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1-Aminohydantoin (AHD), the residual marker of nitrofurantoin, is usually detected after derivatisation using the derivatisation reagent 2-nitrobenzaldehyde. Avoiding the antibody recognition of the derivatisation reagent is essential for the accurate detection of AHD residues. In this paper, a novel hapten called hapten D was designed, and then, a monoclonal antibody that did not recognise 2-nitrobenzaldehyde was prepared based on this novel hapten. An ultra-sensitive indirect competitive enzyme linked-immunosorbent assay (icELISA) was established under optimal conditions. The 50% inhibition concentration and limit of detection of AHD were 0.056 and 0.0060 ng/mL, respectively, which improved the sensitivity by 9-37-fold compared with the previously reported icELISA methods. The average recovery rates were 88.1%-97.3%, and the coefficient of variation was <8.6%. The accuracy and reliability of the icELISA were verified using liquid chromatography-tandem mass spectrometry. These results demonstrated that the developed icELISA is a useful and reliable tool., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

In the current era of rapid population growth, there has been an increase in resource consumption and the subsequent release of organic pollutants into water bodies by various industries. To address this issue, we have developed a nanocomposite material, Bi 2 S 3 -TiO 2 /HNTs, for electrochemical sensors capable of simultaneously detecting nitrofurantoin (NFT) and 4-nitrophenol (4-NP) contaminants. The nanocomposite material was synthesized using a novel one-pot sol-gel method, and its structural morphology was characterized using techniques such as FE-SEM, FT-IR, HR-TEM, and XRD. The electrochemical sensor exhibited a remarkably low limit of detection (3.2 nM for NFT and 3.5 nM for 4-NP) and a wide concentration range from 0 μM to 260 μM for both NFT and 4-NP, demonstrating their high sensitivity and accuracy for pollutant detection, and furthermore its potential for real-world application was assessed considering pond and tap water as real samples.

The excessive use of nitrofurantoin (NFT) represents a threat to ecosystems and food safety, making it necessary to develop efficient and accurate detection methods. Herein, the Ru/NiFe-LDH-MXene/SPCE electrode was successfully synthesized by one-step electrodeposition and employed to the NFT electrochemical sensing. Combining 2D MXenes with multifunctional 2D layered double hydroxides (LDHs) creates synergistic interactions within the MXene-LDH heterostructures, modifying the electrochemical performance. Furthermore, the incorporation of noble metal nanoparticles and nanoclusters can significantly enhance electrochemical performance by promoting favorable interactions at the metal-carrier interface and optimizing the rearrangement of electronic structure. Based on this, the developed Ru/NiFe-LDH-MXene/SPCE sensor demonstrates remarkable sensitivity (152.44 μA μM -1  cm -2 ) and an ultralow detection limit (2.2 nM). Notably, the sensor was employed for NFT detection in food samples with satisfactory recoveries, making it a promising electrochemical sensor for the detection of NFT., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

More and more attention has been paid to food safety. Due to the overuse and misuse of antibiotics, the problem of antibiotic residues in animal food is one of the important challenges to ensure food safety. The development of a feasible strategy to detect antibiotic residues in animal food has become desirable. In this paper, we creatively synthesize a water-stable fluorescence sensing material, namely, Co(Ⅱ)-Coordination polymer [Co 2 (CA) (L) 0.5 (H 2 O) 3 ] n (L = 1,4-bis(imidazole-1-ylmethyl) benzene, CA= Citric acid). The single crystal X-ray diffraction shows that it crystallizes in tetragonal space group I-4. It is worth mentioning that there exists the rare Co 4 (μ 3 -O) 4 cubane cluster structure and Co 8 cluster units. Those adjacent Co 8 cluster units are connected into an infinite two-dimensional net structure by four flexible bridged L ligands. Finally, the Co(Ⅱ)-Coordination polymer (CP) further develops into the three-dimensional supramolecular structure via the hydrogen bonds of O-H⋯O and C-H⋯O. It could selectively detect the antibiotic-nitrofurantoin (NFT) residue by way of fluorescence quenching, Co-CP for the detection of NFT shows broad linearity from 0 to 200 μM, with a detection limit of 0.13 μM and strong anti-interference ability. It is used to detect the NFT residual of tap water and milk with a spiked recovery of 86.35-112.47 %., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Herein, a facile and highly effective nonenzymatic electrochemical sensing system is designed for the detection of the antibacterial drug nitrofurantoin (NFT). This electrocatalyst is a combination of a trimetallic Prussian blue analogue and conductive polyaniline coated onto a three-dimensional porous nickel foam substrate. A comprehensive set of physicochemical analyses have verified the successful synthesis. The fabricated electrochemical sensor exhibits an impressively low limit of detection (0.096 nM) and quantification (0.338 nM, S/N = 3.3), coupled with a wide linear range spanning from 0.1 nM to 5 mM and a sensitivity of 13.9 μA nM -1 cm -2 . This excellent performance is attributed to the collaborative effects of conducting properties of polyaniline (PANI) and the remarkable redox behavior of the Prussian blue analogue (PBA). When both are integrated into the nickel foam, they create a significantly enlarged surface area with numerous catalytic active sites, enhancing the sensor's efficiency. The sensor demonstrates a high degree of specificity for NFT, while effectively minimizing responses to potential interferences such as flutamide, ascorbic acid, glucose, dopamine, uric acid, and nitrophenol, even when present in 2-3-fold higher concentrations. Moreover, to validate its practical utility, the sensor underwent real sample analysis using synthetic urine, achieving outstanding recovery rates of 118 and 101%.

