title: Structural characterization of low level degradants in aztreonam injection and an innovative approach to aid HPLC method validation.
abstract: Three new degradants have been identified from drug product and active pharmaceutical ingredient stability samples of aztreonam, a marketed synthetic monocyclic beta-lactam antibiotic. The degradants were detected following the implementation of a new, more selective HPLC method for the determination of impurities and degradants. The new method was developed in response to changes in the regulatory requirement for mature products. Two of the new unknown Degradants (I and II) were observed in chromatograms from stability samples of aztreonam injection. The third new Degradant (III) was observed during a stability study of the aztreonam active pharmaceutical ingredient. These degradants were structurally characterized. A small amount (ca. 1-3mg) of each degradant was isolated via preparative HPLC for structure elucidation using accurate MS, one and two-dimensional NMR spectroscopy. The small amount of each NMR sample was then reused as a standard for HPLC purity/impurity method validation. Their exact concentrations were determined using quantitative NMR which enabled the execution of the quantitative elements of the HPLC method validation. This innovative approach eliminated the need to isolate or synthesize larger quantities of markers for HPLC/UV method validation, thus saving significant time and reducing costs.
authors.affiliation: Analytical and Bioanalytical Development, Bristol-Myers Squibb Company, New Brunswick, NJ 08903, USA. Electronic address: qingmei.ye@bms.com.
authors.forename: Qingmei
authors.initials: Q
authors.lastname: Ye
authors.affiliation: Analytical and Bioanalytical Development, Bristol-Myers Squibb Company, New Brunswick, NJ 08903, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Ding
authors.affiliation: Analytical and Bioanalytical Development, Bristol-Myers Squibb Company, New Brunswick, NJ 08903, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Rinaldi
authors.affiliation: Analytical and Bioanalytical Development, Bristol-Myers Squibb Company, New Brunswick, NJ 08903, USA.
authors.forename: Yande
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Analytical and Bioanalytical Development, Bristol-Myers Squibb Company, New Brunswick, NJ 08903, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Miller
authors.affiliation: Analytical and Bioanalytical Development, Bristol-Myers Squibb Company, New Brunswick, NJ 08903, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Bolgar
mesh_terms: D001398:Aztreonam / Q000008:administration & dosage* / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D013058:Mass Spectrometry; D015394:Molecular Structure
chemical_list: D001398:Aztreonam
keywords: Aztreonam; Degradants; Identification; Quantitative NMR; Structure elucidation