Leachable diphenylguanidine from rubber closures used in pre-filled syringes: A case study to understand solid and solution interactions with oxytocin

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Leachables derived from multi-component drug-device syringe systems can result in changes to the quality of drug products. Diphenylguanidine (DPG), a leachable released from styrene butadiene rubber syringe plungers, interacts with Oxytocin to form protein-adducts. This study investigated the mechanism and kinetics of this interaction in both solid and solution states through in-vitro tests and spectroscopic methods For solid state interaction, the protein-adducts with DPG were characterized using SEM, XRD, DSC, FTIR, 13C ss NMR, and dissolution analysis. For solution state interaction, LC–HRMS was used to assess stability of Oxytocin solutions in presence of various concentrations of DPG at 25 °C and 40 °C for 4 weeks. Moreover, molecular docking analysis was used to identify possible molecular configurations of the interaction.Results were consistent with the formation of a new solid state with distorted surface morphology for oxytocin-DPG adducts, in which the oxytocin carbonyl group(s) and the secondary amine groups of DPG interact. This interaction was also confirmed by molecular docking analysis through hydrogen bonding (2.31 Å) and Van der Waal attraction (3.14 Å). Moreover, LC–HRMS analysis revealed an increase in Oxytocin stability and suppression of Oxytocin dimerization by DPG. A potential reduction in the rate of Oxytocin dissolution from the formed adducts was indicative of its strong association with DPG. Hence, the leaching potential of DPG from rubber closures and plungers should be monitored and controlled to maintain the quality and stability of the pharmaceutical product.

Graphical abstract

Docking configuration of Oxytocin dimers (A) and Oxytocin binding site with DPG (B). Red dots are water molecules oriented around Oxytocin dimer. Hydrogen bond interaction between carbonyl group of Cys (6) of Oxytocin and H atom of amino group of DPG is represented by dotted lines (For interpretation of the references to colour in this caption, the reader is referred to the web version of this article.).

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