N-Nitrosodimethylamine Contamination in the Metformin Finished Products (original) (raw)
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N-nitrosodimethylamine (NDMA) and the industrial solvent, N,N-dimethylformamide (DMF), are both probable human carcinogens that have been detected in pharmaceutical drug products like metformin, which is used to treat type II diabetes. Some lots of metformin drug products have exceeded the United States Food and Drug Administration (FDA) daily allowable intake limit for NDMA, while the presence of DMF has been detected at several orders of magnitude higher than NDMA. A recent study found that a low abundance isotope of DMF interferes with NDMA quantification by using a unique subset of LC-MS instruments capable of high mass resolution. In this study, an LC-HRMS method is developed that chromatographically separates NDMA from DMF in metformin drug products to eliminate interference. The method can detect nitrosamines and DMF under the current regulatory guidance for industry and provides a solution for simultaneously quantifying nitrosamines and DMF for a broad range of LC-MS instrum...
NDMA analytics in metformin products: Comparison of methods and pitfalls
2022
Background: For nearly three years, the concerns regarding trace levels of N-nitrosamines in pharmaceuticals and the associated cancer risk have significantly expanded and are a major issue facing the global pharmaceutical industry. N-nitrosodimethylamine (NDMA) found in formulations of the popular anti-diabetic drug metformin is a prominent example. This has resulted in product recalls raising the profile within the media. Issues of method robustness, sample preparation and several unexpected sources of nitrosamine contamination have been highlighted as false positive risks. It has become apparent that the identification of the root causes of artefactual formation of nitrosamines must be identified to mitigate risk associated with the analysis. Methods: A comparison study between four laboratories, across three companies was designed, employing orthogonal mass spectrometric methods for the quantification of NDMA in two metformin immediate release (IR) formulations and one extended release (XR) formulation. These were 2x LC-MS/MS, GC-MS/MS and GC-HRMS. Results: Good agreement of results was obtained for the IR formulations. However, we measured higher concentrations of NDMA in the XR formulation using GC-MS/MS compared to LC-MS/MS. We could show that this was due to artefactual (in situ) formation of NDMA when samples were extracted with dichloromethane. Removal of dimethylamine (DMA) and nitrite from the extracted sample or the addition of a nitrosation scavenger are shown to be effective remedies. NDMA in situ formation was not observed in 10% MeOH or acetonitrile. Conclusion: Metformin pharmaceuticals contain traces of the API impurity DMA as well as inorganic nitrite from excipients. This can lead to artefactual formation of NDMA and hence false positive results if DCM is used for sample extraction. Similar artefacts are likely also in other pharmaceuticals if these contain the secondary amine precursor of the respective nitrosamine analyte.
Presence of nitrosamine impurities in medicinal products
Archives of Industrial Hygiene and Toxicology, 2021
In 2018, some sartan medicinal products were reported to be contaminated with nitrosamine compounds, which are potent mutagenic carcinogens. Two nitrosamines received particular attention: N -nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA). These have since been confirmed in different types of medicinal products, including ranitidine and metformin. Consequently, the European Medicines Agency (EMA) started an investigation into the cause of contamination and an assessment of the risk to patients taking contaminated medicinal products. The main source of contamination were changes in production, which involves combinations of amines and nitrogen compounds and the use of specific catalysts and reagents. Withdrawals of medicinal products that took place in Croatia did not lead to a shortage of sartan- or metformin-containing medicines. Moreover, ranitidine had been preventively withdrawn all over the EU, including Croatia, creating shortages at the time, but was subsequentl...
NAVIGATING NITROSAMINES: ORIGIN, DETECTING, ANALYSING AND REGULATING IMPURITIES IN PHARMACEUTICALS
International Journal of Applied Pharmaceutics, 2024
N-nitrosamines are carcinogenic impurities mostly found in groundwater, treated water, foods, beverages, and consumer products like processed meats, alcoholic beverages, cosmetics, and cigarette smoke. The recent discovery of N-nitrosamines in pharmaceutical products and subsequent recalls pose a significant health risk to patients. Nitrosamine impurities in drug products have appeared as a critical concern in pharmaceuticals prompting extensive scrutiny from regulatory agencies and stakeholders. To avoid carcinogenic and mutagenic effects in patients relying on these medications, authorities have established specific guidelines in risk assessment scenarios and proposed control acceptable limits for nitrosamine impurities in pharmaceuticals. This review provides an information on historical background of Nitrosamine impurities; its carcinogenic effect; the sources and formation of impurities; associated risks of nitrosamines in drug formulations; different analytical techniques for nitrosamine detection. It also gives an understanding of the general Quality Risk management (QRM) process, techniques for measuring nitrosamine impurities with control strategies as directed by the regulatory authorities and how to avoid them in pharmaceutical drug products. A brief review on recalls of drug classes including angiotensin II receptor antagonists, histamine-2 receptor antagonists, antimicrobial agents, and antidiabetic drugs by regulatory bodies due to its potential harm produced by nitrosamine have been discussed. Moreover, the regulatory landscape governing nitrosamine impurities are explored, encompassing recent guidelines from major regulatory bodies such as the United States Food and Drug Administration (USFDA), European Medicines Agency (EMA) and Health Canada (HC) in controlling/eliminating the nitrosamine impurities in pharmaceuticals.
