Metformin drugs under simulated gastric conditions can generate high nitrite-dependent levels of N-nitrosodimethylamine.

N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA), group 2A carcinogens, were detected in finished drug products, including metformin, ranitidine, sartans and other drugs which caused multiple recalls in the USA and Europe. Important studies also reported the formation of NDMA when ranitidine and nitrite were added to simulated gastric fluid. Our objective was to screen finished drug products from Europe and USA for nitrosamine impurities and investigate the formation of NDMA in metformin finished drug products when added to simulated gastric fluid. One dosage unit of 30 different commercially available drugs, including metformin, sartans, and ranitidine were tested for NDMA, NDEA, and dimethylformamide (DMF) impurities, using a liquid chromatography-mass spectrometry (LC-MS) method. Then, 6 metformin finished drug products were tested in stomach conditions for 2 h at 37 °C in a 100 mL solution with a pH of 2.5 and different nitrite concentrations (40, 10, 1, 0.1 mM) and tested for NDMA, and DMF using LC-MS. We measured NDMA, NDEA, and DMF in 30 finished drug products. NDMA and DMF were quantified for metformin drug products in simulated gastric fluid with different nitrite concentrations. None of the 30 drugs showed concerning levels of NDMA, NDEA, or DMF when tested as single tablets. However, when metformin tablets are added to simulated gastric fluid solutions with high nitrite concentrations (40 mM and 10 mM), NDMA can reach amounts of thousands of nanograms per tablet. At the closest concentration to physiologic conditions we used, 1 mM, NDMA is still present in the hundreds of nanograms in some metformin products. In this in vitro study, nitrite concentration had a very important effect on NDMA quantification in metformin tablets added to simulated gastric fluid. 1 mM nitrite caused an increase above the acceptable daily intake set by the U.S. Food and Drug Administration (FDA) for some of the metformin drugs. 10 mM, 40 mM nitrite solutions generated NDMA amounts exceeding by more than a hundred times the acceptable daily intake set by the FDA of 96 nanograms. These findings suggest that metformin can react with nitrite in gastric-like conditions and generate NDMA. Thus, patients taking metformin could be exposed to NDMA when high nitrite levels are present in their stomach, and we recommend including a statement within the Patient Package Inserts/Instructions for use.

Development and validation of high-performance liquid chromatography-Orbitrap mass spectrometric method for quantification of NDMA in ranitidine drug products and evaluation of antioxidants as inhibitors of classical nitrosation reaction.

RATIONALE: N-Nitroso dimethylamine (NDMA) is a mutagenic impurity detected in several ranitidine products. The amino functional group of ranitidine is a risk factor for classical nitrosation-induced NDMA formation in ranitidine drug products during storage conditions. The United States Food and Drug Administration (US FDA) recommended the use of antioxidants to control NDMA in drug products. Considering the need for sensitive analytics, a liquid chromatography/high-resolution mass spectrometry (LC-HRMS) method was developed and validated to detect NDMA in this pilot study to demonstrate the antioxidants as inhibitors of nitrosation reactions. METHODS: The method, utilizing an EC-C18 column and tuned to atmospheric pressure chemical ionization/selected ion monitoring (APCI/SIM) mode, separated NDMA (m/z: 75.0553; tR: 3.71 min) and ranitidine (m/z: 315.1485; tR: 8.61 min). APCI mode exhibited four times higher sensitivity to NDMA than electrospray ionization (ESI) mode. Classical nitrosation of the dimethyl amino group of ranitidine was studied with sodium nitrite in solid pellets. Antioxidants (alpha-tocopherol, ascorbic acid, and trolox) were evaluated as NDMA attenuators in ranitidine pellets under vulnerable storage conditions. The developed method quantified NDMA levels in samples, extracted with methanol through vortex shaking for 45 min. RESULTS: The method achieved a limit of detection (LOD) and limit of quantitation (LOQ) of 0.01 and 0.05 ng/mL, respectively, with linearity within 1-5000 ng/mL (R1: 0.9995). It demonstrated good intra-day and inter-day precision (% RSD [relative standard deviation]: <2) and accuracy (96.83%-101.72%). Nitrosation of ranitidine induced by nitrite was significant (p < 0.001; R2 = 0.9579) at various sodium nitrite levels. All antioxidants efficiently attenuated NDMA formation during ranitidine nitrosation. Ascorbic acid exhibited the highest NDMA attenuation (96.98%), followed by trolox (90.58%). This study recommends 1% ascorbic acid and trolox as potent NDMA attenuators in ranitidine drug products. CONCLUSIONS: This study compared the effectiveness of antioxidants as NDMA attenuators in ranitidine under storage conditions susceptible to NDMA generation. The study concluded that ascorbic acid and trolox are potent inhibitors of NDMA formation and nitrosation attenuators in ranitidine drug products.

