ADRENALINE AMPOULES QUALITY ASSESSMENT–THE ISRAELI EXPERIENCE
Keywords:Adrenaline ampoules, Stability, Shelf-life, Chiral HPLC-based assay
Objective: To characterize the differences in stability of L-adrenaline in adrenaline ampoules from different manufacturers that are used by the Israel Defense Forces (IDF).
Methods: Adrenaline ampoules from three different vendors (Products A, B and C; 52, 13, and 19 batches, respectively) were purchased by the IDF and were stored under the recommended storage conditions (room temperature) for different time periods. The content of L-adrenaline in these samples was determined using a chiral high-performance liquid chromatography (HPLC) assay with UV detection.
Results: The three analyzed drug products showed very dissimilar patterns of L-adrenaline degradation. The content of L-adrenaline in Product C was variable and declined below the 85% threshold much earlier than at the end of the 24-months storage period. Products A and B had less variable content of L-adrenaline and were more stable.
Conclusion: L-adrenaline is prone to degradation in solution. Its content in adrenaline ampoules from certain vendors can decline rapidly, below the stipulated threshold, and compromise their clinical effectiveness (e. g., during resuscitation). Stability of adrenaline ampoules from individual vendors should be analyzed at different storage conditions, using a chiral HPLC-based assay, to define the shelf-life period that can differ substantially between the vendors.
Wark H, Sara C. The stability of adrenaline injection. Br J Anaesth 1983;55:1139-40.
Allgire JF, Juenge EC, Damo CP, Sullivan GM, Kirchhoefer RD. High-performance liquid chromatographic determination of d-/l-epinephrine enantiomer ratio in lidocaine-epinephrine local anesthetics. J Chromatogr 1985;325:249-54.
Schroeter LC, Higuchi T, Schuler EE. Degradation of epinephrine induced by bisulfite. J Pharm Sci 1958;47:723-8.
Lundgren P, Ström S. Stability of adrenaline in 0.1% solutions. Acta Pharm Suec 1966;3:273-80.
Connors KA, Amidon GL, Stella VJ. Clinical stability of pharmaceuticals. A handbook for pharmacists. 2nd ed. Wiley; 1986.
Fyllingen G, Langvik TA, Hasselgård P, Roksvaag PO. Racemisation and oxidation in adrenaline injections. Acta Pharm Nord 1990;2:355-62.
Hoellein L, Holzgrabe U. Ficts and facts of epinephrine and norepinephrine stability in injectable solutions. Int J Pharm 2012;434:468-80.
Taylor JB, Sharma SC, Simpkins DE. Effect of sodium metabisulphite and anaerobic processing conditions on the oxidative degradation of adrenaline injection BP. Pharm J 1984;242/243:646-8.
Riegelman S, Fischer EZ. Stabilization of epinephrine against sulfite attack. J Pharm Sci 1962;51:206-13.
Fyhr P, Brodin A. The effect of anaerobic conditions on epinephrine stability. Acta Pharm Suec 1987;24:89-96.
Grubstein B, Milano E. Stabilization of epinephrine in a local anesthetic injectable solution using reduced levels of sodium metabisulfite and EDTA. Drug Dev Ind Pharm 1992;18:1549-65.
Backe Hansen K, Drottning Aarnes E, Venneröd AM, Briseid Jensen K. On the stability of adrenaline in injections: a comparison of chemical and bioassay methods. J Pharm Pharmacol 1963;15:804-9.
Nimura N, Kasahara Y, Kinoshita T. Resolution of enantiomers of norepinephrine and epinephrine by reversed-phase high-performance liquid chromatography. J Chromatogr A 1981;213:327-30.
Stepensky D, Chorny M, Dabour Z, Schumacher I. Long-term stability of L-adrenaline injections: kinetics of sulfonation and racemization pathways of drug degradation. J Pharm Sci 2004;93:969-80.
British Pharmacopoeia. British Pharmacopoeia Commission. London: TSO; 2018.
United States Pharmacopeia and National Formulary (USP42-NF37). United States Pharmacopeial Convention, Rockville (MD); 2019.
Milano EA, Sigmund M, Dirubio R. Aluminum catalysis of epinephrine degradation in lidocaine hydrochloride with epinephrine solutions. PDA J Pharm Sci Technol 1982;36:232-6.