Short-Term Physicochemical and Colloidal Behavior of Dexamethasone Palmitate Admixed with Local Anesthetics

Background/Objectives: Dexamethasone palmitate (DXP) is a corticosteroid prodrug formulated as an oil-in-water lipid emulsion. We investigated its short-term physicochemical and colloidal behavior when admixed with local anesthetics (LAs). Methods: Seven DXP–LA mixtures containing ropivacaine, lidocaine, or bupivacaine (stress-test or clinically relevant preparations) were stored in polypropylene syringes at 24 °C and assessed at 0, 1, and 2 h (n = 5) by visual inspection, optical microscopy with blinded scoring, dynamic and electrophoretic light scattering, pH, and high-performance liquid chromatography. Results: No visible precipitation or phase separation occurred. Microscopy revealed time-dependent aggregation-like changes, most pronounced in saline-diluted ropivacaine and bupivacaine mixtures (interobserver weighted κ = 0.954). Bulk particle-size metrics showed no consistent corresponding increase. The maximum pH change was 0.178 units, and parent-drug concentrations remained at 97.86–99.63% of baseline. Zeta-potential results were variable. Conclusions: Despite no overt incompatibility over 2 h, microscopy-detectable changes were not consistently reflected in bulk particle-size metrics or parent-drug concentrations. Without matched DXP-alone and saline-diluted DXP controls, whether these changes require the LA or arise from dilution of the emulsion alone could not be determined. These findings do not establish emulsion stability or clinical safety; further in vitro and in vivo studies are needed.