Nitrosamine Formation Research Articles

Highly Sensitive and Robust LC-MS/MS Method for Determination up to 15 Small Molecule Nitrosamine Impurities in Pharmaceutical Drug Substances.

Nitrosamine impurities have been classified as probable human carcinogens for decades. These impurities were reported in water, food, tobacco, pesticides, and plastics but received attention in mid-2018 when N-nitrosodimethylamine (NDMA) was reported in valsartan drug products. Subsequently, it was revealed that several small molecule and complex nitrosamine impurities can form in any active pharmaceutical ingredient (API) or drug product in which secondary or tertiary amines are present (as API or as impurities) along with a nitrosating agent. Consequently, regulators have provided several guidelines for the risk assessment of nitrosamine formation during manufacturing, storage, or from contaminated supply chains. This has led to a demand for validated analytical methods that quantify N-nitrosamine impurities in pharmaceutical products. In this study, a highly sensitive and robust analytical method was developed and validated for quantitatively determining up to 15 small nitrosamines at low levels (0.01 ppm) in sartan drug substances. The study also suggests that this method can be extended not only to corresponding sartan drug products but could also be used as a generic screening method to test a variety of drug substances, and drug products with the minimum required optimization of method conditions.

A headspace GC-MS method to quantify nitrosamine impurities and precursors in drug products: Method validation and product testing.

Pharmaceutical manufacturers are working to mitigate the formation of nitrosamine impurities in drug products. The work herein describes the development and validation of a headspace GC-MS method according to ICH Q2(R1) guidelines for the detection and quantification of NDMA, NDEA, NDIPA, and NEIPA in drug products. The analytical procedure was further modified to include detection and quantitation of DMF due to the potential decomposition pathway of DMF to form dimethylamine, a known precursor for NDMA formation. The NDMA impurity was detected in the "sartan" class of drug products between 0.1 and 113 ppm. The validated analytical procedure was applied in an investigation of approaches to mitigate nitrosamine formation in metformin drug products. The developed analytical procedures provide another tool for pharmaceutical manufacturers to evaluate drug products for nitrosamine impurities.

Using Celery Powder in a Semi-Dry Fermented Sausage 'Heat-Treated Sucuk': Nitrosamine Formation, Lipid Oxidation, and Volatile Compounds.

This study investigated the effect of using celery powder (CP) as source of pre-converted nitrite (treatments: A: 150 mg/kg NaNO2, B: 100 mg/kg NaNO2 + CP as 50 mg/kg NaNO2 equivalent, C: 50 mg/kg NaNO2 + CP as 100 mg/kg NaNO2 equivalent, D: CP as 150 mg/kg NaNO2 equivalent) on the physicochemical and microbiological properties in heat-treated sucuk (HTS), a kind of semi-dry fermented sausage. The influence of cooking time (CT) on the nitrosamine formation in HTS with and without CP was also determined. The results indicated that the use of CP increased the pH value and decreased the aw value. Micrococcus/Staphylococcus and residual nitrite were not affected by the use of CP. TBARS value varied from 0.78 to 0.90 mg MDA/kg. CP did not affect the abundance of hexanal in HTS, however, it increased the abundance of camphene. The results of PCA showed that treatments A, B, and C had similar volatile compound profiles. CP did not affect both N-nitrosodimethylamine and N-nitrosodiethylamine, but their levels increased as the CT increased. Increased CT also resulted in increased N-nitrosopiperidine (NPIP) in all treatments, but the cooking for 1 min did not cause a significant increase in treatments A, B, and C. CP leads to a significant increase in NPIP content, especially after 3 and 5 min of cooking in HTS.

Formation of Nitrosamines from the Heterogeneous Reaction of Nitrous Acid and Organic Amines in Indoor Environments.

