High-performance liquid chromatographic determination of d-/l-epinephrine enantiomer ratio in lidocaine-epinephrine local anesthetics.
A procedure for the determination of the ratio of d- to l-epinephrine in lidocaine-epinephrine local anesthetics is described. Epinephrine was isolated via Sep-Pak cartridges and derivatized with 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl isothiocyanate; the d- and l-chiral derivatives were separated and measured by high-performance liquid chromatography. About 70 samples of various dosage forms and concentrations from four manufacturers were successfully analyzed by the method.
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.
Reaction of amino acids with D-glycosyl- and D-gluconyl isothiocyanates.
Reaction of glycosyl isothiocyanate (1a) with amino acids such as ethyl L-phenylalaninate hydrochloride, ethyl L-leucinate hydrochloride and ethyl β-alaninate hydrochloride afforded glycosyl thioureides (3a. b, c) in good yields. Reaction of D-gluconyl isothiocyanate (1c) with amino acids (glycine, β-alanine, γ-aminobutyric acid, e-aminocaproic acid) or p-aminobenzoic acid gave the corresponding D-gluconamides (4a, b, c, d) and/or D-gluconyl thioureides (5a, b, 7, 8). Treatment of 1a, b, c with 6-aminopenicillanic acid (6-APA) or ampicillin in the presence of triethylamine gave triethylammonium 6-(substituted thioureido) penicillanates (9a, b, c) and triethylammonium 6-(D-glycosyl thioureido) benzylpenicillanates (10a, b). The reaction between 1c and phenacyl 6-APA afforded phenacyl 6-(D-gluconyl thioureido) penicillanate (9d).