title: Identification by LC/MS(n) of degradates of a novel carbapenem antibiotic in an aqueous matrix.
abstract: Increased drug resistance in Staphylcocci and Enterococci to currently available antibiotics has significantly limited therapeutic options. Recently, a novel carbapenem antibiotic (Compound A) with a releasable side chain adjacent to the carbapenem was investigated to combat methicillin- and vancomycin-resistant Staphylococci and vancomycin-resistant Enterococci. The major advantage of Compound A over existing antibiotics can be attributed to the fact that cleavage of the side chain upon beta-lactam ring opening retained anti-bacterial activity while expelling the immunodominant epitope of the presumed beta-lactam hapten. In this work, LC/MS methods were developed to identify degradates of Compound A in an aqueous matrix utilized in assessing product safety and supporting analytical method and formulation development. A total of eight significant degradates were observed in this Compound A sample by LC/MS(n) and other techniques. Detailed structural analysis of degradates based upon LC/MS(n) data and other supporting results will be described in this work. Proposed molecular structures were confirmed by synthesis and use of authentic standards for several degradates. Degradates 1 and 4 were identified as degradates formed through the reversal of Michael reaction from Degradate 3 that is apparently formed by hydrolysis. Degradates 2 and 8 were found to be Hofmann elimination degradates. Degradates 5 and 6 are believed to be formed through dimerization of two parent molecules followed by the reversal of Michael reaction. Finally, Degradate 7 is attributed to a displacement reaction. Potential degradation pathways based upon these preliminary studies will also be discussed.
authors.affiliation: Merck Research Laboratories, WP78-210, West Point, PA 19486, USA. zack_zhao@merck.com
authors.forename: Zhongxi Zack
authors.initials: ZZ
authors.lastname: Zhao
authors.forename: Xue Zhi
authors.initials: XZ
authors.lastname: Qin
authors.forename: Robert A
authors.initials: RA
authors.lastname: Reed
mesh_terms: D015780:Carbapenems / Q000032:analysis* / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D013058:Mass Spectrometry / Q000379:methods*
chemical_list: D015780:Carbapenems