Carcinogenic nitrosamines have been widely studied due to their risk to human health. However, the universality and evolutionary processes of their generation, particularly concerning their secondary sources, remain unclear at present. We demonstrated through laboratory flow tube experiments that corresponding nitrosamines were generated from heterogeneous reactions of nitrous acid (HONO) with five structurally diverse amines commonly found indoors, including diphenylamine (DPhA), dibenzylamine (DBzA), dioctylamine (DOtA), N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD), and N-phenyl-1-naphthylamine (PANA). The heterogeneous reaction rate constants of DBzA and DOtA with HONO (∼70 ppb) were 1.21 × 10-3 and 2.13 × 10-3 min-1 at 30% relative humidity (RH), resulting in a lifetime of 13.8 and 7.8 h. As compared to higher RH (∼80%), more nitrosamines were produced from the reaction of HONO with surface-sorbed DBzA, DOtA, 6PPD, and PANA at lower RH (30%), with product yields ranging from <0.1% to 0.5%. Furthermore, we observed the formation of nitroso-6PPDs and nitro-6PPDs during room air exposure of 6PPD in a genuine indoor environment, in addition to various other transformation products indicative of reactions of 6PPD with HONO, NOx, and ozone indoors. This study confirmed the universality of the heterogeneous reaction of surface-sorbed amine with HONO as a source of nitrosamines indoors.

Nitrosamine mitigation: NDMA impurity formation and its inhibition in metformin hydrochloride tablets

The mitigation of nitrosamine formation in drug products has been studied and approaches such as using formulations with pH modifiers and antioxidants have been shown to decrease the formation of nitrosamines. However, more studies are needed to explore the effectivness of mitigation strategies with different drug models and formulations. The primary objective of this work was to assess the role of different antioxidants and pH modifiers in tablet formulations to mitigate the formation of NDMA, prepared in-house, using metformin hydrochloride as a model drug. A study design for manufacturing metformin hydrochloride formulations was created to evaluate potential mitigation stratigies. The formulations were prepared by wet granulation that included a sodium nitrite spike and various antioxidants such as ascorbic acid, caffeic acid and ferulic acid at various concentrations that may inhibit nitrosamine formation. The study design also included pH modifiers such as hydrochloric acid and sodium carbonate. The metformin hydrochloride formulations were placed under stability conditions that included humidity, temperature and time over a six month period. NDMA inhibition was found to be most effective in formulations with basic pH, followed by the addition of tested antioxidants with 0.1% concentrations in the formulations. All tested antioxidants showed complete mitigation in formulations with 0.5% and 1% concentrations. In summary, basic pH and the inclusion of antioxidants exhibited the potential to mitigate the formation of NDMA in metformin hydrochloride tablets.

Limosilactobacillus fermentum CGMCC 1.7434 and Debaryomyces hansenii GDMCC 2.149 synergize with ultrasound treatment to efficiently degrade nitrite in air-dried ducks

Nitrites in meat products are important food additives with coloring, antibacterial and antioxidant effects, but excessive intake of nitrites can pose health risks, including an increased risk of cancer due to the formation of carcinogenic nitrosamines. In the present study, Limosilactobacillus fermentum CGMCC 1.7434 was screened and the effects of it and Debaryomyces hansenii GDMCC 2.149 and their combination on nitrite degradation were investigated. It was found that the co-culture of L. fermentum CGMCC 1.7434 and D. hansenii GDMCC 2.149 significantly enhanced nitrite degradation (99.58%). The findings on salt and ethanol tolerance suggest suitability for application in meat fermentation processes. Scanning electron microscopy and additional data indicate that D. hansenii GDMCC 2.149 facilitates the growth, acid production, adhesion, secretion of AI-2 signaling molecules, and biofilm formation of L. fermentum CGMCC 1.7434. Metabolomics analysis suggests that these microorganisms reduce nitrite levels by converting NH3 derived from nitrite into L-glutamine, which is further transformed into N-nitroso compounds and their downstream derivatives through the ABC transporter pathway, the TCA cycle, and the amino acid metabolism pathway. Microbial community analyses showed that L. fermentum CGMCC 1.7434 and D. hansenii GDMCC 2.149 were successfully inoculated into air-dried ducks, becoming dominant strains and effectively inhibiting the growth of pathogenic bacteria. Furthermore, during the processing of air-dried duck, the combination of ultrasonic cavitation (250 W, 4 min, 30°C, 40 kHz) with the co-fermentation of L. fermentum CGMCC 1.7434 and D. hansenii GDMCC 2.149 effectively reduced nitrite content (84.55%) and TVB-N levels in the meat, without compromising color or TBARS values. This is crucial for understanding the mechanism of nitrite degradation by LAB in synergy with yeast and for the advancement of low-nitrite air-dried duck products.

