Hypothesis: The purpose of this study was to find a suitable co-surfactant to replace non-food grade bile salts in solid lipid nanoparticle (SLN) formulations. The hypothesis was that the molecular structure and physical properties of co-surfactant modulate the stabilization of SLNs upon polymorphic transition. Experiments: Tristearin SLNs were prepared by using two main surfactants: saturated high-melting lecithin, and unsaturated low-melting lecithin. As co-surfactants we used sodium taurodeoxycholate (i.e. bile salt), Pluronic F68, Tween 60 and 80, and amino acids tyrosine, tryptophan, and phenylalanine. The influence of co-surfactants on crystallization behavior and physical stability of SLNs was investigated by differential scanning calorimetry and static light scattering, respectively. Findings: The results showed that the aromatic amino acids had optimal structures and properties to act as effective co-surfactants in SLNs. Our study suggests that ideal co-surfactants are amphiphilic with pronounced hydrophobic areas, but highly water soluble so that they can have a reservoir of molecules readily available for interfacial stabilization. They adsorb fast to the interfaces, but without inducing polymorphic transition. This work demonstrates how the right structure can facilitate the desired function. (C) 2014 Elsevier Inc. All rights reserved.