Leaching of antioxidants and vulcanization accelerators from rubber closures into drug preparations

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Abstract
A thin-layer chromatographic method was used to highlight the leaching into drug preparations of several constituents of elastomeric closures. Among the 150 preparations analysed, the twenty-eight local anaesthetics presented in single-dose delivery syringe-cartridges, one Epinephrine injection in prefilled syringes, eight insulin preparations and two Prednisolone acetate suspensions in the form of small volume flasks (20ml) were contaminated by one or more of the following: 2-mercaptobenzothiazole (MBT), 2-mercaptobenzothiazole disulphide and 2-mercaptobenzimidazole (MBI). Prednisolone acetate suspensions also contained 2,2'-methylene-bis(4-methyl-6-α-methylcyclohexylphenol). No contamination was found in drug preparations presented in large volume flasks (250-1000 ml). 2-(2-Hydroxyethylthio)-benzothiazole was not present, which indicated that the rubbers had not been sterilized with ethylene oxide. Elastomeric parts of drug closures analysed in the same way contained the same compounds as those found in drugs, one case excepted, which confirms the origin of the contamination. The lowest and the highest concentrations were found in syringe-cartridges; they ranged from 8.3 to 13.8 μg ml-1 for MBT, from 2.9 to 9.3 μg ml-1 for MBTS and from 2.8 to 11.1μg ml-1 for MBI. Variable results were obtained, for a same preparation, depending upon the batches analysed, which indicates that rubber formulations and/or vulcanization conditions differed. The allergenic, toxic, embryotoxic and mutagenic properties of the compounds leached are discussed.

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