Evaluating Health Risks Associated With Fluoride and Nitrate Contaminants in Drinking Water to Residents Living in the Chikkaballapur Taluk of Karnataka, India

ABSTRACTAddressing fluoride and nitrate contamination in groundwater is crucial for safeguarding public health. Fluoride contamination in groundwater can cause dental and skeletal fluorosis, along with potential neurotoxic effects. Nitrate contamination can lead to methemoglobinemia in infants and increase cancer risk due to the formation of nitrosamines. The major goal of this study was to examine groundwater quality in the Chickkaballapur urban (CBU) and Chikkaballapur rural (CBR) parts of the Chikkaballapur taluk (CBT), Karnataka, and to investigate the potential health hazards associated with the presence of fluoride and nitrate contaminants. Hazard quotient and total hazard index (THI) calculation methods, as suggested by the United States Environmental Protection Agency, were used in the present study to evaluate non‐carcinogenic risks for individuals of various age categories, including men, women, and children (MWC). A total of 112 samples from rural areas and 41 samples from urban areas of Chikkaballapur taluk were collected during the post‐monsoon season. According to the study's findings, groundwater samples from CBU and CBR surpassed acceptable fluoride concentration limits by 41% and 40%, respectively, while samples from CBR exceeded acceptable nitrate limits by 17%, set by the Bureau of Indian Standards (1 mg/L for fluoride and 45 mg/L for nitrate). All CBU samples remained within the acceptable nitrate limits. The total non‐carcinogenic health risks for MWC ranged from 0.34 to 2.18, 0.40 to 2.58, and 0.46 to 2.95, respectively, for CBU, and from 0.16 to 6.51, 0.19 to 7.69, and 0.21 to 8.80, respectively, for CBR. Furthermore, a significant percentage of the groundwater samples that were collected in CBU (60.98%, 68.29%, and 75.61%) and CBR (48.21%, 62.50%, and 73.21%) exceeded the THI limit for MWC (THI = 1). Hence, based on the health risk assessment, it is evident that children in the study area have greater health risks than men and women.

Strategy to Assess and Control Nitrosamine Formation in API during Storage: A Sitagliptin Case Study

Strategy to Assess and Control Nitrosamine Formation in API during Storage: A Sitagliptin Case Study

Effect of Nitrates supplementation on Muscle Hypertrophy and Athletic Performance: A Narrative Review

Background and Study Aim. The consumption of nitrate has been linked to various advantages, including aiding recovery by lessening fatigue, enhancing oxygen supply to muscles, and increasing the elimination of metabolic by-products during intense physical activity. Given the rising trend of utilizing dietary supplements for peak athletic performance, this literature review aims to explore the role and promise of nitrate supplementation in influencing muscle function and boosting physical prowess, while also shedding light on its potential perks and drawbacks. Material and Methods. Electronic databases including Web of Science (all databases), PubMed, Scopus, Google Scholar, Science Direct, were explored on June 11, 2022. The search terms were drawn from prior systematic reviews on nitrate supplementation and exercise and informed by a recent narrative review on Nitrates impact on athletic performance and muscle hypertrophy. Results. The findings of this review indicate that nitrate intake, owing to its ability to widen blood vessels, could potentially enhance blood flow and oxygen delivery to muscles during exercise. Consequently, this improved circulation might facilitate better nutrient and oxygen transportation to muscle tissue, thereby fostering muscle development through enhanced nutrient absorption and waste removal during physical exertion. However, it's crucial to note that excessive nitrate consumption might trigger adverse effects related to the formation of nitrosamines. Conclusion. In summary, investigations into the potential advantages of nitrate supplementation, whether through dietary sources or supplements, in augmenting athletic performance are promising. This is evident from the observed effects of increased muscle protein synthesis, reduced muscle soreness, and enhanced cognitive function under stressful conditions. Nonetheless, it's imperative to exercise caution against over-supplementation due to the potential risks of toxicity and associated side effects.

