Compatibility and stability of ciprofol with different concentrations of remifentanil or esketamine

Combination anesthesia with ciprofol, remifentanil, and esketamine enhances clinical efficacy but poses stability risks due to the emulsion formulation. Given the lack of compatibility data, this study investigated the physicochemical stability of ciprofol mixed with varying concentrations of remifentanil or esketamine. Ciprofol emulsions were mixed with varying concentrations of esketamine or remifentanil at a volume ratio of 1:1. The admixtures were prepared at room temperature (25 ± 1 °C) under ambient light, and samples were collected at predefined time points (0, 2, 4, 6, and 8 h) for stability analysis. To assess the stability of the mixtures, drug concentrations (measured by high-performance liquid chromatography), macroscopic and microscopic appearance, pH, mean particle diameter (MPD), polydispersity index (PDI), zeta potential, and osmolality were evaluated. Over the 8-h period, no visual changes were observed in any mixture, and drug concentrations remained between 96% and 104% of the initial value. The MPD remained stable at 205 ± 7 nm, with a uniform particle size distribution (PDI = 0.1 ± 0.03). Notably, in contrast to the esketamine group, the remifentanil group exhibited significant changes in pH and osmolality (P < 0.05), along with a significantly lower absolute zeta potential. Microscopic analysis further revealed mild droplet aggregation in the remifentanil group. Ciprofol exhibits chemical stability and acceptable physical compatibility with esketamine or remifentanil at the tested concentrations for up to 8 h. However, given the mild physical instability (e.g., droplet aggregation) observed in ciprofol-remifentanil mixtures, prolonged storage is not recommended, because it may affect their stability.