In the current research, a novel coordination polymer (CP) containing Zn(II) ions as nodes with the chemical formula of [Zn(IPT) 2 ] n (1) has been produced via reaction of Zn(NO 3 ) 2 ·6H 2 O with 5-(3-(1H-imidazol-1-yl)phenyl)-1H-tetrazolate (HIPT), a heterotopic imidazole-tetrazole-bifunctional ligand. The as-prepared complex 1 has been charactered via single crystal X-ray diffraction, elemental analysis, powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA) and fourier transform infrared spectroscopy (FT-IR). Because of its outstanding luminescent performances and stability, the synthesized complex 1 is a kind of excellent material of luminescent sensor of nitrofurantoin (NFT) in the water. The value of K sv for the complex 1 to NFT is about 1.4 × 10 4  M -1 . For the treatment of the peri-implantitis with complex 1, the ELISA test was carried out to determine the levels of the inflammatory cytokines released into the gingival crevicular fluid. The results showed that the levels of the inflammatory cytokines could be significantly reduced by complex 1 treatment. In addition to this, the real time RT-PCR was also conducted, and the data suggested the signaling pathway of TLR-4-NF-κB activation was inhibited by complex 1.

Lutetium vanadate (LuVO 4 ) is a promising material for electrochemical application owing to its good conductivity and electrocatalytic activity. Herein, we demonstrate a facile technique for the synthesis of a LuVO 4 / graphene sheet (GRS) nanocomposite where LuVO 4 is encapsulated with an ultrathin GRS to form a hierarchical structure (LuVO 4 /GRS). The resulting hierarchical LuVO4/GRS architecture was characterized by several analytical and spectroscopic techniques. The resultant electrocatalyst shows superior electrochemical sensing for nitrofurantoin (NFT) with a low detection limit (0.001 μM), wide linear range (0.008-256.0 μM) and excellent sensitivity (1.709 μA μM -1  cm -2 ). It has been demonstrated that the enhanced electrocatalytic performance of LuVO 4 /GRS nanocomposite is due to their excellent electrical conductivity, suitable surface area, high redox reaction and large number of electron transport. In addition, the LuVO 4 /GRS nanocomposite exhibited excellent response towards NFT detection with adequate reproducibility, good repeatability, long-term stability and excellent selectivity over its structural analogs and common interferents. Furthermore, the practical applicability of the proposed electrochemical sensor was successfully applied for determination of NFT in environmental samples with satisfactory results. The LuVO 4 /GRS nanocomposite presented here can serve as a favorable candidate for developing electrochemical sensor and plays an important role in widespread fields., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Despite the ban of nitrofurans (NFs) for use in food production in many countries in the 1990s, NF metabolites in food are still regularly detected during import control testing. We have developed a confirmatory routine method for the detection and quantification of NF metabolites in seafood using LC-MS/MS and validated the method according to the strict criteria in European legislation and Codex Alimentarius. Method characteristics were found to fulfill the criteria. We report for the first time a new false positive for 1-amino-2,4-imidazolidinedione (AHD), the metabolite of Nitrofurantoin (NFT). By using optimized washing procedures, the non tissue bound false positives can be minimized. The results from the validation on both lean and fatty fish and crustaceans, results from proficiency tests and routine use over many years, demonstrates that the method is fit for purpose to determine NF metabolites in the seafood category., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Nitrofurantoin is nitrofuran antibacterial drug that is most used as a veterinary pharmaceutic compound. This compound, as well as other pharmaceuticals can greatly affect the environment, the soil and organisms in it and pollute aquatic ecosystems. Since it has been used for only a few decades, knowledge of their fate and behaviour in the environment is still limited. Because of that, the aim of this study was to experimentally determine the K d values of nitrofurantoin in seven different natural soil and seven different sediment samples with different physico-chemical properties. Sorption phenomena were described with Linear, Freundlich and Dubinin-Radushkevich sorption isotherms. Obtained sorption coefficients (K d ) ranged from 3.967 to 5.121 mLg -1 for sediment samples and 3.634-43.06 mL g -1 for soil samples. The influence of ionic strength and pH of the nitrofurantoin solution and kinetics of the sorption and desorption process were also investigated. Results show that an increase in ionic strength and pH reduces the values of sorption coefficient while the mechanism of nitrofurantoin sorption is the best described with the kinetic model of pseudo-second order., (Copyright © 2019 Elsevier B.V. All rights reserved.)