Closing Dichloramine Decomposition Nitrogen and Oxygen Mass Balances: Relative Importance of End-Products from the Reactive Nitrogen Species Pathway.

In drinking water chloramination, monochloramine autodecomposition occurs in the presence of excess free ammonia through dichloramine, the decay of which was implicated in N-nitrosodimethylamine (NDMA) formation by (i) dichloramine hydrolysis to nitroxyl which reacts with itself to nitrous oxide (N2O), (ii) nitroxyl reaction with dissolved oxygen (DO) to peroxynitrite or mono/dichloramine to nitrogen gas (N2), and (iii) peroxynitrite reaction with total dimethylamine (TOTDMA) to NDMA or decomposition to nitrite/nitrate. Here, the yields of nitrogen and oxygen-containing end-products were quantified at pH 9 from NHCl2 decomposition at 200, 400, or 800 µeq Cl2·L-1 with and without 10 µM-N TOTDMA under ambient DO (∼500 µM-O) and, to limit peroxynitrite formation, low DO (≤40 µM-O). Without TOTDMA, the sum of free ammonia, monochloramine, dichloramine, N2, N2O, nitrite, and nitrate indicated nitrogen recoveries ±95% confidence intervals were not significantly different under ambient (90 ± 6%) and low (93 ± 7%) DO. With TOTDMA, nitrogen recoveries were less under ambient (82 ± 5%) than low (97 ± 7%) DO. Oxygen recoveries under ambient DO were 88-97%, and the so-called unidentified product of dichloramine decomposition formed at about three-fold greater concentration under ambient compared to low DO, like NDMA, consistent with a DO limitation. Unidentified product formation stemmed from peroxynitrite decomposition products reacting with mono/dichloramine. For a 2:2:1 nitrogen/oxygen/chlorine atom ratio and its estimated molar absorptivity, unidentified product inclusion with uncertainty may close oxygen recoveries and increase nitrogen recoveries to 98% (ambient DO) and 100% (low DO).

Occurrence of N-nitrosodimethylamine in roasted Alaska pollock fillets during processing and storage and preliminary cancer risk assessment.

BACKGROUND: Dried and salt-fermented fish products are important sources of N-nitrosodimethylamine (NDMA) exposure for human. As a potent carcinogen, NDMA was frequently detected in roasted Alaska pollock fillet products (RPFs), which is among the most common fish products in China. Until now, the occurrence and development of NDMA and its precursors (nitrites, nitrates and dimethylamine) in RPFs during processing and storage were not well elucidated, and safety evaluation of this fish product is also urgently needed. RESULTS: The presence of precursors in the raw material was verified and significant increase of nitrates and nitrites during processing was observed. NDMA was found generated during pre-drying (3.7 µg kg-1 dry basis) and roasting (14.6 µg kg-1 dry basis) process. Continuous increase in NDMA content can also be found during storage, especially at higher storage temperature. The 95th percentile of Monte Carlo simulated cancer risk (3.73 × 10-5 ) surpassed the WHO threshold (1.00 × 10-5 ) and sensitivity analysis implies the risk was mainly attributable to NDMA level in RPFs. CONCLUSION: The occurrence of NDMA in RFPs was mainly a result of endogenous factors originating in Alaska pollock during processing and storage rather than exogenous contamination, and temperature played a pivotal role. The preliminary risk assessment results suggest that long-term consumption of RPFs would impose potential health risks for consumers. © 2023 Society of Chemical Industry.

Comparative Evaluation of Chemical and Photolytic Denitrosation Methods for Chemiluminescence Detection of Total N-Nitrosamines in Wastewater Samples.

