title: Compatibility study of a parenteral microdose polyethylene glycol formulation in medical devices and identification of degradation impurity by 2D-LC/MS.
abstract: Polyethylene glycol (PEG) based formulation and polyvinylchloride (PVC) tubing are frequently used for drug delivery and administration. The compatibility of a parenteral drug microdose formulation in intravenous infusion (IV) devices was studied to support the clinical determination of absolute bioavailability by the microdosing method. The investigational microdose formulation containing PEG was found prone to significant loss of potency within hours of storage in the PVC IV tubing due to degradation. Degradation occurred only when both PEG and PVC tubing were present. The degradation product could not be detected by LC/MS due to the significant interference from the high concentration of PEG (4%) matrix and the extremely low level of drug (0.6ppm). To obtain structural information of the degradation impurity and understand the cause of the degradation, a simple heart-cutting 2D-LC/MS approach was utilized to effectively separate the impurity from the complex PEG oligomers and overcome the matrix interference, enabling mass spectrometric analysis of the impurity. An oxidation- dominated mechanism was proposed in which the combination of PEG auto-oxidation and dehydrochlorination of the PVC tubing yielded an oxidative environment that enhanced radical propagation and accelerated degradation of the investigational parent drug.
authors.affiliation: Small Molecule Pharmaceutical Sciences, Genentech, 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Lulu
authors.initials: L
authors.lastname: Dai
authors.affiliation: Small Molecule Pharmaceutical Sciences, Genentech, 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Geoffrey K
authors.initials: GK
authors.lastname: Yeh
authors.affiliation: Small Molecule Pharmaceutical Sciences, Genentech, 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Yingqing
authors.initials: Y
authors.lastname: Ran
authors.affiliation: Small Molecule Pharmaceutical Sciences, Genentech, 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Yehl
authors.affiliation: Small Molecule Pharmaceutical Sciences, Genentech, 1 DNA Way, South San Francisco, CA 94080, United States. Electronic address: zhang.kelly@gene.com.
authors.forename: Kelly
authors.initials: K
authors.lastname: Zhang
mesh_terms: D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002853:Chromatography, Liquid; D004340:Drug Contamination / Q000517:prevention & control; D004355:Drug Stability; D013058:Mass Spectrometry / Q000379:methods; D010084:Oxidation-Reduction; D004364:Pharmaceutical Preparations / Q000032:analysis* / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*
chemical_list: D004364:Pharmaceutical Preparations; D011092:Polyethylene Glycols
keywords: 2D-LC/MS; Compatibility; Impurity identification; Microdosing; Polyethylene glycol (PEG)