Abstract
N -nitrosodimethylamine (NDMA) contamination in several drugs has been reported since 2018, and there is also a potential risk of the NDMA contamination in various other drug substances and their pharmaceutical products. To quantitate NDMA in various drugs having diverse physicochemical properties, a specific, sensitive and durable analytical method is required, in addition to methods that can be applied to a class of nitrosamines. We aimed to develop an off-line isolation method for NDMA in drug substances using solid-phase extraction (SPE) for quantification using high-performance liquid chromatography (HPLC)–atmospheric pressure chemical ionization (APCI)–tandem mass spectrometry (MS/MS).Impediments to accurate quantitation of NDMA in drug substances using LC–MS/MS and insufficient durability of the system is due to the extremely large amounts (≈ 10 8 times) of active pharmaceutical ingredients (APIs) in sample solutions in comparison to the trace amount of NDMA. It is occasionally possible to encounter a reduced retention of NDMA and/or decreased separation from other substances in LC, matrix effect in MS detection, and undesirable contamination of instruments with API and other substances, which consequently results in deterioration of system performance and generation of unreliable data even in the cases where divert valve is configured between the column and ion source of the MS instrument.To address the problems, an off-line isolation methodology for NDMA from APIs having diverse physicochemical properties, namely ranitidine hydrochloride (ranitidine), metformin hydrochloride (metformin), nizatidine, valsartan, and telmisartan , was developed. The applicability of the method was confirmed by batch analysis of metformin and ranitidine. Furthermore, contrary to previous reports, NDMA was found to be stable over a wide pH range. The methodology and information would contribute the control of NDMA concentration in various drugs to realize the safe delivery of pharmaceuticals to patients.
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