title: Strategy for identification of leachables in packaged pharmaceutical liquid formulations.
abstract: Drug stability is one of the key properties to be monitored in pharmaceutical drug development. Drug degradation products, impurities and/or leachables from the drug product and packages may have significant impacts on drug efficacy, safety profile and storage conditions. In the registration stability samples of an ophthalmic pharmaceutical drug product, an unknown compound was found at a level of 0.19% by HPLC analysis. Subsequent liquid chromatography/mass spectrometry (LC/MS) analysis with electrospray ionization (ESI) indicated that the unknown was not related to the drug substance and was most likely a leachable. Identification of this unknown leachable was needed to evaluate the impact on drug safety. Through systematic extraction of various components or component combination of the packaging materials, and subsequently LC/MS analysis, the unknown was found to be a leachable coming from the varnish applied to the label. In general, using LC/MS alone is not sufficient to elucidate the structure of a complete unknown. Gas chromatography/mass spectrometry (GC/MS) was then conducted with a chemical ionization (CI) source to determine the retention time and mass of the compound of interest. Both CI and ESI sources generated the same protonated molecular ion [M+H] and similar fragmentation ions, which provides a good correlation of the unknown eluted in the liquid chromatogram and in the gas chromatogram. GC/MS with electron impact (EI) was then conducted to obtain the EI mass spectrum of this unknown. It was identified as monomethyl derivative of mephenesin through the NIST library search. The identification strategy utilized electrospray LC/MS and GC/MS with chemical and electron ionization sources which provided complimentary information for structure elucidation of this unknown compound. This combination approach in conjunction with systematic extraction was necessary for the determination of the source of this unknown in the pharmaceutical drug stability studies.
authors.affiliation: Pharmaceutical and Analytical Development, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936, USA. charles.pan@novartis.com
authors.forename: Changkang
authors.initials: C
authors.lastname: Pan
authors.forename: Ferris
authors.initials: F
authors.lastname: Harmon
authors.forename: Karen
authors.initials: K
authors.lastname: Toscano
authors.forename: Frances
authors.initials: F
authors.lastname: Liu
authors.forename: Richard
authors.initials: R
authors.lastname: Vivilecchia
mesh_terms: D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D004340:Drug Contamination; D004349:Drug Packaging; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods*; D012996:Solutions; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*
chemical_list: D012996:Solutions