Nitrosamine formation driven by electrochemical chlorination of urine-containing source waters: Effects of operational conditions

We investigated the formation of nitrosamines from urine during electrochemical chlorination (EC) using dimensionally stable anodes. Short-term electrolysis (< 1 h) of urine at 25 mA cm−2 generated seven nitrosamines (0.1–7.4 µg L−1), where N-nitrosodimethylamine, N-nitrosomethylethylamine, and N-nitrosodiethylamine were predominant with concentrations ranging from 1.2 to 7.4 µg L−1. Mechanistic studies showed that the formation kinetics of nitrosamines was influenced by urine aging and composition, with fresh urine generating the highest levels (0.9–5.8 µg L−1) compared with aged, centrifuged, or filtered urine (0.2–4.1 µg L−1). Concurrently, studies on urine pretreatment through filtration and centrifugation underscored the significance of nitrogenous metabolites (such as protein-like products and urinary amino acids) and particle-associated humic fractions in nitrosamine formation during EC of urine. This finding was confirmed through chromatographic and spectroscopic studies utilizing LCOCD, Raman spectra, and 3DEEM fluorescence spectra. Parametric studies demonstrated that the ultimate [nitrosamines] increased at a pH range of 4.5–6.2, and with increasing [bromide], [ammonium], and current density. Conversely, sulfate and carbonate ions inhibited nitrosamine formation. Moreover, the implications of EC in urine-containing source waters were evaluated. The results indicate that regardless of the urine source (individual volunteers, septic tank, swimming pool, untreated municipal wastewater), high levels of nitrosamines (0.1–17.6 µg L−1) were generated, surpassing the potable reuse guideline of 10 ng L−1. Overall, this study provides insights to elucidate the mechanisms underlying nitrosamine formation and optimize the operating conditions. Such insights facilitate suppressing the generation of nitrosamine byproducts during electrochemical treatment of urine-containing wastewater.

Effect of carnosine on nitrosamine formation in gastric-simulated aqueous and lipid environments.

Nitrite salts are frequently utilized as meat additives to improve the quality and safety of processed meat products. However, these salts are associated with the formation of carcinogenic nitrosamines. Given its potential regulating effect on the formation of intermediate molecules, such as nitric oxide, it is hypothesized that carnosine, a meat constituent possessing antioxidant activity and other multiple health benefits, could dampen the formation of nitrosamines. The current study therefore assessed the effect of carnosine on nitrosamine formation in both a monophasic aqueous system and a biphasic water-lipid system simulating a gastric environment. In the monophasic system, relatively high levels of carnosine were required to significantly reduce the formation of different species of nitrosamine compared with the control (no carnosine). While higher levels of some nitrosamines were generated in both phases of the biphasic system, low carnosine concentrations significantly suppressed nitrosamine formation in the aqueous phase, while in the lipid phase, intermediate levels of carnosine were required. At higher carnosine levels, further reduction in nitrosamines was observed in the lipid phase. This study demonstrates the capacity of carnosine to reduce nitrosamine formation in aqueous and lipid environments and suggests the potential of dietary carnosine to lower the risks associated with the consumption of processed meat products. © 2024 His Majesty the King in Right of Canada and The Author(s). Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. Reproduced with the permission of the Minister of Agriculture and Agri-Food Canada.

Highly sensitive two-dimensional ion chromatography mass spectrometry method for nitrite determination in hydroxypropyl methylcellulose

Due to their potential adverse health effects, some N-nitrosamines in drug products are strictly regulated with very low maximum daily intake limits. Nitrosamines can be formed from the reaction of nitrite and secondary or tertiary amines when both species co-exist in the drug synthesis or formulation process. One key strategy to mitigate nitrosamine risk in drugs is to select low-nitrite containing pharma excipients for formulation. It is necessary to develop a sensitive method for trace nitrite determination in pharma excipients as it enables drug producers to study nitrosamine formation kinetics and select excipient suppliers. This study details the development and validation of a two-dimensional ion chromatography mass spectrometry (2D-IC/MS) method for trace nitrite determination in hydroxypropyl methylcellulose (HPMC), one of the most important pharmaceutical excipients used in many drug formulations. The 2D-IC system was operated in heart-cutting mode with a concentrator column coupling the two dimensions. A standard bore anion-exchange column was used in the first dimension (1D) to enable a large volume injection for increased sensitivity and provide improved resolution between nitrite and the interfering chloride peak. A high efficiency microbore anion-exchange column with different selectivity was used in the second dimension (2D) to resolve nitrite from other interfering species. The use of 2D-IC resulted in significantly improved resolution, solving the sensitivity loss issue due to ion suppression from an otherwise 1D separation. MS detection with selective ion monitoring and isotope labeled nitrite internal standard further improve the method specificity, accuracy, and ruggedness, as compared with conductivity detection. For trace determination, it is also extremely important to have a clean blank. For this purpose, a novel cleaning procedure using a strong anion wash was developed to remove nitrite contamination from labware. The optimized method was validated with linearity of nitrite in the concentration range of 18.5–5005.8 ng/g having a regression coefficient of >0.9999, precision with RSD at 3.5–10.1 % and recovery of 90.5–102.4 %. The limit of detection and limit of quantitation were 8.9 and 29.6 ng/g relative to the HPMC sample, or equivalent to 89 and 296 pg/g in the sample solution, respectively.