N-Nitrosamines form as byproducts during oxidative water treatment and occur as impurities in consumer and industrial products. To date, two methods based on chemiluminescence (CL) detection of nitric oxide liberated from N-nitrosamines via denitrosation with acidic triiodide (HI3) treatment or ultraviolet (UV) photolysis have been developed to enable the quantification of total N-nitrosamines (TONO) in environmental water samples. In this work, we configured an integrated experimental setup to compare the performance of HI3-CL and UV-CL methods with a focus on their applicability for TONO measurements in wastewater samples. With the use of a large-volume purge vessel for chemical denitrosation, the HI3-CL method achieved signal stability and detection limits comparable to those achieved by the UV-CL method which utilized a microphotochemical reactor for photolytic denitrosation. Sixty-six structurally diverse N-nitroso compounds (NOCs) yielded a range of conversion efficiencies relative to N-nitrosodimethylamine (NDMA) regardless of the conditions applied for denitrosation. On average, TONO measured in preconcentrated raw and chloraminated wastewater samples by the HI3-CL method were 2.1 ± 1.1 times those measured by the UV-CL method, pointing to potential matrix interferences as further confirmed by spike recovery tests. Overall, our comparative assessment of the HI3-CL and UV-CL methods serves as a basis for addressing methodological gaps in TONO analysis.

Release regularity and cleaning measures of magnetic anion exchange resin during application.

Anion exchange resin is responsible for removing harmful anionic contaminants in drinking water treatment, but it may become a significant source of precursors for disinfection byproducts (DBPs) by shedding material during application without proper pretreatment. Batch contact experiments were performed to investigate the dissolution of magnetic anion exchange resins and their contribution to organics and DBPs. Dissolved organic carbon (DOC) and dissolved organic nitrogen (DON) released from the resin were highly correlated with the dissolution conditions (contact time and pH), in which 0.7 mg/L DOC and 0.18 mg/L DON were distributed at exposure time of 2 h and pH 7. The formation potential of four DBPs in the shedding fraction was also revealed that trichloromethane (TCM), dichloroacetonitrile (DCAN), nitrosodimethylamine (NDMA), and dichloroacetamide (DCAcAm) concentrations could reach 21.4, 5.1, 12.1 µg/L, and 69.6 ng/L, respectively. Furthermore, the hydrophobic DOC that preferred to detach from the resin mainly originated from the residues of crosslinkers (divinylbenzene) and porogenic agents (straight-chain alkanes) detected by LC-OCD and GC-MS. Nevertheless, pre-cleaning inhibited the leaching of the resin, among which acid-base and ethanol treatments significantly lowered the concentration of leached organics, and formation potential of DBPs (TCM, DCAN, and DCAcAm) below 5 µg/L and NDMA dropped to 10 ng/L.

Solid State Kinetics of Nitrosation Using Native Sources of Nitrite.

While many reactive species are known to cause N-nitrosation, trace nitrite (NO2-), which may be present in several excipients, is a source of nitrosating agents in pharmaceutical formulations. In this study we have found that the salt form of NO2- can influence the favored nitrosation conditions and final amount of nitrosamine being formed. Using native levels of NO2-, most likely present as ammonium nitrite (NH4NO2), in microcrystalline cellulose, we have determined the kinetics of nitrosamine formation in solid state with dimethylamine substrate present in metformin, used as model compound. It was found that the competing degradation of NH4NO2 into N2 and H2O limited the amount of nitrosamine formation to a great extent. Empirically modelling the kinetic data predicted reaching at maximum 1.6% conversion over a hypothetical 3-year shelf-life. These results also showed that using other sources of NO2- as spiking reagents, such as NaNO2, may lead to unrealistic worst-case situations when the main form of NO2- in the drug product (DP) under evaluation may be NH4NO2. As well, measuring NO2- in freshly manufactured excipients containing NO2- potentially as NH4NO2 may lead to biased high NO2- content, which is not representative of the actual amounts present at the time of DP manufacture.

Ranitidine: A Proposed Mechanistic Rationale for NDMA Formation and a Potential Control Strategy.

The formation of N-nitrosodimethylamine (NDMA) in ranitidine hydrochloride drug substance (DS) and drug products has attracted considerable attention over the last few years. The drug structure is unusual in that it contains a vinyl nitro moiety. Although a variety of studies have been carried out to understand how NDMA is formed in the DS solids, a mechanistic description of NDMA formation has remained elusive. A new mechanistic view of NDMA formation is detailed here. Autoxidation of ranitidine can rationalize nitrite ion and dimethylamine liberation from ranitidine. The subsequent nitrosation is argued to be due to conversion of nitrite ion to the gas phase nitrosating agent nitrosyl chloride, NOCl. Oxygen scavenging packaging systems should be able to stop the autoxidation, and thus shut down the nitrite release from ranitidine. Without nitrite release NDMA cannot form. This may provide a practical means to stabilize ranitidine DS and solid dosage formulations against NDMA formation.