Chemical Science Transactions, 2014
A novel method to identify the metformin with a good selectivity has been established by using sodium nitroprusside as a chromogenic reagent. The experiment indicates that in basic solution sodium nitroprusside can react with the oxidized product (obtained by the action of sodium hypochlorite) of metformin to form a green colored 1, 3 dinitrosyl-N'-(iminomethyl)-N, N-dimethyl formamidine with maximum absorption at 680 nm. The test when compared with blank is sensitive for spectrophotometric detection of metformin up to 16.56 g in 10 mL solution. The reaction stoichiometric ratio of the oxidized product of metformin to sodium nitroprusside is 1:2. The reaction mechanism of the green product is discussed in present investigation. The proposed method has been successfully applied for identification of metformin in aqueous solution containing glibenclamide, glimepiride, glipizide and gliclazide. Because of the dissociative nature of the green colored product, for a large linear range of microgram concentration of metformin the absorbance of the green colored product is not found to be linear. Hence it can concluded from this analysis that sodium nitroprusside is not suitable chromogenic reagent for spectrophotometric determination of metformin in aqueous solution.
Nitrosamine Impurities in Drug Substances and Drug Products
Journal of Advances in Pharmacy Practices, 2020
Nitrosamine impurities are known to be mutagenic and carcinogenic, very small exposure of these impurities can lead to cancer. These impurities may be formed and get incorporated into drug substance or drug product through reagent, catalyst, solvent or raw materials used in the process of manufacturing. The various regulatory authority has published the press release or notice regarding the control of these impurities with the interim limit. Nitrosamine impurities can be avoided by taking precaution in the manufacturing of drug substance and drug products. Validated analytical methods are to be used to identify and quantify these impurities hence it needs highly sensitive instrument which can detect these impurities to the trace level at given interim limit. Liquid chromatography or Gas chromatography, along with mass detector is majorly used for their determination.
Chemical Science Transactions, 2015
A fixed time kinetic spectrophotometric method has been developed for the selective determination of metformin hydrochloride in bulk and in tablet formulation. This experiment indicates that at room temperature alkaline solution metformin is oxidized to -diketone by the action of sodium hypochlorite, the product is subsequently reacts with sodium nitroprusside to give a green colored 1, 3 dinitrosyl-N'-(iminomethyl)-N, N-dimethyl formamidine complex with maximum absorption at 685 nm. In sodium hydroxide-boric acid buffer solution, this time dependent chromophoric reaction reaches to a state of maximum absorbance within 5 minutes. At a preselected time of 5 minutes (after initiation of reaction) readings of maximum absorbance were adopted for constructing the calibration curve. Beer's law is obeyed over the concentration range of 10-120 g.mL-1 with molar absorptivity and Sandell's sensitivity of 6.335 x 10 4 L. Mol-1 .cm-1 and 0.0261 g.mL-1 respectively. The linear regression equation is A= 0.004 + 0.003C (g. mL-1) with a regression coefficient (r 2 =0.999). The percent recovery of the method is 100.04% with average relative error 0.038% and average relative standard deviation (RSD) 0.319%. The parameters with regard to determination of metformin by proposed method are optimized. The reaction mechanism and reaction stoichiometry is discussed. The proposed method was successfully applied for estimation of metformin in commercially available metformin tablets containing glibenclamide, glimepiride, glipizide and gliclazide. The average accuracy was found good, which was evaluated by comparison of the results obtained with those claimed by the manufacturer.
Biological and Pharmaceutical Bulletin, 2019
Valsartan products, commonly used to treat high blood pressure and heart failure, have been recalled in many countries due to the presence of an impurity, N-nitrosodimethylamine (NDMA), in the recalled products. We present and evaluate a GC-MS-based analytical method for the determination of NDMA levels and attempt an investigation of NDMA concentrations in valsartan drug substances and associated products. The limit of detection and limit of quantification for the method were estimated to be 0.1 and 0.5 µg/g, respectively, when testing a 0.5-g sample. A good trueness (99%) with a small relative standard deviation (1.9%) was obtained for a valsartan product spiked with NDMA at a concentration of 1.0 µg/g. Additionally, a valsartan drug substance and the associated product, which were previously determined to have NDMA contamination, were analyzed by the method. The NDMA content by our method was very close to previously determined values. Finally, six samples, including valsartan drug substances and associated, commercially available products in Japan, all of which were derived from the company implicated in the NDMA contamination, were analyzed by our method, revealing that none of these samples contained detectable concentrations of NDMA. Overall, the data indicate that the present method is reliable and useful for determination of NDMA in valsartan drug substances and associated products.
Indian Journal of Pharmaceutical Education and Research, 2017
Context: A Simple, selective, precise, and Stability indicating High Performance Thin Layer Chromatography (HPTLC) method of analysis of Metformin Hydrochloride (MET) and Benfotiamine (BENT) both as a bulk drug and in their combined formulation has been developed. Method: The basic aim of this method is to separate both the drugs by HPTLC and measure their spots at 249 nm. The separation was carried out on TLC aluminium sheets of silica gel 60F 254 using Benzene: Methanol: Triethylamine (8.5:1:0.5, v/v/v) as a mobile phase. Stability of MET and BENT was carried out by forced degradation study. Result: MET and BENT gave distinct and well defined peak at Rf 0.26 and 0.72, respectively. Calibration curves were linear in range of 500-3000 and 75-450 ng/spot for MET and BENT, respectively. Method was successively applied to tablet formulation. Stability study shows that the chromatograms of samples degraded with acid, base, hydrogen peroxide, light and dry heat showed well separated spots of pure MET and BENT as well as some additional peaks at different RF values. Conclusion: The HPTLC method was also able to selectively quantitate Metformin hydrochloride and Benfotiamine in presence of their degradation products obtained in forced degradation study. Hence, the method can be used as stability indicating. The method was validated as per ICH guidelines and it is applied for the analysis of pharmaceutical dosage form containing these two drugs.