A simple ultrasonic energy assisted synthesis of β-cyclodextrin (β-CD) supported carbon nanofiber composite (CNF) and its potential application in electrochemical sensing of antibiotic nitrofurantoin (NFT) is reported. The elemental composition and surface morphology of the β-CD/CNF composite was validated through Field emission scanning electron microscopy, energy dispersive X-ray microscopy, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and thermogravimetric analysis. The uniform enfolding of hydrophilic β-CD over CNF enhance the aqueous dispersion and offer abundant active surface to the β-CD/CNF composite. Further, the electrocatalytic efficacy of the β-CD/CNF composite is utilized to fabricate an electrochemical sensor for the high sensitive quantitative detection of NFT. Under optimized analytical conditions, the sensor displays a broad working range of 0.004-308 µM and calculated detection limit of 1.8 nM, respectively. In addition, the sensor showcased a good selectivity, storage, and working stability, with amiable reproducibility. The point-of-care applicability of the sensor was demonstrated with NFT spiked human blood serum and urine sample with reliable analytical performance. The simple, cost-effective NFT sensor based on β-CD/CNF offered outstanding analytical performance in real-world samples with higher reliability., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Transformation of the solid-state form of a drug compound in the lumen of the gastrointestinal tract may alter the drug bioavailability and in extreme cases result in patient fatalities. The solution-mediated anhydrate-to-hydrate phase transformation was examined using an in vitro model with different biorelevant media, simulated fasted and fed state intestinal fluids containing bile salt and dioleoylphosphatidylcholine (DOPC) micelles, DOPC/sodium dodecyl sulfate (SDS) mixture, bile salt solution and water. Two anhydrate compounds (carbamazepine, CBZ and nitrofurantoin, NF) with different overall transformation time into hydrate form were used as model compounds. The transformations were monitored using direct structural information from time-resolved synchrotron X-ray diffraction. The kinetics of these transformations were estimated using multivariate data analysis (principal component analysis, PCA) and compared to those for nitrofurantoin (NF). The study showed that the solution-mediated phase transformation of CBZ anhydrate was remarkably faster in the DOPC/SDS medium compared to transformation in all the other aqueous dispersion media. The conversion time for CBZ anhydrate in water was shorter than for DOPC/SDS but still faster than the conversion seen in fed and fasted state micellar media. The conversion of CBZ anhydrate to hydrate was the slowest in the solution containing bile salt alone. In contrast, the solution-mediated phase transformations of NF did only show limited kinetic dependence on the dispersion media used, indicating the complexity of the nucleation process. Furthermore, when the CBZ and NF material was compacted into tablets the transformation times were remarkably slower. Results suggest that variations in the composition of the contents of the stomach/gut may affect the recrystallization kinetics, especially when investigating compounds with relatively fast overall transformation time, such as CBZ., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Despite the increased request for robust quality systems, the end product may contain unidentified defects or discoloured regions. The foreign matter has to be monitored, identified and its source defined in order to prevent further contamination. However, the identification task can be complicated, since the origin and nature of foreign matter are various. The aim of this study is to provide an efficient foreign matter identification procedure for various substances possibly originating from pharmaceutical manufacturing environment. The surface or cross-section of the uncoated and coated tablets was analysed by utilization of different analytical techniques, such as light microscopy (LM), scanning electron microscopy in combination with energy dispersive X-ray microanalysis (SEM/EDX), Fourier transform infrared spectroscopy (FT-IR) and time-of-flight secondary ion mass spectrometry (ToF-SIMS). The results indicate that the combination of different analytical techniques proved to be a powerful approach in foreign matter identification. Light microscopy and SEM generate information on the morphology of foreign matter particles. EDX provides elemental analysis, which most often serves as final confirmation of the identification. However, FT-IR can be used to obtain information on the compounds chemical structure and conformation, and ToF-SIMS provides sensitivity in cases, where the entire solid dosage form is contaminated with foreign matter., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The present article measured the absorption coefficient spectra and refractive index spectra of nitrofurantoin original drug, which is one kind of nitrofuran drugs, in the terahertz frequency range from 0.2 to 1.8 THz using terahertz time-domain spectroscopy. The results showed that there exist a number of characteristic absorption peaks of nitrofurantoin with different intensity in the range and the absorption coefficient spectra can be used to identify nitrofurantoin. The article also simulated absorption coefficient spectra of nitrofurantoin molecule within 0.2 - 1.8 THz using density functional theory by Gaussian software, and vibrational modes of some peaks in the experimental absorption coefficient spectra were analyzed and identified. The results show that the experimental absorption peaks at 1.25 and 1.60 THz correspond with the theoretical peaks at 1.30 and 1.67 THz, and these experimental peaks were caused by intramolecular vibrational modes of nitrofurantoin.

