In vitro Evaluation of the Physicochemical Stability of Multi-Drug Y-Site Admixtures Using Dynamic Monitoring and Chemometrics

Purpose: Concurrent continuous infusions of propofol, midazolam, insulin, dexmedetomidine, and morphine are commonly used in ICU for sedation, analgesia, and glycemic control. However, physicochemical compatibility data for Y-site administration are lacking, leading to risky empirical practice. This study evaluated their physicochemical stability to guide safe infusion. Patients and Methods: Twenty-six admixtures were prepared at clinical concentrations and stored at room temperature. Samples were analyzed at 0, 2, 4, 8, 12, and 24 h for appearance, pH, osmolality, subvisible particles, mean droplet diameter (MDD), polydispersity index (PDI), zeta potential, microscopic aggregation, and drug content by high-performance liquid chromatography (HPLC). Principal component analysis (PCA), hierarchical cluster analysis (HCA), Spearman correlation, and orthogonal partial least squares-discriminant analysis (OPLS-DA) were performed to explore stability patterns and key discriminating variables. Results: No obvious alterations in appearance, pH, or osmolality were observed over 24 h. In propofol-free admixtures, subvisible particles met pharmacopeial limits. In propofol-containing admixtures, MDD (95.6– 124.3 nm) and PDI (0.338– 0.469) remained acceptable, whereas zeta potential ranged from − 12.50 to 6.14 mV. Microscopic aggregation was observed in seven propofol-containing admixtures. HPLC showed that all drugs retained > 90% of their initial concentrations. OPLS-DA identified four independent variables with VIP values greater than 1 ( R2 Y=0.71, Q 2 =0.689), and permutation tests confirmed no overfitting. Conclusion: Under the conditions studied, seven propofol-containing admixtures showed aggregation, while the other 19 remained stable for 24 h. Chemometric analysis supported the stability classification and indicated that drug composition, pH and zeta potential were key contributors to emulsion aggregation. Keywords: compatibility, chemometric analysis, propofol emulsion, sedation, analgesia, HPLC