Ultra-Sensitive LC-MS/MS Method for the Trace Level Quantification of Six Potential Genotoxic Nitrosamine Impurities in Telmisartan (original) (raw)
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A proficient GC-MS/MSS method was developed for determination of N-Nitrosodimethylamine, N-Nitrosodiethylamine, N-Nitrosodiisopropylamine, N-Nitrosoisopropylethylamine, N-Nitrosodibutylamine impurities in Telmisartan Drug Substance using column Rtx-5 Amine (30m length X 0.32mm diameter) 1.5µm film thickness, Part No.: 12369, Make: Restek. Helium is used as Carrier gas at with Linear velocity of 44.3 cm/sec. The proposed method was validated for System suitability, Specificity, Linearity, LOD and LOQ, Method precision, Intermediate precision and Recovery. All the parameters were found within the acceptable limits. Linearity in the range of LOQ to 150% for each impurity. The established methodology was commercially useful, specific, accurate, precise and suitable for the analysis of Nitrosamines impurities in Telmisartan drug substance Keywords: Gas chromatography with mass spectrometry (GC-MS/MS), Telmisartan drug substance, Nitrosamine impurities, ICH guideline and Method Validation.
Innovare Academic Sciences Pvt Ltd, 2020
Objective: A simple and sensitive method development and validation for the simultaneous determination of the N-nitrosamine dimethylamine (NDMA) and N Nitrosamine diethylamine (NDEA) in Olmesartan medoxomil (OLM) API and formulations by a tandem mass spectrometer (GC-MS/MS). Methods: Gas chromatography with a programmed oven temperature controller, Elite Wax (30 m × 0.25 mm × 0.5 µm) column, Helium as carrier gas and hyphenated to the tandem mass spectrometer powered with triple quadrupole mass analyzer, and photomultiplier tube detector. The method was validated as per the United States Food and Drug Administration (USFDA) guidelines. Results: With the selected GC-MS/MS conditions, the NDMA and NDEA 0.08 µg/ml (80 ng/ml) and 0.16 µg/ml (160 ng/ml) injected and Rt. for NDMA 5.634 and NDEA 6.516 min, respectively. A linear/range lies in between 0.024 and 0.120 µg/ml and 0.048 and 0.240 µg/ml for NDMA and NDEA with r2 >0.99. The precision, accuracy, and system suitability are established as per USFDA and ICH guidelines, the sensitivity of NDMA limit of detection and limit of quantification 0.08, 0.024 and NDEA 0.16, 0.048. Conclusion: Other nitrosamine impurities are not involved in the determination of NDMA and NDEA in the OLM using GC-MS/MS and the method is simple, sensitive, rapid, accurate, and precise.
Journal of Chromatography A, 2011
A gas chromatography/mass spectrometry (GC/MS) method for determination of nine N-nitrosamines (NAs) in water is described. Two ionization modes, electron impact (EI) and chemical ionization (CI) with methanol, as well as different ion analysis techniques, i.e. full scan, selected ion storage (SIS) and tandem mass spectrometry (MS/MS) were tested. Chemical ionization followed by SIS resulted the mass spectrometric method of choice, with detection limits in the range of 1-2 ng/L. Solid Phase Extraction (SPE) with coconut charcoal cartridges was applied to extract NAs from real samples, according EPA Method 521. Drinking water samples were collected from seven surface-and two groundwater treatment plants. Three surface water treatment plants were sampled before and after addition of O 3 /ClO 2 to observe the effect of disinfection on NAs' formation. N-nitrosodiethylamine (NDEA), n-nitrosodipropylamine (NDPA), n-nitrosomorpholine (NMOR) and n-nitrosodibutylamine (NDBA) were found up to concentrations exceeding three times the risk level of 10 ng/L set by the California Department of Public Health. Because dermal adsorption has been recently indicated as a new contamination route of exposure to NAs for people who practice swimming activity, water samples from five swimming pools in the Bologna (Italy) area were collected. N-nitrosopyrrolidine (NPYR) was detected in all samples at concentrations larger than 50 ng/L, likely as a disinfection by-product from the amino acid precursor proline, a main constituent of skin collagen.
ACS Omega
Nitrosamine impurities in angiotensin II receptor antagonists (sartans) containing a tetrazole group represent an urgent concern for active pharmaceutical ingredient (API) manufacturers and global regulators. Regarding safety, API manufacturers must develop methods to monitor the levels of each nitrosamine impurity before individual batch release. In this study, we developed and validated a sensitive, selective, and highthroughput method based on headspace gas chromatography− mass spectrometry (HS-GC−MS) for the simultaneous determination of four nitrosamines in losartan potassium API with simple sample preparation. N-Nitrosodimethylamine (NDMA, m/z 74), N-nitrosodiethylamine (NDEA, m/z 102), N-nitrosoethylisopropylamine (EIPNA, m/z 116), and N-nitrosodiisopropylamine (DIPNA, m/z 130) levels were quantified using an electron impact, single quadrupole mass spectrometer under a selected-ion-monitoring acquisition method. The method was validated according to the Q2(R1) ICH guidelines. The calibration curves of the assay ranged from 25 to 5000 ng/mL with limits of quantitation of 25 ppb for NDMA and NDEA and 50 ppb for DIPNA and EIPNA. The accuracy of the developed method ranged from −7.04% to 7.25%, and the precision %CV was ≤11.5. Other validation parameters, including specificity, stability, carryover, and robustness, met the validation criteria. In conclusion, the developed method was successfully applied for the determination of nitrosamines in losartan potassium APIs.