Molecularly imprinted polymers (MIPs) for nitrofurantoin (NFT) recognition addressing in parallel of two complementary functional groups were created using a noncovalent imprinting approach. Specific tailor-made functional monomers were synthesized: a diaminopyridine derivative as the receptor for the imide residue and three (thio)urea derivatives for the interaction with the nitro group of NFT. A significantly improved binding of NFT to the new MIPs was revealed from the imprinting factor, efficiency of binding, affinity constants and maximum binding number as compared to previously reported MIPs, which addressed either the imide or the nitro residue. Substances possessing only one functionality (either the imide group or nitro group) showed significantly weaker binding to the new imprinted polymers than NFT. However, the compounds lacking both functionalities binds extremely weak to all imprinted polymers. The new imprinted polymers were applied in a flow-through thermistor in organic solvent for the first time. The MIP-thermistor allows the detection of NFT down to a concentration of 5 μM in acetonitrile + 0.2% dimethyl sulfoxide (DMSO). The imprinting factor of 3.91 at 0.1 mM of NFT as obtained by thermistor measurements is well comparable to the value obtained by batch binding experiments., (© 2011 American Chemical Society)

Unlabelled: Due to the potential toxic effects of the nitrofuran family of antibiotics, their use in animals in the food industry has raised health concerns. This study was aimed to develop a lateral flow assay (LFA) based on competitive format for the detection of 1-aminohydantoin (AHD) in meat samples. The assay could be completed in 1 min and detected AHDs derivates (CPAHD) at 3 ng/mL, equivalent to 1.40 ng/mL of AHD, which was much lower than that reported in the literature by similar method. The antibody showed no cross-reactivity with a panel of more than 10 nitrofuran analogs except for nitrofurantoin at a high concentration. The test strip was stable at room temperature for up to 8 wk or at 37 °C for 4 wk. Parallel analyses of meat samples with LFA and enzyme-linked immunosorbent assay (ELISA) obtained data in good agreement. This developed gold nanoparticle based LFA had a good specificity, sensitivity, stability, and reliability. It was potentially suitable for on-the-spot large-scale screening of meat samples, and even more other applications., Practical Application: Nitrofurantoin is one of antibiotics of the nitrofuran family, which has been used not only to prevent and treat diseases, but also to promote growth in animals. However, concerning the carcinogenicity of the metabolite of nitrofurantoin (AHD), a new fast and convenient method for monitoring AHD should be established. We describe the development of a new test assay for rapid screening of meat samples., (© 2011 Institute of Food Technologists®)

The influence of the boron-doping levels in boron-doped diamond film electrodes on the electrochemical response of nitrofurantoin (NFT) and the development of an electroanalytical procedure for NFT determination were investigated. The investigations were carried out using the techniques of cyclic voltammetry and square wave voltammetry on diamond film electrodes with different boron-doping levels (i.e., 5000, 10,000 and 20,000 mg L(-1)). The level of boron-doping in the diamond film electrodes influenced the electrochemical reduction of NFT. The appropriate cyclic voltammetric response of NFT was obtained with Britton-Robinson buffer at pH 4 and for diamond films doped with 10,000 and 20,000 mg L(-1) of boron. These two films were selected for the development of the electroanalytical procedure. The use of square wave voltammetry with the optimized parameters demonstrated a good linear relationship between the peak current and the NFT concentration for a wide range of concentration. The lower limit of detection for the electrodes doped with 10,000 and 20,000 mg L(-1) of boron were 2.69 x 10(-8) mol L(-1) (6.40 microg L(-1)) and 8.15 x 10(-9) mol L(-1) (1.94 microg L(-1)), respectively, while the lower limits of quantification were 8.96 x 10(-8) mol L(-1) (21.33 microg L(-1)) and 2.72 x 10(-8) mol L(-1) (6.47 microg L(-1)), respectively. The applicability of the proposed procedure was tested using a commercial pharmaceutical formulation of NFT, and the results were compared with the procedure recommended by the British Pharmacopeia. The proposed procedure was sensitive, accurate and precise for analysis of NFT and did not require complex preparations or renovations of the electrode surface. This presents the advantage of eliminating mercury waste and minimizing the adsorptive problems related to the use of other electrodic solid surfaces., (Copyright (c) 2009 Elsevier B.V. All rights reserved.)

Studies on residues in milk used for human consumption have increased due to health concerns and priority interest in the control of potentially risky drugs. The protein BCRP/ABCG2, present in the mammary epithelia, actively extrudes drugs into milk and can be modulated by isoflavones. Nitrofurantoin is a specific BCRP substrate which is actively excreted into milk by this transporter. In this research, we studied nitrofurantoin transport into milk in four experimental groups: G1-calves fed forage with isoflavones; G2-calves fed forage with isoflavones and administered exogenous genistein and daidzein; G3-calves fed forage without isoflavones; G4-calves fed forage without isoflavones and administered exogenous genistein and daidzein. Results show increased levels of nitrofurantoin in milk from calves without isoflavones (G3) and decreased nitrofurantoin residues in milk when isoflavones were present, either by forage (G1 and G2) or by exogenous administration (G4). The values of C(max) in milk were significantly lower in those groups with isoflavones in forage (G1, G2). Plasma levels were low and unmodified among the groups. Inter-individual variation was high. All these results seem to point to a feasible control of drug secretion into milk through isoflavones in the diet when the drug is a good BCRP/ABCG2 substrate.