Nitrite in Pharmaceutical Manufacturing Water: Development of an Ultra-Sensitive Analytical Method, Typical Data, and Discussion of Potential Nitrosamine Formation in Drug Substance and Drug Product from Water

Nitrite in Pharmaceutical Manufacturing Water: Development of an Ultra-Sensitive Analytical Method, Typical Data, and Discussion of Potential Nitrosamine Formation in Drug Substance and Drug Product from Water

Loquat and its phytochemical potential: A promising application in food technology

AbstractThis review study highlights the importance of loquat (Eriobotrya japonica Lindl.) in terms of its nutritional, pharmaceutical, and nutraceutical value. The entire plant, including its seeds, leaves, flowers, fruits, and peel, contains a wide range of bioactive compounds, such as phenolics, carotenoids, triterpenic acids, and organic acids. These compounds exhibit a wide range of beneficial properties such as fighting cancer, reducing inflammation, managing diabetes, combating viruses, preventing mutations, inhibiting nitrosamine formation, killing harmful microorganisms, lowering blood sugar levels, inducing cell death, and protecting the liver. The extraction and separation of such compounds will greatly enhance and expand its potential. Furthermore, the waste generated from the seeds and peel can be effectively used for submerged and solid state biomass production.

A combined metagenome and disease enrichment analysis of nitrosamines present in smokeless tobacco, wiz using molecular docking and functional annotation approach

Smokeless tobacco products (SLTs) are a major concern due to the associated health risks of the carcinogens, toxins, dynamic microbial system and other harmful chemicals present in them. Procured tobacco leaves are sweetened, flavored and processed to yield the various noncombustible forms of SLTs. These SLTs contain a discrete microbial ecosystem which may contribute to the formation of tobacco specific nitrosamines (TSNAs), endotoxins and other pro inflammatory components. In the present study Whole Metagenome Sequencing was carried out for the exploration of microbial communities followed by their functional profiling. In addition to this, novel targets for TSNAs were predicted using the Swiss Target Prediction tool. Further, disease enrichment analysis of various TSNAs present in Wiz was done using Molecular Docking and functional annotation approach using David database. Bacterial, fungal and viral species were found in the sample where more than 50 % of total bacterial species were Proteobacteria followed by Actinobacteria, Firmicutes, Apicomplexa, Bacteroidetes, Basidiomycota and Cyanobacteria phyla. Total 22,766 genes with 64.9 % GC content were found, which were associated with nitrogen metabolism, antibiotic resistance, multidrug transportation, multitoxins, and pro-inflammation. The presence of phages in wiz showed the possibility of horizontal gene transfer. The pathway enrichment analysis of various TSNAs of wiz were found to be associated with numerous diseases, such as Parkinson's disease, schizophrenia, mental depression, Hypertension, male infertility, Acute Kidney disease and various kinds of cancers.This study will help to understand the possible role of microbiota, TSNAs and their genetic contribution to the overall product's effect on human health. The raw data was submitted to NCBI Short Read Archive (SRA) under Bio Project accession number PRJNA837388.

Evaluation of Knowledge and Awareness of Dietary Nitrate Among Clinical Dietitians in Jeddah, Saudi Arabia: A Cross-Sectional Study.