N-Nitrosodimethylamine formation in metformin hydrochloride sustained-release tablets: Effects of metformin and hypromellose used in drug product formulation.

In recent years, nitrosamines have been discovered in some types of drug products that becomes a current regulatory hotspot, and have attracted a lot attention from both regulatory authorities and industry. This manuscript provided an industry perspective on the nitrosamines research. A liquid chromatography coupled with tandem mass spectrometry（LC-MS/MS）method was developed and applied for the quantification of N-nitrosodimethylamine (NDMA) in metformin hydrochloride sustained-release tablets (MET). The key factors resulting in the NDMA formation in MET were identified through forced degradation and drug-excipient studies, which included high temperature, dimethylamine, strong alkali and oxidation conditions, peroxide and alkaline components contained in the formulation as well as the nitrite and nitrate impurities that might be presented in certain excipients. Further, API particle size and water content of the drug product would also affect the growth rate of NDMA. Therefore, the following mitigation strategies to reduce the risk of nitrosamines in the finished drug product are proposed in this manuscript: 1) avoid the use of excipients containing nitrite, nitrate and peroxide impurities; 2) avoid high temperature and strong alkaline environment in the production and storage condition; 3) maintain an appropriate water content level in the formulation. Based on the above principles, it was recommended to add antioxidant or incorporate excipient such as Na2CO3 to modify the formulation pH to weak basic environment in the formulation of MET, which can could effectively prevent formation of NDMA in the stability process.

Highly effective electrocatalytic reduction of N-nitrosodimethylamine on Ru/CNT catalyst.

N-Nitrosodimethylamine (NDMA) is a commonly identified carcinogenic and genotoxic pollutant in water. In this study, we prepared Ru catalysts supported on carbon nanotube (Ru/CNT) and studied the electrocatalytic reduction of N-nitrosamines on Ru/CNT electrode in a three-electrode system. The results show that Ru-based catalyst exhibits a high activity of 793.3 µmol L-1 gCat-1 h-1 for electrochemical reduction of NDMA. Reaction mechanism study discloses that the electrocatalytic reduction of NDMA is accomplished by both direct electron reduction and atomic H* mediated indirect reduction pathways. Further product analysis indicates that NDMA is finally reduced to dimethylamine (DMA) and ammonia. The reduction efficiency of NDMA strongly relies on cathode potential, initial NDMA concentration and solution pH. To verify the universality of Ru/CNT electrode, electrocatalytic reduction of three dialkyl N-nitrosamines with different alkyl groups was performed and Ru catalyst has high catalytic activities for the three N-nitrosamines, while the catalytic efficiency differs with their structures. Simultaneous electrochemical reduction of the three N-nitrosamines indicates that the reduction rates of N-nitrosamines follow the same order in the multiple-component system as that in the single-component system. Catalyst recycling results demonstrate that after 5 consecutive recycling runs Ru/CNT electrode remains almost identical catalytic activity to the fresh catalyst, manifesting the high catalytic stability of Ru/CNT electrode.

Predictable Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometry Fragmentation of Ozone-Reactive N-Nitrosodimethylamine Precursors Coupled with In Silico Fragmentation and Ion Mobility-Quadrupole Time-of-Flight Facilitates Their Identification in Sewage.

This study investigated the liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF/MS) fragmentation of 10 potent model ozone (O3)-reactive N-nitrosodimethylamine (NDMA) precursors bearing (CH3)2N-N or (CH3)2N-(SO2)-N. Fragments (m/z 61.0766, 60.0688 Da loss, and 72.0688 Da loss) were discovered as pertinent diagnostic fragments for precursors bearing (CH3)2N-N, whereas a loss of 108.0119 Da was consistent for precursors bearing (CH3)2N-S(O2)-N. Using the fragments as structural hints on a sewage fraction with a high concentration of O3-reactive precursors, peaks of precursors sharing m/z 61.0766, a 60.0688 Da loss, or both were flagged. Then, using in silico fragmenters and (CH3)2N-N as a substructure filter on online-chemical structure databases, we identified PubChem's compound identifier (PCCID) 141210417 and 1,1,1',1'-tetramethyl-4,4'-(methylene-di-p-phenylene)disemicarbazide (TMDS). TMDS was confirmed using an authentic standard, and ion mobility (IM)-QTOF/MS confirmed its rider peak as PCCID 141210417. PCCID 141210417 is an isomer of TMDS, and its environmental occurrence is associated with technical-grade TMDS and industrial effluents. The estimated contribution of TMDS to the total NDMA formation potential of the sewage fraction was 20-24%, which was suggestive of the significance of PCCID 141210417 and other precursors.