Novel molecularly imprinted polymers (MIPs) for the recognition of nitrofurantoin (NFT) were prepared by photoinitiated polymerisation in polar solvent using 2,6-bis(methacrylamido) pyridine (BMP) as the functional monomer and carboxyphenyl aminohydantoin (CPAH) as the analogue of the template. The binding constants of the complex between BMP and nitrofurantoin or CPAH in DMSO were determined with 1H NMR titration to be 630+/-104 and 830+/-146 M(-1), respectively. To study the influence of the functional monomer, two polymer compositions were prepared containing the template, the functional monomer and the crosslinker in the molar ratio 1:1:12 for MIP1 and 1:4:20 for MIP2, respectively. The imprinting factor at saturation concentration of nitrofurantoin, which is the ratio of the amount bound to the MIP and the non-imprinted control polymer (NIP), was determined to be 2.47 for MIP1 and 2.49 for MIP2. The cross reactivity of the imprinted polymers seems to be determined by the ability to form hydrogen bonds to the functional monomer while the shape of the molecule has no real influence.

A simple, rapid, selective and sensitive spectrofluorimetric method was described for the analysis of three nitrofuran drugs, namely, nifuroxazide (NX), nitrofurantoin (NT) and nitrofurazone (NZ). The method involved the alkaline hydrolysis of the studied drugs by warming with 0.1 M sodium hydroxide solution then dilution with distilled water for NX or 2-propanol for NT and NZ. The formed fluorophores were measured at 465 nm (lambda (Ex) 265 nm), 458 nm (lambda (Ex) 245 nm) and 445 nm (lambda (Ex) 245 nm) for NX, NT and NZ, respectively. The reaction pathway was discussed and the structures of the fluorescent products were proposed. The different experimental parameters were studied and optimized. Regression analysis showed good correlation between fluorescence intensity and concentration over the ranges 0.08-1.00, 0.02-0.24 and 0.004-0.050 microg ml(-1) for NX, NT and NZ, respectively. The limits of detection of the method were 8.0, 1.9 and 0.3 ng ml(-1) for NX, NT and NZ, respectively. The proposed method was validated in terms of accuracy, precision and specificity, and it was successfully applied for the assay of the three nitrofurans in their different dosage forms. No interference was observed from common pharmaceutical adjuvants. The results were favorably compared with those obtained by reference spectrophotometric methods.

Nitrofurans are used widely to treat animal diseases and were identified as the major compounds in many worldwide drug residue violations. To develop a rapid and convenient detection method to measure the residue of nitrofurantoin, we designed an immunogen and prepared a polyclonal antibody to develop an immunoassay in this study. The antibodies obtained were characterized by an indirect cELISA method and showed excellent specificity and sensitivity with IC50 of 3.2 ppb and no cross-reaction with most related species and compounds. Considering that nitrofurans often are used illegally to feed animals through drinking water, we measured the residue of nitrofurantoin in water spiked by the drug. The recovery rates are in the ranges of 88-103% for interassay and 90-103% for intra-assay. The CVs are in the ranges of 3.1-11.4% for interassay and 2.7-6.2% for intra-assay. The detection limit was determined to be 0.2 ppb. The immunoassay developed in this study is suitable to be used as a screening method to detect residues of nitrofurantoin in drinking water for animals.

Within the EU, the use of nitrofurans is prohibited in food production animals. For this reason detection of these compounds in feedingstuffs, at whatever limit, constitutes an offence under EU legislation. This detection generally involves the use of analytical methods with limits of quantification lowers than 1 mg kg(-1). These procedures are unsuitable for the detection and confirmation of trace amounts of nitrofurans in feedingstuffs due to contamination. It is well known that very low concentrations of these compounds can be the source of residues of nitrofuran metabolites in meat and other edible products obtained from animals consuming the contaminated feed. The present multi-compound method was capable of measuring very low concentrations of nitrofurantoin (NFT), nitrofurazone (NFZ), furazolidone (FZD) and furaltadone (FTD) in animal feed using nifuroxazide (NXZ) as internal standard. Following ethyl acetate extraction at mild alkaline conditions and purification on NH2 column, the nitrofurans are determined using liquid chromatography with photodiode-array detection (LC-DAD). It was observed a CCalpha ranged from 50 to 100 microg kg(-1). The liquid chromatography-tandem mass spectrometric (LC-MS/MS) procedure was used to confirm the identity of the suspected presence of any of the nitrofuran compounds.

Nitrofuran antibiotics have been banned for use in food-producing animals in many countries, including the European Union, owing to the threat they pose to human health. Research continues into the accumulation of these drugs in animal tissues and into the appropriate methods for their detection. In this study, an LC-MS/MS method is presented for the detection of the parent compounds, furazolidone, nitrofurantoin, furaltadone and nitrofurazone, in eggs. The parent compounds are first extracted into ethyl acetate, fats are removed by partition between acetonitrile and hexane, and the concentrated sample is analysed by LC-MS/MS. Decision limits (CCalpha) for the parents were < or =1 microg kg-1 for all four compounds. Within-day and between-day CVs are well within the limits stated in Commission Decision 2002/657/EC. The method provides an alternative to the testing of side-chain metabolites in eggs, which is particularly important in the case of nitrofurazone, where semicarbazide contamination of food has been attributed to sources other than nitrofurazone use. This method was used together with a method for the detection of the side-chain metabolite compounds, 3-amino-2-oxazolidinone (AOZ), 3-amino-5-morpholinomethyl-1,3-oxazolidin-2-one (AMOZ), 1-amino-hydantoin (AHD) and semicarbazide (SEM), to study the accumulation and distribution of nitrofurans in eggs. Eggs were collected from four groups of hens that had been treated with one of the nitrofurans at a feed concentration of 300 mg kg-1 for 1 week. Parent compounds and metabolites were found in the yolk, albumen and shell. Albumen/yolk ratios for the parent compounds were 0.7, 0.82, 0.83 and 0.31 for furazolidone, furaltadone, nitrofurantoin and nitrofurazone, respectively. Ratios for the side-chain metabolites were 1.02, 1.06, 0.83 and 0.55 for AOZ, AMOZ, AHD and SEM, respectively. However, 50% of the total SEM residues were found in eggshell. This may be significant if eggshell products reach the consumer.

