Compatibility and Physico-Chemical Stability of Six Intravenous Mixtures for Postoperative Multimodal Analgesia

Abstract

Purpose: To evaluate the physical-chemical compatibility of six drug combinations used in intravenous multimodal postoperative analgesia under differing storage conditions and different containers. Methods: The analgesic mixtures studied were ternary and quaternary combinations of tramadol and ketamine with dexketoprofen or ketorolac, plus methadone in some mixtures, all diluted in saline solution. Physical compatibility, pH and concentration of drugs (ultra high performance liquid chromatography (UHPLC-DAD)) were determined 48 hours post-preparation (room temperature) and after 30 days (2°-8°C) for the mixtures in polyolefin bags, and after 14 days at room temperature for those mixtures in silicone and polyisoprene elastomers. Results: No physical changes were observed, and pH remained stable throughout the study. For all five drugs in polyolefin bags the recovery percentage remained within the range 95– 105%. Regarding mixtures prepared in elastomers, the recovery percentage for tramadol and dexketoprofen stayed within the range 95– 105%, while for methadone it was less than 40%. A subsequent extraction with methanol demonstrated the methadone adsorption on the container walls, more pronounced in the silicone than in the polyisoprene reservoirs. Conclusion: Analgesic mixtures of tramadol and ketamine with adjuvants (dexketoprofen or ketorolac, with or without methadone) showed physicochemical stability for 48 hours at room temperature and up to 30 days at 2°– 8°C in polyolefin bags. However, the combination of tramadol, dexketoprofen, and methadone was unstable in both tested elastomeric devices due to methadone adsorption, making it unsuitable for clinical use. These findings underscore the critical role of container material in drug stability.