surfactant consists of polyethylene glycol (PEG) hydrophilic headgroups and alkane chains for the hydrophobic tail. The figure shows benzene and toluene within the alkane core, salicylic acid (2-hydroxybenzoic acid) at the interface between the core and PEG chains, and then para-hydroxybenzoic acid (4-hydroxybenzoic acid) located between the PEG chains. Molecular dynamics simulations of octaethylene glycol monododecyl ether micelles were performed with a series of probe molecules, including those within the Martin's figure, to determine their solubilization location. Relative placement of molecules within the micelle was correct; however, some specifics were different. In particular, benzene and toluene are excluded from the core, and 4-hydroxybenzoic acid prefers to maintain contact with the core. A series of molecules containing 6 carbon atoms were also studied to determine the effects of cyclization (moves out of core), polar functionalization (anchored to interface), and aromatization (excluded from central core). Molecular dynamics was found to be a useful tool for gaining insight into interactions important in solubilization of molecules.

Influence of Bile Composition on Membrane Incorporation of Transient Permeability Enhancers

“…An attractive alternative to experimental measurements is molecular simulations. Recently, coarse-grained molecular dynamics (CG-MD) has been used for the study of molecular aggregation related to PEs, such as the aggregation behavior of various MCFA molecules, ,, structural details of bile salts and phospholipids micelles as well as the octaethylene glycol monododecyl ether micelles with different small molecules, and the interaction of PE molecules with lipid membranes. − CG-MD has also been used to investigate the complex micelle kinetics of various surfactant molecules , and bile salts …”

Synergistic Computational Modeling Approaches as Team Players in the Game of Solubility Predictions

“…108 While simple surfactant systems have been studied extensively by computational means in colloid sciences, there is clearly less work reported about pharmaceutical surfactants with a focus on drug solubilization. The MD simulation research at Monash University on non-ionic surfactant micelles was mentioned before in this commentary 27 and such atomistic simulations provide valuable insights into the location of a solute in a surfactant micelle. It was also mentioned that COSMO-RS theory has been extended to solute partitioning into surfactant micelles, which was called the COSMOmic approach.…”

“…26 This preferential solvation location can be, for example, identified and visualized by molecular dynamics (MD) simulations. 27 This provides important insights and mechanistic understanding that would complement any other modeling attempt to predict micellular-drug partitioning, localization and solubilization. Therefore, a synergistic combination of methods can come in different ways.…”

Prediction of Micellar Thermodynamics of Nonionic Surfactants Based on the Square Gradient Theory

“…A second approach is to determine the thermodynamic and micellization properties by stating that the whole surfactant solution is a binary mixture whose free energy can be modeled through a homogeneous equation of state (EoS) or an activity coefficient model, − both of which have a theoric or semiempiric origin, or group contribution methods (GCMs) that are empirical formulations capable of correlating high volumes of experimental data with a high degree of precision. − A third approach is the use of energy functionals to represent the free energy of the system at each space point in the system through classical density functional theory (CDFT), − square gradient theory (SGT), or Ginzburg–Landau theory, in which the equilibrium properties of the system are obtained by minimizing the functional. Recently, molecular dynamics (MD) simulations increased in popularity due to their capability to model complex internal micellar interactions and structure properties. − …”