In this study, solvent-mediated phase transformations of theophylline (TP) and nitrofurantoin (NF) were measured in a channel flow intrinsic dissolution test system. The test set-up comprised simultaneous measurement of drug concentration in the dissolution medium (with UV-Vis spectrophotometry) and measurement of the solid-state form of the dissolving solid (in situ with Raman spectroscopy). The solid phase transformations were also investigated off-line with scanning electron microscopy. TP anhydrate underwent a transformation to TP monohydrate, and NF anhydrate (form beta) to NF monohydrate (form II). Transformation of TP anhydrate to TP monohydrate resulted in a clear decrease in the dissolution rate, while the transformation of NF anhydrate (form beta) to NF monohydrate (form II) could not be linked as clearly to changes in the dissolution rate. The transformation of TP was an order of magnitude faster than that of NF. The presence of a water absorbing excipient, microcrystalline cellulose, was found to delay the onset of the transformation of TP anhydrate. Combining the measurement of drug concentration in the dissolution medium with the solid phase measurement offers a deeper understanding of the solvent-mediated phase transformation phenomena during dissolution., ((c) 2006 Wiley-Liss, Inc. and the American Pharmacists Association)

Depletion of the nitrofuran antibiotics furazolidone, furaltadone, nitrofurantoin and nitrofurazone and their tissue-bound metabolites AOZ, AMOZ, AHD and SEM from pig muscle, liver and kidney tissues is described. Groups of pigs were given feed medicated with one of the nitrofuran drugs at a therapeutic concentration (400?mg?kg(-1)) for ten days. Animals were slaughtered at intervals and tissue samples collected for analysis for six weeks following withdrawal of medicated feed. These samples were analysed both for parent nitrofurans (using LC-MS/MS and HPLC-UV), and for tissue-bound metabolites (using LC-MS/MS). The parent drugs were detectable only sporadically and only in pigs subjected to no withdrawal period whatsoever. This confirms the instability of the four major nitrofuran antibiotics in edible tissues. In contrast, the metabolites accumulated to high concentrations in tissues (ppm levels) and had depletion half lives of between 5.5 and 15.5 days. The metabolites of all four drugs were still readily detectable in tissues six weeks after cessation of treatment. This emphasizes the benefits of monitoring for the stable metabolites of the nitrofurans.

Nitrofuran antibiotics were previously used in animal healthcare but are now prohibited. Semicarbazide is a breakdown product of 5-nitrofurazone and protein-bound semicarbazide is used as a marker residue for the illegal use of 5-nitrofurazone. However, the presence of the prohibited semicarbazide has been reported in some food items of animal origin. A novel observation is reported that semicarbazide can be detected in Finnish crayfish samples, i.e. crustacea, never medicated with nitrofurazone. The origin of the semicarbazide is presently unknown. Positive identification was undertaken by liquid chromatography coupled with tandem mass spectrometry detection. The level of semicarbazide was determined as the protein-bound form as well as the total amount of semicarbazide in the sample. The average levels of total semicarbazide and the protein-bound form were 4.2 and 0.5 ng g(-1) fresh crayfish meat, respectively. All the tested samples (n = 18) contained traces of semicarbazide, the highest amount being 12 ng g(-1) fresh crayfish meat.

An UV spectroscopic method is proposed to analyze mixtures of the nitrofuran derivatives, nitrofurantoin, furaltadone and furazolidone, used in veterinary. The change of absorption spectra due to photo-decomposition is used. A 20% dimethylformamide/water, basic medium of pH 9.4 (ammonium chloride/ammonia) and a time of irradiation of 15 s are selected. Calibration graphs are established, with the percentage of decrease of absorbance as analytical signal, in the range 2-10 microg ml(-1). To analyze mixtures of the three compounds the partial least-squares (PLS) multivariate analysis method is used with the spectra obtained by subtracting the spectra after irradiation to the original spectra. Good results have been obtained in the analysis of synthetic samples and a formulation containing all these compounds.

N-Allyl-4-(N-2'-hydroxyethyl)amino-1,8-naphthalimide (AHEAN), a naphthalimide derivative, was synthesized as a new fluorophore for optical chemical sensor preparation. To prevent leakage of the fluorophore, AHEAN was photo-copolymerized with 2-hydroxypropyl methacrylate on a glass surface treated with a silanizing agent. An optical chemical sensor based on AHEAN can be utilized for nitrofurantoin assay based on fluorescence quenching. The sensor shows sufficient repeatability, selectivity and a fast response of less than 30 s. Nitrofurantoin can be determined in the range between 1.00 x 10(-6) and 1.00 x 10(-3) mol l(-1) with a detection limit of 4.8 x 10(-7) mol l(-1). Most commonly co-existing drug substances and ions do not interfere with the nitrofurantoin assay. The sensor was applied to the analysis of pharmaceutical and urine samples.