Talanta, 2012
We developed a methodology for the separation, identification, and quantification of eight N-nitrosamines. For a range of wastewater samples, including raw sewage and final-discharge wastewater, the methodology, which was based on solid-phase extraction (SPE) and a purification technique followed by analysis using a gas chromatograph equipped with a triple-quadrupole mass spectrometer, gave effective separation of the targeted compounds. The limits of detection of this method for N-nitrosamines in wastewaters ranged from 0.1 to 1.0 ng L À 1 and the limits of quantification ranged from 0.4 to 3.3 ng L À 1. As a result of preliminary recovery testing, we decided on a combination of two types of sorbent cartridges for SPE-one was aminoprophyl for sample purification and the other was activated charcoal for analyte concentration-that gave excellent recovery rates (98% to 152%) of three deuterided nitrosamines (surrogates). Using this combination of SPE, internal surrogates, and an injection surrogate, we obtained good recovery rates (80% to 131%) with low relative standard deviations (1% to 14%, n ¼3) for eight N-nitrosamines in all samples of influent, secondary effluent, and final discharge. We applied the newly developed pre-treatment method to an influent wastewater samples. All of the N-nitrosamines except two (NMEA and NDPA) were detected in the influent sample, at 1 to 1057 ng L À 1 .
Journal of Applied Pharmaceutical Science
Nitrosamine impurities are potential carcinogens, which are forming from the synthesis of drug substance as byproduct and also forming in presence of NaNO2/HNO3 and secondary amines (e.g., dimethyl amines, diethyl amine etc.,), which should be controlled in the medication of the human beings. Hence, robust and sensitive analytical method is required to control the nitroso amine impurities in drugs. The object of this method is to quantify the N-Nitrosodimethylamine (NDMA) impurity at 0.01 ppm level in ranitidine drug substance (form-1 and form-2) and drug product (tablets and capsules) of different geography. The source of NDMA impurity is also from the dimethyl amine as a key starting material using the ranitidine synthetic process. NDMA is forming when dimethyl amine is reacting with nitrous acid. The optimized LC method conditions were ACE C18-AR 3 µm, 150 × 4.6 mm column, mobile phase A as 0.1% formic acid in water, mobile phase B as 100% methanol, 0.8 ml/minute flow with gradient (time/%mobile phase B): 0/3, 3/3, 15/15, 15.1/100, 17/100, 17.1/3, 22/3, column temperature: 40°C, injection volume 50 µl, and total run time as 22 minutes. The final response achieved with multiple reaction monitoring (MRM) type: MRM [Q1 Mass (Da):75 Q3:58.2 Time (msecond)] in atmospheric chemical ionization positive mode. The optimized method was validated against the International Council for Harmonisation Q2 (R1) and United States of Pharmacopeia general chapter for compendial method validations 1225. This method can detect up to 0.01 ppm and quantify up to 0.03 ppm, the method shows linearity from 0.03 to 20 ppm.
Determination of N-nitrosamine precursors in DW by UFLC-MSMS
a b s t r a c t N-Nitrosamines are potent mutagenic and carcinogenic emerging water disinfection by-products (DBPs). The most effective strategy to control the formation of these DBPs is minimizing their precursors from source water. Secondary and tertiary amines are dominating precursors of N-nitrosamines formation during drinking water disinfection process. Therefore, the screening and removal of these amines in source water are very essential for preventing the formation of N-nitrosamines. A rapid, simple, and sensitive ultrafast liquid chromatography-tandem mass spectrometry (UFLC-MS/MS) method has been developed in this study to determine seven amines, including dimethylamine, ethylmethylamine, diethylamine, dipropylamine, trimethylamine, 3-(dimethylaminomethyl)indole, and 4-dimethylaminoantipyrine, as major precursors of N-nitrosamines in drinking water system. No sample preparation process is needed except a simple filtration. Separation and detection can be achieved in 11 min per sample. The method detection limits of selected amines are ranging from 0.02 μg/L to 1 μg/L except EMA (5 μg/L), and good calibration linearity was achieved. The developed method was applied to determine the selected precursors in source water and drinking water samples collected from Midwest area of the United States. In most of water samples, the concentrations of selected precursors of N-nitrosamines were below their method detection limits. Dimethylamine was detected in some of water samples at the concentration up to 25.4 μg/L.
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.