Long-term stability study of L-adrenaline injections: Kinetics of sulfonation and racemization pathways of drug degradation.
Injectable formulations of L-adrenaline are commonly used in emergency medicine. Despite numerous studies, the comparative contribution and kinetics of the L-adrenaline inactivation pathways during storage have not been conclusively evaluated. We examined the kinetics of L-adrenaline degradation in a prospective study and determined the extent of drug inactivation by different pathways during and beyond the stipulated product shelf-life in 42 batches of adrenaline ampules stored under controlled conditions. The content of L-adrenaline and degradation products was determined with a chiral high-performance liquid chromatography (HPLC) assay, and the degradation products were identified by mass spectrometric detection as D-adrenaline and L- and D-adrenaline sulfonate. The kinetics of the content change with storage was analyzed simultaneously for L-adrenaline and the degradation products using kinetic modeling. The lower acceptable level of adrenaline content in the formulation stated by US Pharmacopoeia (90% as a sum of L- and D-isomers) was attained after 2.0 years of storage, at which time the content of the therapeutically active L-isomer amounted to as low as 85%. The modeling revealed significant differences in the degradation kinetics in the formulations produced before and after 1997, whose cause remained unidentified in this study.
Stepensky
David
D
Research & Quality Control Laboratory, The Medical Corps, Mil. P.O. Box 02149, Israel Defense Forces, Israel Defense Forces, Israel.
Chorny
Michael
M
Dabour
Ziad
Z
Schumacher
Ilana
I
D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000737:chemistry*; D000465:Algorithms; D000535:Aluminum / Q000032:analysis; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D004837:Epinephrine / Q000008:administration & dosage / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007202:Indicators and Reagents; D007267:Injections; D007700:Kinetics; D013058:Mass Spectrometry; D008956:Models, Chemical; D019999:Pharmaceutical Solutions; D015203:Reproducibility of Results; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism; D013451:Sulfonic Acids / Q000737:chemistry
D000316:Adrenergic alpha-Agonists; D007202:Indicators and Reagents; D019999:Pharmaceutical Solutions; D013451:Sulfonic Acids; D000535:Aluminum; D004837:Epinephrine