A HPLC method with coulometric detection has been established to carry out the separation of the three nitrofuran derivatives, nitrofurantoin, furazolidone and furaltadone. A Nova-Pak C18 column (150 x 3.9 mm) and a Coulochem II detector from ESA have been used. After obtaining the hydrodynamic curves of the three compounds in the porous graphite electrode a potential of -600 mV was selected as the working potential. The influence of other variables such as mobile phase composition and flow-rate were studied. The mobile phase considered as an optimum was acetonitrile-0.1 M aqueous solution of sodium perchlorate (28:72), with 0.5% glacial acetic acid. The oxygen of the mobile phase was removed with a vacuum system on-line and a nitrogen stream was used to remove the oxygen of the samples. The calibration graphs and the detection limits were established. The method proposed was used, with good results, for the determination of the three compounds in milk.

A highly sensitive and selective HPLC method was developed and validated for the determination of nitrofurantoin in human plasma and urine. The method involves the liquid-liquid extraction of drug and internal standard from plasma with ethyl acetate followed by evaporation and reconstitution in mobile phase. Urine samples were simply diluted with purified water. UV detection was done at 370 nm. The limit of quantification for nitrofurantoin in plasma was 0.010 micrograms/ml. In urine nitrofurantoin could be quantified down to 0.380 microgram/ml. Linearity was proven over the whole calibration range in plasma (2.48-0.0100 microgram/ml) as well as in urine (187 micrograms/ml-0.380 microgram/ml). The method was validated according to Good Laboratory Practice guidelines and its suitability was demonstrated by analysis of samples from a pharmacokinetic study.

A liquid chromatographic (LC) method was developed for the simultaneous determination of nitrofurazone (NFZ), nitrofurantoin (NFT), and furazolidone (FZD) in catfish muscle tissue. The drugs were extracted from the tissue with acetonitrile, and the lipids were removed from the extract with hexane. The acetonitrile extract was evaporated by rotary evaporation, and the resultant drug residues were dissolved with LC mobile phase. The mixture was sonicated, centrifuged, and filtered. The drugs were determined by using LC with a C18 reversed-phase (ODS Hypersil) column, a mobile phase of acetonitrile-1% aqueous acetic acid (25 + 75), and a photodiode array ultraviolet detector at 375 nm. NFZ, NFT, and FZD were each determined in catfish tissue at 5 fortification levels (80, 40, 20, 10, and 5 ng drug/g tissue). Average recoveries of each of the 3 drugs at each level ranged from 70.7 to 101.5%, and relative standard deviations ranged from 2.2 to 18.6%. The limit of detection of each drug was approximately 1 ng drug/g tissue, and the limit of quantitation was 5 ng drug/g tissue. In the second part of the study, the method was used to determine nitrofuran residues incurred in catfish tissue. Live channel catfish were intravascularly doses (10 mg/kg body wt) with NFZ to generate drug-incurred fish muscle tissue. Incurred NFZ levels exceeded 400 ng drug/g tissue at 2 h after dosing but decreased rapidly to approximately 1 ng drug/g tissue by 8 h after dosing, as determined by this method.

The stability and redispersion properties of nitrofurantoin dispersions are experimentally studied using simple but reproducible techniques. Solutions of different electrolyte concentrations and pH values are employed as dispersing media. The pH appears to be a determinant factor in the properties studied. Thus, with all the electrolytes considered (NaCl, CaCl2, and AlCl3, almost optimum redispersion was achieved when the pH was maintained close to neutrality. However, the important effect of AlCl3 as compared with the other electrolytes is also clearly demonstrated. Especially interesting are the results obtained when 0.1% Carbopol is added to the suspensions. The important effect of this polymer on the surface charge of nitrofurantoin, mainly at pH 7, manifests in excellent redispersion of the suspensions with either of the electrolytes employed. Using simple expressions that approximate the equations proposed in the DLVO theory of interaction between colloidal particles, the variation of the total interaction energy between nitrofurantoin particles is calculated as a function of interparticle distance. The results are compared with the experimental determinations of the sedimentation and redispersion properties of nitrofurantoin. Although some discrepancies between theory and experiments are found, the results indicate a reasonable agreement between the general features of both.

The electrophoretic mobility of nitrofurantoin (based on the microelectrophoresis method) has been studied in dilute dispersions of the drug. Specifically, the effect of NaCl, CaCl2 and AlCl3, pH, and a thickener, Carbopol 934, was determined. The electrophoretic mobility (mu) increases in absolute terms when the pH is raised between 3 and 9, although mu remains negative in this pH range. The variation of absolute mobility ([mu[) with NaCl concentration shows a pronounced maximum for a concentration of about 10(-4) M. However, when the concentration of CaCl2 in the medium is increased, [mu[ decreases steadily. The effect of AlCl3 concentration on the mobility is markedly influenced by the pH of the dispersing medium although a general trend is observed for mu to become more positive with increasing concentration of the salt. Finally, Carbopol 934 appears to impart an extra negative charge to the nitrofurantoin surface, since higher negative mobilities were measured in the presence of the polymer.