N-Nitrosodimethylamine (NDMA) Formation from Ranitidine Impurities: Possible Root Causes of the Presence of NDMA in Ranitidine Hydrochloride.

N-Nitrosodimethylamine (NDMA) is a probable human carcinogen. This study investigated the root cause of the presence of NDMA in ranitidine hydrochloride. Forced thermal degradation studies of ranitidine hydrochloride and its inherent impurities (Imps. A, B, C, D, E, F, G, H, I, J, and K) listed in the European and United States Pharmacopeias revealed that in addition to ranitidine, Imps. A, C, D, E, H, and I produce NDMA at different rates in a solid or an oily liquid state. The rate of NDMA formation from amorphous Imps. A, C, and E was 100 times higher than that from crystalline ranitidine hydrochloride under forced degradation at 110 °C for 1 h. Surprisingly, crystalline Imp. H, bearing neither the N,N-dialkyl-2-nitroethene-1,1-diamine moiety nor a dimethylamino group, also generated NDMA in the solid state, while Imp. I, as an oily liquid, favorably produced NDMA at moderate temperatures (e.g., 50 °C). Therefore, strict control of the aforementioned specific impurities in ranitidine hydrochloride during manufacturing and storage allows appropriate control of NDMA in ranitidine and its pharmaceutical products. Understanding the pathways of the stability related NDMA formation enables improved control of the pharmaceuticals to mitigate this risk.

Investigating the root cause of N-nitrosodimethylamine formation in metformin pharmaceutical products.

BACKGROUND: FDA limited N-nitrosodimethylamine (NDMA) - a carcinogenic impurity formed during metformin (MET) tablets manufacturing - level to 96 ng/day; a step which led to recall of MET products. This work aims to investigate the root cause of NDMA formation during MET tablets manufacturing. RESEARCH DESIGN AND METHODS: We focused on three main contributing causes: use of water and heat during intra-granulation, and the nitrite/nitrate quantities in excipients. Thirteen MET tablet formulations (immediate or sustained-release) were manufactured, on batch level. Each batch was manufactured using one excipient and excluding one cause at a time and NDMA level was assayed. RESULTS: NDMA traces were undetectable in MET tablets manufactured using polyvinyl pyrrolidone or hydroxypropyl cellulose SSL, even when water and/or heat were employed during intra-granulation. Levels of NDMA in MET tablets with hydroxypropyl methyl cellulose (HPMC) E5 or carboxymethyl cellulose sodium 4000 were 67.08 ± 2.3 and 66.21 ± 2.5 ng/day, in the presence of water and/or heat. No impact of employing extra-granular PolyoxTM, HPMC E5 or HPMC K15 on NDMA formation, despite the high nitrite and nitrate content in these excipients. CONCLUSIONS: Water, heat, and excipients' nitrite and nitrate levels are the key players, which should collectively exist, to cause NDMA formation during MET tablets manufacturing.

N-Nitrosodimethylamine Contamination in the Metformin Finished Products.

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.

Temperature-Dependent Formation of N-Nitrosodimethylamine during the Storage of Ranitidine Reagent Powders and Tablets.

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.

Nitrosamine formation in a semi-dry fermented sausage: Effects of nitrite, ascorbate and starter culture and role of cooking.

In this study, effects of ingoing nitrite level (0, 50, 100 and 150 mg/kg), use of sodium ascorbate, addition of starter culture (Lactobacillus plantarum GM77 + Staphylococcus xylosus GM92) and cooking level (control, medium, medium well, well done and very well done) on nitrosamine formation in heat-treated sucuk, a type of semi-dry fermented sausage, were investigated. The use of ascorbate had no significant effect on NDMA (N-Nitrosodimethylamine) and NPIP (N-Nitrosopiperidine) contents in the presence of starter culture. A higher NPYR (N- Nitrosopyrrolidine) content was detected in the group with starter culture at 150 mg/kg nitrite level in comparison to the group without starter culture. Cooking level affected all identified nitrosamines very significantly. Ingoing nitrite level × cooking level interaction was only effective on NPIP and advanced cooking levels (well done and very well done) at higher ingoing nitrite levels (100 and 150 mg/kg) resulted in significant increases in NPIP content.

