Degradation of a Lyophilized Formulation of BMS-204352: Identification of Degradants and Role of Elastomeric Closures

Abstract

The purpose of this study was to identify two degradation products formed in the parenteral lyophilized formulation of BMS-204352, investigate the possible role of elastomeric closures in their formation, and develop a strategy to minimize/control their formation. The first degradant was identified as the hydroxymethyl derivative (formaldehyde adduct, BMS-215842) of the drug substance formed by the reaction of BMS-204352 with formaldehyde. Structure confirmation was based on liquid chromatography/mass spectroscopy (LC/MS), nuclear magnetic resonance (NMR), and chromatographic comparison to an authentic sample of the hydroxymethyl degradation product, BMS-215842. To confirm the hypothesis that formaldehyde originated from the rubber closure, migrated into the product, and reacted with BMS-204352 drug substance to form the hydroxymethyl degradant, lyophilized drug product was manufactured, the vials were stoppered with two different rubber closure formulations, and its stability was monitored. The formaldehyde adduct degradant was observed only in the drug product vials stoppered with one of the rubber closures that was evaluated. Although formaldehyde has not been detected historically as leachable and is not an added ingredient in the rubber formulation, information obtained from the stopper manufacturer indicated that the reinforcing agent used in the stopper formulation may be a potential source of formaldehyde. The second degradant was identified as the desfluoro hydroxy analog (BMS-188929) based on LC/MS, NMR, and chromatographic comparison to an authentic sample of the desfluoro hydroxy degradation product.