Determination of 3-quinuclidinyl benzilate impurity in clidinium bromide by thin-layer chromatography and single ion monitoring after gas chromatography mass spectrometry

Article abstract of DOI:10.1002/bms.1200060702

A simple gas chromatographic mass spectrometric determination of the impurity 3-quinuclidinyl benzilate in the anticholinergic agent clidinium bromide (3-hydroxy-1-methylquinuclidinium bromide benzilate) is not feasible because clidinium bromide decomposes to 3-quinuclidinyl benzilate in the injection port of the gas chromatograph; the trimethylsilyl derivative of clidinium bromide also decomposes to the trimethylsilyl derivative of 3-quinuclidinyl benzilate. Therefore, a quantitative thin-layer chromatographic gas chromatographic mass spectrometric method has been developed for determining 3-quinuclidinyl benzilate in clidinium bromide, using β-piperidylethyl benzilate as an internal standard. A band containing only 3-quinuclidinyl benzilate and β-piperidylethyl benzilate can be eluted from the thin-layer chromatographic plate. The samples are analyzed by single ion monitoring of m/z 255 produced by the trimethylsilyl derivatives of 3-quinuclidinyl benzilate and β-piperidylethyl benzilate which are separated by gas chromatography. A level of 0.03% of 3-quinuclidinyl benzilate can be determined with a precision of about 6%; the lower limit of detection of 3-quinuclidinyl benzilate alone is about 1 ng on the thin-layer chromatographic plate. Analysis of a reference standard of clidinium bromide by the thin-layer chromatographic gas chromatographic mass spectrometric procedure showed that it contained no detectable 3-quinuclidinyl benzilate. One commercial bulk sample of clidinium bromide contained about 0.018% of 3-quinuclidinyl benzilate, while a formulated sample of clidinium bromide contained no detectable 3-quinuclidinyl benzilate. Commercial samples of clidinium bromide containing chlordiazepoxide can be analyzed for 3-quinuclidinyl benzilate only with difficulty using this method.