Supersaturation of self-nanoemulsifying drug delivery systems: Correlation between equilibrium solubility and supersaturation concentration, effect on droplet size and impact of polymer addition

Supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS) have emerged as a promising approach to increase the drug load of hydrophobic molecules, compared to conventional SNEDDS (con-SNEDDS). This study aimed to explore the relationship between equilibrium solubility (S_eq) and the maximum supersaturation concentration (CS_max) in SNEDDS preconcentrates for three model drugs: carvedilol (CVL), ritonavir (RTV) and nilotinib (NTB). The emulsion droplet size of con-SNEDDS (90 % of S_eq) and super-SNEDDS (90 % of CS_max), and the influence of polyvinylpyrrolidone-vinyl acetate copolymers 64 (PVP/VA 64) was assessed, as well as the relationship between physical stability and viscosity of super-SNEDDS in the presence of PVP/VA 64. A Design of Experiment (DoE) approach was applied to optimize SNEDDS compositions. The results showed linear correlations between S_eq and CS_max across all three model drugs, leading to a consistent (but drug dependent) maximum degree of supersaturation (DS_max) (CVL = 2.49, RTV = 4.56, NTB = 2.54) within the DoE design space. Dissolving 4 % (w/w) PVP/VA 64 in the SNEDDS preconcentrates did not influence the described correlations or DS_max. Emulsion droplet size remained unchanged upon drug loading to 90 % of S_eq (con-SNEDDS) compared to drug-free SNEDDS. Further loading to 90 % of CS_max (super-SNEDDS) also resulted in negligible size changes in emulsions with initial droplet sizes below 60  nm, whereas those above 60  nm exhibited pronounced droplet size increase, following a quadratic relationship compared with their initial con-SNEDDS droplet size. Incorporation of PVP/VA 64 enhanced both the physical stability and viscosity of super-SNEDDS; however, only a weak correlation was observed between these two parameters, suggesting that viscosity alone did not govern the stabilization of super-SNEDDS. In summary, within the design space, DS_max is drug-dependent, but independent of SNEDDS composition or polymer addition; droplet size of super-SNEDDS is dependent on both drug and SNEDDS composition, but is unaffected by polymer; in contrast, physical stability is jointly influenced by drug properties, SNEDDS composition, and polymer addition.