Determination of N,N-dimethylaminoethyl chloride and the dimethylaziridinium ion at sub-ppm levels in diltiazem hydrochloride by LC-MS with electrospray ionisation

Abstract

An LC-MS method is described for the determination of the synthetic reagent N,N-dimethylaminoethyl chloride (DMC) in the drug substance diltiazem hydrochloride, for which the permissible limit is not more than 1 ppm (microgram g-1). The N,N-dimethylaziridinium ion (DMA), the reactive intermediate formed by cyclisation of DMC, is also detected. A column switching arrangement is used: diltiazem hydrochloride is trapped on a reversed-phase HPLC column, and the polar analytes are separated by ion exchange chromatography. Ionisation is effected by positive-ion electrospray, and the quadrupole filter mass spectrometer is operated in the selected ion recording mode. The detection limit (peak height-to-baseline noise ratio = 3) for DMC varies from day to day in the range < 0.05 to 0.1 ppm. The response for DMC is linear (r > 0.999) over the concentration range 0.2-10 ppm, and the repeatability is better than 7% (relative standard deviation) at 1.0 ppm. Concentrations of DMC in diltiazem hydrochloride from the manufacturing facility under study ranged from undetectable to about 0.07 ppm. An indirect TLC method has been published for the determination of DMC in mepyramine maleate, but it lacks the necessary sensitivity and specificity. The LC-MS method presented is direct, straightforward and suitable for routine use.

Identification of unknown impurities in simvastatin substance and tablets by liquid chromatography/tandem mass spectrometry

“…Peaks were tracked by comparing the peak areas, retention times and UV spectra of separated components, but the final confirmation of compound identity was achieved by the column-switching technique. This technique is basically described as a collection of mobile phase zone containing the unknown impurity peak, after passing through a UV (DAD) detector cell, in a holding loop, which will act as an injection loop on another LC system with MS compatible mobile phase [8,17]. After adjustment of all chromatographic parameters and optimisation of ESI-MS conditions to achieve the satisfactory sensitivity of the method (the obtained detection limit was around 400 pg of simvastatin injected on-column), the focus was on the evaluation and interpretation of the results obtained from various MS and MS/MS experiments, designed according to a specific analytical goal.…”

Determination of polar alkylating agents

“…A carcinogenic analogue of mustine is an intermediate in the synthesis of diltiazem hydrochloride [7,8], and questions have been raised about this on several occasions. Regulatory authorities have 1 A trivial but telling example is the notion that scientists are not expected to know how to convert between the (admittedly non-standard) concentration units of % and ppm [2,10].…”

“…The article in question [1] is one of several written by the team I worked with [6][7][8][9] which could, in retrospect, be considered inconvenient for the current position of industry representatives [10] with respect to a regulatory initiative on genotoxic impurities dating from 2004. Our contributions tend to contradict notions and attitudes frequently expressed or implied since 2004, for example that the regulatory authorities were not previously preoccupied by the subject of genotoxic impurities, that retrospective studies of existing products should not normally be required, and that the determination of analyte concentrations as high as 1 g g −1 presents a significant analytical challenge (a proposition that may surprise readers of the bioanalytical section of this journal).…”

Identification, control strategies, and analytical approaches for the determination of potential genotoxic impurities in pharmaceuticals: A comprehensive review

“…Strong acid–base interactions during the process of drug salt formation produce alkylating agents such as alkyl halides and alkyl esters of alkyl sulfonic acids. As the salt formation is a common method in drug formulation processes, alkyl halides exist as impurities in several drug substances and leads to mutagenicity . The nucleophilic attack mechanisms of alkylating compounds determine their reactivity against DNA .…”