Aggregation Behavior of Medium Chain Fatty Acids Studied by Coarse-Grained Molecular Dynamics Simulation

Area of Science:

• Physical Chemistry
• Colloid Science
• Computational Chemistry

Background:

• Medium chain fatty acids (MCFA) are crucial as transient permeability enhancers in drug formulation, influencing drug absorption through mechanisms like solubilization and membrane modification.
• Understanding MCFA aggregation behavior is vital for optimizing lipid-based formulations, yet experimental determination of critical micelle concentration (CMC) is sensitive to varying system conditions.
• Existing experimental methods for CMC determination are subject to environmental factors like pH, temperature, and ionic strength, necessitating complementary simulation approaches.

Purpose of the Study:

• To investigate the aggregation behavior of four different MCFAs in aqueous solutions using coarse-grained molecular dynamics (CG-MD) simulations.
• To assess the suitability of CG-MD for studying MCFA interactions and aggregation phenomena relevant to formulation science.
• To explore the influence of pH on MCFA aggregation by manipulating the ratio of deprotonated to non-charged molecules.

Main Methods:

• Coarse-grained molecular dynamics (CG-MD) simulations were employed to model MCFA aggregation in water.
• Simulations were conducted at different pH conditions by varying the deprotonated/non-charged MCFA ratio within specified box sizes (22x22x44 nm³ and 44 nm³).
• Critical micelle concentrations (CMC) were determined by analyzing aggregate size distribution and free MCFA counts across simulations with increasing MCFA numbers.

Main Results:

• CG-MD simulations yielded CMC values for C8, C10, and C12 MCFAs that were 1.8-3.5 times lower than those obtained experimentally via the Wilhelmy method.
• The simulations successfully captured the variation in MCFA aggregate sizes and morphologies across different pH conditions, consistent with previous experimental observations.
• The study demonstrated that CG-MD simulations can effectively model the aggregation behavior of MCFAs in aqueous environments.

Conclusions:

• Coarse-grained molecular dynamics (CG-MD) is a suitable computational tool for investigating the aggregation behavior of medium chain fatty acids (MCFA) in colloidal systems.
• Despite quantitative differences in CMC values, CG-MD provides valuable qualitative insights into MCFA aggregation dynamics and pH-dependent behavior.
• This simulation approach offers a complementary method to experimental techniques for understanding MCFA interactions in formulation development.