Reversible photochromic photocatalyst Bi2O3/TiO2/Al2O3 with enhanced visible photoactivity: application toward UDMH degradation in wastewater.

1,1-Dimethylhydrazine (UDMH) and its by-products were considered carcinogenic toxins and represent a serious health hazard to the population once present in water under natural conditions without treatment. The conventional degradation method suffers from incomplete removal of intermediate products (especially N-nitrosodimethylamine (NDMA)), the powdery catalysis being difficult to recover and results in high energy consumption. In this study, a series of Bi2O3/TiO2/Al2O3 (BTA) photocatalysts have been successfully synthesized by a simple dry mixing method with powder material followed by their immobilization. It was evaluated by the photocatalytic degradation of UDMH present in wastewater, which can be recovered by rapid filtration and utilizes only solar energy. The catalyst exhibited markedly enhanced photocatalytic activity for the degradation of UDMH wastewater compared with conventional TiO2/Al2O3 (TA) catalysts under UV, visible and solar irradiation. Besides, the intermediate NDMA was gradually completely degraded. The photocatalysts were extensively characterized using scanning electron microscopy, energy dispersive spectrometry, specific surface area (BET), X-ray diffraction, X-ray photoelectron spectroscopy, UV-visible diffuse reflectance spectroscopy and photo-electrochemical I-t curves evaluation. The results revealed that all the BTA composites exhibited high stability and stronger absorbance in visible light. In addition, the BTA exhibited a reversible photochromic property that can effectively expand the range of light absorption and enhance the photocatalytic activity. The reversible photochromic properties of BTA explained in the proposed mechanism model are expected to be useful for detecting and sensing UDMH or other organic contaminants.

Application of stabilized hypobromite for controlling membrane fouling and N-nitrosodimethylamine formation.

Chloramination is a conventional and successful pre-disinfection approach to control biological fouling for reverse osmosis (RO) treatment in water reuse. This study aimed to evaluate the possibility of using a new disinfectant-stabilized hypobromite-in controlling membrane fouling and the formation of a particular carcinogenic disinfection byproduct (DBP)-N-nitrosodimethylamine (NDMA). Our accelerated chemical exposure tests showed that the new disinfectant reduced the permeability of a polyamide RO membrane permeability from 6.7 to 4.1 L/m2hbar; however, its treatment impact was equivalent to that of chloramine. The disinfection efficacy of stabilized hypobromite was greater than that of chloramine when evaluated with intact bacterial counts, which suggests its potential for mitigating membrane biofouling. Additional pilot-scale tests using synthetic wastewater demonstrated that pre-disinfection with the use of stabilized hypobromite inhibits membrane fouling. Among 13 halogenated DBPs evaluated, the formation of bromoform by stabilized hypobromite was higher than that by chloramine at a high dose of 10 mg/L, thus suggesting the need for optimizing chemical doses for achieving sufficient biofouling mitigation. NDMA formation upon stabilized hypobromite treatment in two different types of actual treated wastewaters was found to be negligible and considerably lower than that by chloramine treatment. In addition, NDMA formation potential by stabilized hypobromite was 2-5 orders of magnitude lower than that by chloramine. Our findings suggest the potential of using stabilized hypobromite for controlling NDMA formation and biofouling, which are the keys to successful potable water reuse.

Rapid and efficient high-performance liquid chromatography analysis of N-nitrosodimethylamine impurity in valsartan drug substance and its products.

In July 2018, certain valsartan-containing drugs were voluntary recalled in Japan owing to contamination with N-nitrosodimethylamine (NDMA), a probable human carcinogen. In this study, an HPLC method was developed for the quantitative detection of NDMA simultaneously eluted with valsartan. Good linearity with a correlation coefficient (R2) > 0.999 was achieved over the concentration range of 0.011-7.4 µg/mL. The limits of detection and quantification were 0.0085 µg/mL and 0.0285 µg/mL, respectively. When the recalled valsartan samples were subjected to this method, the observed NDMA contents were in agreement with the reported values, indicating that our method achieved sufficient linearity, accuracy, and precision to detect NDMA in valsartan drug substances and products. Moreover, six samples (valsartan drug substances and tablet formulations), which had a possibility for NDMA contamination, were analyzed; none of the samples contained NDMA at detectable levels. Our method would be useful for the rapid screening and quantification of NDMA impurity in valsartan drug substances and products.