Quantitative Analysis and Risk Assessment of 3 Thiuram Vulcanization Accelerators in Pharmaceutical Elastomeric Seals

A method for the simultaneous determination of tetramethylthiuram disulfide (TMTD), tetraethyl thiuram disulfide (TETD)and tetrabutylthiuram disulfide(TBTD) in pharmaceutical elastomeric seals by ultra-high performance liquid chromatography-tandem mass spectrometry was proposed, and risk assessment was conducted on whether they could react with nitrite to form N-nitrosamine carcinogens. The cut pharmaceutical elastomeric seal sample (1.00 g) was taken, and 10 mL of methanol was added for ultrasonic extraction for 40 min. The extract and methanol washing solution were combined and filtered by 0.45 μm microporous filter membrane, and TMTD, TETD and TBTD in the filtrate were determined by ultra-high performance liquid chromatography-triple quadrupole mass spectrometer. Gradient elution was performed on Eclipsepluse C₁₈ column as the stationary phase and 0.1% (volume fraction) formic acid solution-methanol system as the mobile phase. Electrospray ion source with positive ion mode and multiple reaction monitoring mode were used for mass spectrometry analysis, and external standard method was used for quantitative determination. It was shown that linear relationships between the mass concentrations and the peak areas of 3 thiuram vulcanization accelerators were kept in definite ranges, with detection limits (3S/N) in the range of 0.02-0.03 mg·kg^-1. Test for recovery was made on the negative sample by the standard addition method, giving results in the range of 80.9%-103%, with RSDs (n=6) of the determined values ranged from 2.4% to 6.3%. The method was used to analyze 6 batches of actual samples, in which TETD was detected in 3 batches of samples, with detected amounts in the range of 1.86-2.55 mg·kg^-1, and TMTD and TBTD were not detected. The above 3 batches of positive sample extracts were reacted with sodium nitrite solution under acidic condition, and the detected amounts of N-nitrosodiethylamine were in the range of 0.019 0-0.020 1 mg·kg^-1, which did not meet the regulatory requirements, indicating that the risk of N-nitrosamines produced in pharmaceutical elastomeric seals was high.