Background and objectives Dietary nitrate (NO3) plays an important role in human physiological processes.In the past, inorganic NO3was viewed negatively due to its link with carcinogenic effects, notably nitrosamine formation in the stomach; yet, current perspectives acknowledge NO3 as a potentially beneficial dietary element. Nutrition professionals (NPs) are crucial in promoting NO3 awareness in health and academic settings. The study aimed toevaluate the knowledge of NPs in Jeddah,Saudi Arabia, regarding the biological roles of dietary NO3, taking into consideration their qualifications and years of experience. Methods A cross-sectional study was conducted among NPs who had graduated from clinical nutrition programs or were employed in clinical or academic settings. A validated 12-item online questionnaire was used to assess dietary NO3 knowledge across five areas: health effects, dietary sources, recommendations, biomarkers of intake, andmetabolism. The nitrate knowledge index (NKI) score was used to evaluate responses. Results Eighty-nine female NPs out of 144 completed the questionnaire. Most were ≤30 years old (75.4%) and had an undergraduate degree in clinical nutrition (70.8%), but 37 of them had ≤3 years of experience (62.7%). Overall, poor knowledge scores were observed among NPs, with a median (25th and 75th percentile) score of 10 (6, 13) out of 23. The majority (64%) perceived NO3 to be beneficial. However, most of the participants did not know its benefits in lowering blood pressure (BP) (68.5%) and were unsure about the effects of nitrate on cognitive function (60.7%) or kidney function (57.3%). Almost half of the NPs were unaware of NO3 sources and unsure about the mechanisms of the conversion of NO3into nitrogen dioxide(NO2) in the mouth (48.3%). Overall, knowledge of factors that affect NO3 content in food was good. No significant differences were observed in the median NKI scores among the participants based on their level of education or years of experience. Conclusion This study suggests NPs lack knowledge about dietary NO3.To address this, educational programs should be developed and implemented in clinical and academic settings.

Development and Validation of a Rapid and Sensitive LC-APCI-MS/MS Method for the determination of three N-nitrosamine impurities in Varenicline tartrate drug substance and drug products

Nitrosamines impurities may be present in low levels in a variety of products that people are exposed to every day. After thorough investigations, regulatory agencies have outlined that the formation of nitrosamines is possible in the presence of secondary, tertiary, or quaternary amines and nitrite salts under acidic reaction conditions. For safety purpose, all API manufacturers must be developed methods to monitor the low levels of each nitrosamine impurity before the release the individual batches. In this article, we have developed novel, rapid and sensitive liquid chromatography Atmospiric pressure chemical ionization Mass spectroscopy (LC-APCI-MS/MS) method for the determination of N-Nitroso Dimethylamine (NDMA), N-Nitroso Diethylamine (NDEA) and N-Nitroso varenicline impurities in the Varenicline Tartrate drug substance and Drug products. Chromatographic separation is achieved using Inert sustain AQ C18 150 × 4.6mm, 3.0μ column with 0.1% formic acid in water as mobile phase A and 0.1% formic acid in methanol as mobile phase B at the 0.6 mL/min flow rate by using gradient mode of elution upto the 25 minutes total run time. The three impurities are successfully ionized and quantified in positive mode of atmospheric pressure chemical ionization (APCI) using multiple reaction monitoring (MRM). This method was validated according to ICH Q2 (R1) guidelines. The method provided excellent S/N ratios with a high linearity range of 0.66-19.88 ppm with respect to Varenicline Tartrate sample concentrations with a regression coefficient &gt;0.995. The recovery for the method was established with a protocol of three-step sample preparation and was satisfactory within 85-115%. The determined LOQ (0.66 ppm) and LOD (0.22 ppm) values are very low with respect to sample concentration which shows the sensitivity Performance of the method. The method can be routinely applied for the detection of N-nitrosamine impurities (NDMA, NDEA and N-Nitroso varenicline) in Varenicline Tartrate drug substance and Drug products.

Nitrosamine Contamination in Pharmaceuticals: Regulatory Perspectives and Control Strategies of USFDA, EMA &amp; HC

