Determination of N-nitrosodimethylamine and N-nitrosomethylethylamine in drug substances and products of sartans, metformin and ranitidine by precipitation and solid phase extraction and gas chromatography–tandem mass spectrometry

Lim, Hyun‐Hee; Oh, Yun‐Suk; Shin, Ho‐Sang

doi:10.1016/j.jpba.2020.113460

Cited by 64 publications

(35 citation statements)

References 8 publications

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“…Analysis of NAs requires very low detection limits, and therefore, the use of mass spectrometry, preferably with the MS/MS mode, is the obvious choice. The ionization sources previously used in the analysis of NAs include electron impact (EI) with MS/MS mode [22,23] and high-resolution mass spectrometry (HRMS) [24] with positive chemical ionization (PCI) using methanol [25], acetonitrile [26], ammonia [27], or methane [21] as the reagent gas. CI has been shown to yield better specificity than that of EI and CI, thus provides higher sensitivity in the NAs analysis [28].…”

Section: Discussionmentioning

confidence: 99%

N-Nitrosodimethylamine Contamination in the Metformin Finished Products

2020

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A GC–MS/MS method with EI ionization was developed and validated to detect and quantify N-nitrosodimethylamine (NDMA) and seven other nitrosamines in 105 samples of metformin tablets from 13 different manufactures. Good linearity for each compound was demonstrated over the calibration range of 0.5–9.5 ng/mL. The assay for all substances was accurate and precise. NDMA was not detected in the acquired active pharmaceutical ingredient (API); however, NDMA was detected in 64 (85.3%) and 22 (91.7%) of the finished product and prolonged finished product samples, respectively. European Medicines Agency recommends the maximum allowed limit of 0.032 ppm in the metformin products. Hence, 28 finished products and 7 pronged dosage products were found to exceed the acceptable limit of daily intake of NDMA contamination. The implications of our findings for the testing of pharmaceutical products are discussed.

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Section: Discussionmentioning

confidence: 99%

N-Nitrosodimethylamine Contamination in the Metformin Finished Products

2020

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“…However in some of the samples, the US-FDA failed to detect inappropriate NDMA levels, they found that the contamination of some ranitidine products increased over the course of the time, when stored at higher room temperatures. As a consequence, ranitidine products are banned for use in the US (Lim et al, 2020). NDMA (a cancer causative agent) is a possible human carcinogen, and low NDMA levels are normally consumed in diets.…”

Section: History Of Ranitidine Associated Toxicitymentioning

confidence: 99%

Ranitidine Induced Hepatotoxicity: A Review

Bedi

Banerjee

Singh

et al. 2020

JPTRM

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Background: Ranitidine (RAN) is one of the common drugs associated with idiosyncratic adverse drug reactions (IADRs) in humans. It was found to be associated with severe adverse drug reactions due to the presence of contaminants such as N-Nitrosodimethylamine (NDMA) which is claimed to be carcinogenic. As a consequence, on April 1, 2020, United States Food and Drug Administration (USFDA) had decided to call off all the RAN products from the market. The exact cause of RAN associated idiosyncratic hepatotoxicity is not clear yet. Purpose: To summarize and analyze the reason behind the withdrawal of RAN products from the market and whether ranitidine will be available again in future or will FDA withdraw approvals of ranitidine National Drug Authority (NDA) and an abbreviated new drug application (ANDA)? Methods: We performed a systematic PubMed/MEDLINE search of studies investigating the reason behind the withdrawal of RAN products and explored the possible mechanism associated with RAN induced hepatotoxicity.Conclusion: RAN induced liver injury is difficult to diagnose and study because of its relative rarity and unpredictive occurrence. Recent studies suggest that most of the RAN associated idiosyncratic reactions may lead to hepatocyte damage, followed by a series of events, such as activation of specific T- and B-cells, release of proinflammatory mediators like TNFα, interleukins, various cytokines and chemokines. The exact cause of RAN associated idiosyncratic hepatotoxicity is not clear yet. More studies must be carried out on this to know about the exact reason behind RAN associated hepatotoxicity.

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“…The control of potentially mutagenic impurities is a key focus of pharmaceutical development. Recent detection of nitrosamines in multiple marketed pharmaceuticals, both over the counter and prescribed, has resulted in enhanced scrutiny by global regulatory authorities of the control measures for this class of compounds 1–6 . Risk assessments for all commercial products and new market authorization applications are now required specifically for nitrosamine impurities 7,8 .…”

Section: Introductionmentioning

confidence: 99%

“…Recent detection of nitrosamines in multiple marketed pharmaceuticals, both over the counter and prescribed, has resulted in enhanced scrutiny by global regulatory authorities of the control measures for this class of compounds. [1][2][3][4][5][6] Risk assessments for all commercial products and new market authorization applications are now required specifically for nitrosamine impurities. 7,8 If a scientific justification cannot support the absence of these compounds, then testing must be done to demonstrate their absence.…”

Section: Introductionmentioning

confidence: 99%

Mass spectrometry based fragmentation patterns of nitrosamine compounds

Asare

Hoskins

Blessing

et al. 2022

Rapid Comm Mass Spectrometry

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Rationale Nitrosamines are a class of mutagenic substances that can display high carcinogenic potential. New chemical entities may have the potential to form unique nitrosamines specific to the drug substance. It is therefore essential to understand the gas‐phase fragmentation behavior of nitrosamine compounds to enable the development of analytical methods to characterize novel nitrosamine compounds. Methods The gas‐phase fragmentation behavior of eight model nitrosamine compounds representing the common substructures seen in many small molecule pharmaceutical compounds was studied with positive electrospray ionization tandem mass spectrometry (ESI‐MS/MS). The fragmentation patterns of these compounds under various collision parameters available in commercially available mass spectrometers were studied. Results Protonated nitrosamine compounds produced diagnostic fragment ions upon MS/MS. Three primary structure‐dependent fragmentation pathways were observed. The first pathway involves the loss of 30 Da which corresponds to the loss of the NO radical from the protonated nitrosamine compound (Group 1). The second and third fragmentation pathways, which have not been reported for nitrosamine compounds, proceed via the loss of H2O from the protonated nitrosamine compound (Group 2), and elimination and a loss of 46 Da (loss of NH2NO) from the nitrosamine compound (Group 3). Conclusions Results presented in this work provide an overview of the gas‐phase fragmentation patterns of nitrosamine compounds and may be useful in identifying novel nitrosamine compounds in complex matrices.

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Determination of N-nitrosodimethylamine and N-nitrosomethylethylamine in drug substances and products of sartans, metformin and ranitidine by precipitation and solid phase extraction and gas chromatography–tandem mass spectrometry

Cited by 64 publications

References 8 publications

N-Nitrosodimethylamine Contamination in the Metformin Finished Products

N-Nitrosodimethylamine Contamination in the Metformin Finished Products

Ranitidine Induced Hepatotoxicity: A Review

Mass spectrometry based fragmentation patterns of nitrosamine compounds

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