Interfacial Competition between Surfactant and Polymer Excipients on a Drug Nanocrystal Surface

Oral administration is preferred among all drug administration routes due to its simplicity, low cost, and convenience. However, nearly 90% of drug candidates in the pharmaceutical development pipeline and 40% of commercially available drugs are hydrophobic, which significantly limits their dissolution kinetics in the gastrointestinal (GI) tract and consequently decreases oral bioavailability. The Doyle Group has developed a suite of ‘bottom-up’ methods to template drug nanocrystals by embedding active pharmaceutical ingredients (API) in polymeric matrices as an approach to reduce drug aggregate sizes for enhanced bioavailability. However, a mechanistic understanding of excipient-drug interactions and their influence on crystallinity during processing remains a significant hindrance in developing new formulations.

In this work, we present the use of all-atom molecular dynamics (MD) simulations to advance our understanding of interfacial competition between surfactants (Tween 80/Span 20) and polymers (methylcellulose) on the surface of a fenofibrate nanocrystal, a model hydrophobic API. To simulate this system, we establish a novel workflow for simulating two excipients on a triclinic crystal surface, including modification of the crystals to fit the desired simulation box dimensions, structural and topology file preparation for multi-component crystal simulation in GROMACS. Our setup allows convenient access to layer-by-layer structural analysis of the drug crystal, as well as any pairs of interactions among the excipients and the crystal layers. The molecular interactions between drug, polymer, and surfactant on the drug surface control the self-assembled nanostructure, leading to varying degrees of crystallinity based on excipient composition. Furthermore, excipient Lennard-Jones potentials and density along z-axis suggest that strong bulk polymer-surfactant stabilization contributes to preferential polymer surface delocalization. The simulation results are compared against experimental crystallinity data with various polymer-to-surfactant ratios, supporting our hypothesis for interaction mechanism and characteristics on each face of the fenofibrate crystal. This mechanistic insight can inform the design of new drug formulations using our promising bottom-up approach.