Various regulatory authorities were notified the presence of nitrosamine impurities in human medicines including angiotensin II receptor blockers (ARBs), ranitidine, nizatidine and metformin in 2018. The presence of nitrosamines led manufacturers to assessed their products by any means that might inadvertently lead to nitrosamine content and taking steps to mitigate these risks after issuance of safety alerts, recall and withdraw certain batches of these drugs. Importantly, global cooperation by regulatory authorities triggered the investigation of synthetic route, rapid development of analytical procedures and publication of guidelines. This article highlights mainly on risk assessment and control strategies adopted by United States Food and Drug Administration (USFDA) and the European Medicines Agency (EMA), and Health Canada (HC) regulatory bodies. Additionally, compare the acceptable intake (AI) values recommended by these regulatory authorities which will help the manufacturer to either limit or eliminate nitrosamines impurities in their medicines because nitrosamines are probable or possible human carcinogens, hence, it is recommended that the potential causes of nitrosamine formation as well as any other pathways observed and evaluate the risk for nitrosamine contamination or formation in their APIs and drug products. Manufacturers should prioritize evaluation of APIs and drug products based on factors such as maximum daily dose, duration of treatment, therapeutic indication, and number of patients treated for the products which are under pre approval stage and already marketed products.&#x0D; Conclusion: &#x0D; As nitrosamine contamination affects patients worldwide, in case the levels of nitrosamines exceed acceptable limits, or more than one nitrosamine is observed, such products should not be commercialized. All the international regulatory agencies continuing to work with to propose various analytical methodologies to determining nitrosamine content in the API or FPP, risk assessment evaluation and control strategies, extrapolation of toxicological data and various confirmatory test for mutagenicity detection. Due to this rapid action taken by global authorities will help manufacturer to design their manufacturing process to be more robust so that they will timely register their products and reduce the additional cost require for its complete analysis by taking care of consumer’s safety as well.

Lack of Effect of Antioxidants on Biopharmaceutics Classification System (BCS) Class III Drug Permeability

The addition of antioxidants to pharmaceutical products is a potential approach to inhibit nitrosamine formation, particularly in solid oral dosage forms like tablets and capsules. The objective was to assess the effect of ten antioxidants on the permeability of four Biopharmaceutics Classification System (BCS) Class III drugs. Bi-directional drug permeability studies in the absence and presence of antioxidants were performed in vitro across MDCK-II monolayers. No antioxidant increased drug permeability, while the positive control sodium lauryl sulfate always increased drug permeability. Results support that any of the ten antioxidants, up to at least 10 mg, can be added to a solid oral dosage form without modulating passive drug intestinal permeability. Additional considerations are also discussed.

Unveiling the chemical kinetics of aminomethanol (NH2CH2OH): insights into H and O2 photo-oxidation reactions and formamide dominance.

Aminomethanol is released into the atmosphere through various sources, including biomass burning. In this study, we have expounded the chemical kinetics of aminomethanol in the reaction pathways initiated by the hydroxyl radical ( H) with the aid of ab initio//density functional theory (DFT) i.e., coupled-cluster theory (CCSD(T))//hybrid-DFT (M06-2X/6-311++G (3df, 3pd). We have explored various possible directions of the H radical on aminomethanol, as well as the formation of distinct pre-reactive complexes. Our computational findings reveal that the H transfer necessitates activation energies ranging from 4.1 to 6.5kcal/mol from the -CH2 group, 3.5-6.5kcal/mol from the -NH2 group and 7-9.3kcal/mol from the -OH group of three rotational conformers. The H transfer from -CH2, -NH2 and -OH exhibits an estimated total rate constant (k OH) of approximately 1.97 × 10-11cm3 molecule-1s-1 at 300K. The branching fraction analysis indicates a pronounced dominance of C-centered NH2 HOH radicals with a favorability of 77%, surpassing the N-centered HCH2OH (20%) and O-centered NH2CH2 (3%) radicals. Moreover, our investigation delves into the oxidation of the prominently favored carbon-centered NH2 HOH radical through its interaction with atmospheric oxygen molecules. Intriguingly, our findings reveal that formamide (NH2CHO) emerges as the predominant product in the NH2 HOH + 3O2 reaction, eclipsing alternative outcomes such as amino formic acid (NH2COOH) and formimidic acid (HN = C(H)-OH). At atmospheric conditions pertinent to the troposphere, the branching fraction value for the formation of formamide is about 99%, coupled with a rate constant of 5.5 × 10-12cm3 molecule-1 s-1. Finally, we have scrutinized the detrimental impact of formamide on the atmosphere. Interaction of formamide with atmospheric hydroxyl radicals could give rise to the production of potentially perilous compounds such as HNCO. Further, unreacted HCH2OH radicals may initiate the formation of carcinogenic nitrosamines when reacting with trace N-oxides (namely, NO and NO2). This, in turn, escalates the environmental risk factors.