(256h) Molecular Modelling of Hydrophobic Ion Pairing Self Assembly for Nanoprecipitation: From Explicit Solvent United-Atom to Implicit Solvent Coarse Grain Simulations

Encapsulation of active pharmaceutical ingredients (APIs) into nanoparticles is frequently used to provide better bioavailability and longer circulation times for hydrophobic APIs. However, hydrophilic APIs are more challenging to encapsulate using well-established methods, often resulting in poor drug loading and low encapsulation efficiency. To resolve this issue, hydrophobic ion pairs (IPs) are added to form a self-assembled API:IP complex that is more hydrophobic, and therefore more suitable for existing encapsulation techniques, such as nanoprecipitation.

The molecular mechanics of the ion-pairing process are not well studied, so to establish a better understanding we first perform united-atom molecular dynamics in explicit solvent for a model system. We measure the dynamics of API:IP complex assembly and asses the effect of system properties, such as solvent composition and charge ratio, on the structure and hydrophobicity of the resulting complex. Based in these results, we construct a custom coarse-grained implicit solvent model of the system for simulation of larger length and time scales. Using this model, we probe how changes to the chemical and structural properties of the IP can change different properties of the assembled nanoparticle product. Our results should be useful in customizing the next generation of ion-pairing processes for nanoprecipitation.