The high-performance liquid-chromatographic method described here for the quantitative analysis for nitrofurantoin in urine and plasma involves direct analysis of urine samples and analysis of plasma samples after protein precipitation by methanol. The assay, which requires only 0.2 ml of biological fluid and shows a linear relationship in the range 0.02 to 200 mg/liter, can be performed in 9 min and is reproducible (CV less than 2%). Results for nitrofurantoin so obtained correlate well with those obtained by the Hyamine 10-X spectrophotometric method (CV = 2%), but the present method is more sensitive. With no modification, the present procedure can also be used for nitrofurazone. The sensitivity, accuracy, and convenience of the method make it suitable for clinical monitoring and pharmacokinetic/bioavailability studies with 5-nitrofuran derivatives.

A reversed-phase high-performance liquid chromatographic (HPLC) analysis of oral suspensions for nitrofurantoin (1) and 3-(5-nitrofurfurylideneamino)hydantoic acid (2), an impurity derived from 1, is presented. The concentration of the impurity ranged from 20 to 300 micrograms/mL in several lots of commercial oral suspensions. Conversion of 1 to 2 with citrate buffer, an excipient in the oral suspension, was achieved; selective hydantoin ring cleavage was accomplished in preference to the generally observed cleavage at the azomethine linkage. The hydantoic acid 2 was synthesized and identified by NMR, IR, TLC, and elemental analysis.

A fluorescence method is presented for the determination of nitrofurantoin based on conversion of the drug to a fluorescent substance. The method requires 0.1-0.5 ml of plasma or diluted urine and is 10 times more sensitive than the commonly used colorimetric method.

Ethylcellulose was used as an efficient retarding material to prepare nitrofurantoin or nalidixic acid microcapsules. The dissolution rates of the different preparations have found to increase in alkaline rather than in acidic media. Considerable retardation in the rate and extent of release from 2:1, 1:1 and 1:2 drug-polymer ratios were observed as compared with those of the plain drugs. Absorption study in man proved that formulations containing 2:1 ratios have delayed urinary excretion rates by 2 h, however, the total cumulative amounts excreted from all samples remained almost constant. Man volunteers administered the 2:1 drug-polymer microcapsules did not suffer gastric irritation, usually produced after three consecutive d from taking the plain drugs. Experiments in male albino rats showed that the coated drugs did not produce gastric hemorrhage seen with the same doses of the uncoated ones.

Employing the dispersion technique the influence of mannitol and polyethylene glycol (PEG) 6000 on the in-vitro dissolution of nitrofurantoin was investigated. Dispersions of the drug with PEG 6000 showed faster dissolution rates when compared with dispersions of the drug in mannitol. Tablet formulation of the drug--PEG 6000 dispersion exhibited better drug releasing properties as compared to tablets prepared from the drug's PEG 6000 physical mixture, or the drug's formulation with Avicel PH 101.

Nitrofurantoin is a urinary tract antibacterial agent whose clinical effectiveness depends on the high urinary drug levels encountered during therapeutic drug dosage. Under these conditions, only low blood drug concentrations are usually found. On the basis of urinary nitrofurantoin excretion determined after oral and intravenous drug administration, orally administered nitrofurantoin in a suitable dosage form is well absorbed. In vitro testing does not accurately reflect nitrofurantoin bioavailability, which is affected by formulation differences, drug particle size, and dosage form. Nitrofurantoin is readily absorbed and quickly distributed into most body fluids. It is rapidly excreted in large amounts in bile and urine. With the exception of the active drug secretion in the kidney tubule and biliary drug transport, nitrofurantoin transfer across body membranes occurs by diffusion. Nitrofurantoin has a short elimination half-life in whole blood or plasma. In conjunction with its rapid excretion by the primary routes, there is little evidence for any prolonged binding of nitrofurantoin to either plasma proteins or tissues. The first-order kinetics involved in nitrofurantoin absorption and elimination is most appropriately described by a one-compartment open model. Biliary and urinary excretion of unchanged nitrofurantoin and enzymatic degradation are the primary means of elimination.

Experiments were carried out to determine the effect of urea and creatinine on the solubility of nitrofurantoin in water at different temperature and pH conditions. The addition of urea to aqueous media increased nitrofurantoin solubility up to a maximum concentration level and then decreased solubility at higher urea concentrations. The amount of urea needed to bring about maximum nitrofurantoin solubility was dependent on temperature and ranged between 1.75 and 2.50%. Spectral studies suggest a possible interaction between urea and nitrofurantoin molecules. Nitrofurantoin solubility increased with an increasing creatinine concentration ranging from 0.05 to 1.6%. Spectral studies indicate a strong interaction between creatinine and nitrofurantoin molecules in solution. The combined effect of urea and creatinine of the solubility of nitrofurantoin could account for the absence of crystalluria with this drug, even though unusually high concentrations in urine have been reported.