Computational Models of the Gastrointestinal Environment. 1. The Effect of Digestion on the Phase Behavior of Intestinal Fluids

Abstract

Improved models of the gastrointestinal environment have great potential to assist the complex process of drug formulation. Molecular dynamics (MD) is a powerful method for investigating phase behavior at a molecular level. In this study we use multiple MD simulations to calculate phase diagrams for bile before and after digestion. In these computational models, undigested bile is represented by mixtures of palmitoyl-oleoylphosphatidylcholine (POPC), sodium glycodeoxycholate (GDX), and water. Digested bile is modeled using a 1:1 mixture of oleic acid and palmitoylphosphatidylcholine (lysophosphatidylcholine, LPC), GDX, and water. The computational phase diagrams of undigested and digested bile are compared, and we describe the typical intermolecular interactions that occur between phospholipids and bile salts. The diffusion coefficients measured from MD simulation are compared to experimental diffusion data measured by DOSY-NMR, where we observe good qualitative agreement. In an additional set of simulations, the effect of different ionization states of oleic acid on micelle formation is investigated.

A Nonionic Polyethylene Oxide (PEO) Surfactant Model: Experimental and Molecular Dynamics Studies of Kolliphor EL

“…To investigate the phase behavior of the KOL model, we ran a series of simulations at different surfactant concentrations (simulations [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Each simulation was commenced from a random arrangement of KOL molecules.…”

“…7,8 Although our knowledge about the behavior of LBFs within the GI tract is growing, predicting the in vivo performance of LBFs remains difficult, which is a significant impediment to their commercial implementation. We propose that molecular dynamics (MD) simulations can contribute to better understanding of the dynamic processes of molecular assembly and phase separation within the GI tract [9][10][11][12][13][14] and that this can be extended to modeling the behavior of LBFs and their in vivo behavior. For example, in an early study, computational modeling of the fate of LBFs in the gut was investigated by Warren et al, 12 who modeled a simple type I LBF of mixed glycerides, in the presence of propylene glycol and water.…”

“…For example, in an early study, computational modeling of the fate of LBFs in the gut was investigated by Warren et al, 12 who modeled a simple type I LBF of mixed glycerides, in the presence of propylene glycol and water. Subsequent efforts have been directed toward simulating the self-assembly of endogenous surfactants, such as bile salts, 10,[13][14][15] sodium salts of long-chain carboxylic acids, 9,16,17 and gemini surfactants. [18][19][20] Because PEO nonionic surfactants play a central role in oral drug delivery vehicles, validated models for the simulation of these materials are necessary; however, simulations of the phase behavior of these nonionic, C n EO m -type surfactants lag behind.…”

Current Status of Supersaturable Self-Emulsifying Drug Delivery Systems

“…Recently, following the emphasis placed on the importance of in vitro digestion models by many research scientists, promising progress has been made in the development of a biorelevant in vitro digestion model with good IVIVC for predicting the effects of various GI factors on the performance of supersaturable drug delivery systems, including in vivo supersaturation, drug precipitation, and absorption [42,171]. More recently, improved computational models of the gastrointestinal environment using molecular dynamics (MD) showed a great potential to assist the complex process of drug formulation [172][173][174]. This MD is a powerful method for investigating phase behavior at a molecular level.…”

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

“…Molecular dynamics (MD) simulations are becoming an important tool for investigating the phase behavior of liquid and liquid crystal systems and have great potential as a tool to predict the microstructure of lipid-based drug formulations. [1][2][3][4][5][6][7] Of interest to the authors is whether MD can be used to identify the location of solubilization of molecules within colloidal phases. The nonionic surfactant micellar system and probe molecules presented in the Martin's figure (see Fig.…”