The contamination of valsartan and other sartans, part 1: New findings

Sörgel, Fritz; Kinzig, Martina; Abdel‐Tawab, Mona; Bidmon, Clemens; Schreiber, André; Ermel, Steffen; Wohlfart, Jonas; Besa, Axel; Scherf‐Clavel, Maike; Holzgrabe, Ulrike

doi:10.1016/j.jpba.2019.05.022

Cited by 59 publications

(36 citation statements)

References 4 publications

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“…However, EI remains the most popular choice for GC-MS/MS, due to its ability of simultaneous identification by comparing the registered spectra with the spectra stored in the mass spectra library. Alternatively, The NA analysis can be performed using liquid chromatography on a reversed-phase column (mainly C8 or C18) using a combination of electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI) as ionization method used in a mass spectrometer [13]. However, in addition to chromatography and mass spectrometry, sample preparation is an important part of NAs analysis; in the case of GC, the injection method is also important.…”

Section: Discussionmentioning

confidence: 99%

“…However, various pitfalls of complex sample preparation steps have been reported in the analysis of NAs in various matrices. The combination of liquid-liquid extraction with CH 2 Cl 2 , which is the most popular extraction solvent for NAs, with splitless injection in GC appears to be the most frequently used in the case of analysis of sartans by Official Medicines Control Laboratories (OMCLs) [13]. A similar solution was also already used in the method originated from Singapore; however, sample preparation requires using 0.1 M solution of hydrochloric acid as a water phase [33].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, NDMA and other NAs, e.g., N-nitrosodiethylamine (NDEA), have been detected in several pharmaceuticals, including sartans (valsartan, losartan, and candesartan) and raniditine [12,13]. The detection of the NDMA impurity was incidental and happened while performing other tests [14].…”

Section: Introductionmentioning

confidence: 99%

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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%

Section: Discussionmentioning

confidence: 99%

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N-Nitrosodimethylamine Contamination in the Metformin Finished Products

2020

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“…Analysis by HPLC, GC-MS, and/or LC-MS/MS indicated unacceptable amounts of NDMA in some active pharmaceutical ingredients (APIs) and their drug products. [2][3][4][5] Interim criteria to control the levels of mutagenic impurities (e.g., NDMA and N-nitrosodiethylamine (NDEA)) were established on the basis of acceptable daily exposure limits to the particular compound and the drug's maximum daily dose, following the International Conference on Harmonisation (ICH) M7 guideline. 1,[6][7][8] Ranitidine and other H2-receptor antagonists (e.g., nizatidine) represent another group of pharmaceuticals with similar nitrosamine contamination issue.…”

Section: Introductionmentioning

confidence: 99%

Temperature-Dependent Formation of <i>N</i>-Nitrosodimethylamine during the Storage of Ranitidine Reagent Powders and Tablets

Abe¹,

Yamamoto²,

Yoshida³

et al. 2020

Chem. Pharm. Bull.

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The purpose of this study was to elucidate the effect of high-temperature storage on the stability of ranitidine, specifically with respect to the potential formation of N-nitrosodimethylamine (NDMA), which is classified as a probable human carcinogen. Commercially available ranitidine reagent powders and formulations were stored under various conditions, and subjected to LC-MS/MS analysis. When ranitidine tablets from two different brands (designated as tablet A and tablet B) were stored under accelerated condition (40 °C with 75% relative humidity), following the drug stability guidelines issued by the International Conference on Harmonisation (ICH-Q1A), for up to 8 weeks, the amount of NDMA in them substantially increased from 0.19 to 116 ppm and from 2.89 to 18 ppm, respectively. The formation of NDMA that exceeded the acceptable daily intake limit (0.32 ppm) at the temperature used under accelerated storage conditions clearly highlights the risk of NDMA formation in ranitidine formulations when extrapolated to storage under ambient conditions. A forced-degradation study under the stress condition (60 °C for 1 week) strongly suggested that environmental factors such as moisture and oxygen are involved in the formation of NDMA in ranitidine formulations. Storage of ranitidine tablets and reagent powders at the high temperatures also increased the amount of nitrite, which is considered one of the factors influencing NDMA formation. These data indicate the necessity of controlling/monitoring stability-related factors, in addition to controlling impurities during the manufacturing process, in order to mitigate nitrosamine-related health risks of certain pharmaceuticals.

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“…Many methods for the detection of nitrosamines (NAs) in raw materials and finished products of sartans and metformin have been reported, such as high‐performance liquid chromatography (HPLC), 8,9 LC‐tandem mass spectrometry (MS/MS), 10–13 LC‐high resolution MS, 14,15 direct injection (DI) gas chromatography–mass spectrometry (GC–MS), 16–18 headspace GC–MS, 19–21 and GC‐HR MS 22 . Several researchers have reported a DI‐GC–MS/MS method 23 .…”

Section: Introductionmentioning

confidence: 99%

Determination of N‐Nitrosodimethylamine and N‐Nitrosodiethylamine in Sartans and Metformin Raw Materials and Finished Products by Headspace Gas Chromatography‐Tandem Mass Spectrometry

Lim

Oh²,

Shin

2020

Bulletin Korean Chem Soc

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A simple and sensitive headspace (HS) and gas chromatography-isotope dilution tandem mass spectrometric method was studied to determine N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) in sartans and metformin raw materials and their finished products. The HS parameters were optimized and selected. Samples in headspace vial were extracted at 150 C for 15 min and analyzed by injecting 1.0 mL of the headspace into the gas chromatography-mass spectrometry (GC-MS)/MS system. The mass spectrometer was operated using the electrospray ionization and detection was performed in a multiple reaction monitoring mode. Under the established condition, the lower limits of detection was 0.4 μg/kg for NDMA and 0.1 μg/kg for NDEA by using 0.1 g of sample. The precision was in the range of 0.4-3.5% for NDMA, and 0.4-3.3% for NDEA, and the accuracy was in the range of 95.0-105% for NDMA and 93.6-103% for NDEA, respectively. The linear equation of the calibration curve is y = 0.0120x − 0.0202 (4.0-1080 μg/kg, r = 1.000) for NDMA, and y = 0.0144x − 0.0042 (0.5-288 μg/ kg, r = 1.000) for NDEA. The developed method can be applied to all six sartans and one metformin raw materials and their finished products.

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The contamination of valsartan and other sartans, part 1: New findings

Cited by 59 publications

References 4 publications

N-Nitrosodimethylamine Contamination in the Metformin Finished Products

N-Nitrosodimethylamine Contamination in the Metformin Finished Products

Temperature-Dependent Formation of <i>N</i>-Nitrosodimethylamine during the Storage of Ranitidine Reagent Powders and Tablets

Determination of N‐Nitrosodimethylamine and N‐Nitrosodiethylamine in Sartans and Metformin Raw Materials and Finished Products by Headspace Gas Chromatography‐Tandem Mass Spectrometry

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