Compatibility and stability of binary mixtures of ketorolac tromethamine and tramadol hydrochloride injection concentrate and diluted infusion solution

Objective: Ketorolac added to tramadol as an injection mixture convenient for clinical use has been shown to be an effective balanced analgesic regimen in alleviating moderate-to-severe pain. However, analytical confirmation of the compatibility and stability of this combination is not available. This study examined the compatibility and stability of this combination.

Methods: Two different mixtures containing ketorolac tromethamine and tramadol hydrochloride were examined: ketorolac (10 mg/mL) and tramadol (33.3 mg/mL) prepared as injection concentrate in ampoule mingled together in the ratio of one ampoule to one ampoule; diluted ketorolac (2 mg/mL) and tramadol (20 mg/mL) prepared in saline infusion solution, with or without pH adjustment. The mixtures were visually inspected for precipitation and color change. Quantitative chemical analysis was performed on days 0, 1, 3 and 7 by high-performance liquid chromatography.

Results: When stored at room temperature under ambient light, the ketorolac (10 mg/mL)-tramadol (33.3 mg/mL) injection concentrate and ketorolac (2 mg/mL)-tramadol (20 mg/mL) solution, without pH adjustment and adjusted to pH 5-8, were physico-chemically stable, and neither visible precipitation nor loss of concentration was found. With the ketorolac (2 mg/mL)-tramadol (20 mg/mL) solution adjusted to pH 9, however, precipitation occurred immediately, resulting in a significant loss of tramadol.

Conclusion: This study suggests that a ready-to-use ketorolac-tramadol mixture, either undiluted or diluted in physiological saline solution, can be prepared, with a shelf life of at least 7 days when stored at room temperature under ambient light.