Mechanistic Insight of Polymer Effects on the Kinetic of Solution-Mediated Phase Transformation of Nitrofurantoin Anhydrate to Monohydrate.

PURPOSE: Nitrofurantoin is an effective antibacterial drug for the treatment of lower urinary tract infection. However, the anhydrate form can easily transform to the less soluble hydrate form (monohydrate) during dissolution, resulting in a reduction of dissolution rate and oral bioavailability. Therefore, inhibition of phase transformation is vital to stabilize the quality of drugs. METHODS: In this work, the potential of polyethylene glycol (PEG 8000), polyvinyl pyrrolidone (PVP K30), poloxamer 188 and hydroxypropyl methylcellulose (HPMC) to inhibit the hydration of nitrofurantoin during dissolution was investigated by experimental and simulation approaches. RESULTS: The rates of phase transformation were decreased in the presence of PEG 8000 and poloxamer 188, and PVP K30 and HPMC completely inhibited the phase transformation of anhydrate. The abundant hydrogen bond donor and acceptor groups of PVP and HPMC may easily establish intermolecular interactions with nitrofurantoin molecules, accounting for stronger inhibition of nucleation. Besides, the molecular dynamic simulation further indicated the formation of more extensive interactions between PVP K30 (or HPMC) and the (111) face of monohydrate, suggesting that the strong absorption of polymers on the surface and thus block the sites for incorporation of new growth. CONCLUSION: This study provides a mechanistic insight into the inhibition of nitrofurantoin hydration by polymeric additives, which helps design formulations and improve the physical stability of anhydrate.

Dynamics of microbial communities during biotransformation of nitrofurantoin.

The purpose of this research was to investigate the biodegradation of nitrofurantoin (NFT), a typical nitrofuran antibiotic of potential carcinogenic properties, by two microbial communities derived from distinct environmental niches - mountain stream (NW) and seaport water (SS). The collected environmental samples represent the reserve of the protected area with no human intervention and the contaminated area that concentrates intense human activities. The structure, composition, and diversity of the communities were analyzed at three timepoints during NFT biodegradation. Comamonadaceae (43.2%) and Pseudomonadaceae (19.6%) were the most abundant families in the initial NW sample. The top families in the initial SS sample included Aeromonadaceae (31.4%) and Vibrionaceae (25.3%). The proportion of the most abundant families in both consortia was remarkably reduced in all samples treated with NFT. The biodiversity significantly increased in both consortia treated with NFT suggesting that NFT significantly alters community structure in the aquatic systems. In this study, NFT removal efficiency and transformation products were also studied. The biodegradation rate decreased with the increasing initial NFT concentration. Biodegradation followed similar pathways for both consortia and led to the formation of transformation products: 1-aminohydantoin, semicarbazide (SEM), and hydrazine (HYD). SEM and HYD were detected for the first time as NFT biotransformation products. This study demonstrates that the structure of the microbial community may be directly correlated with the presence of NFT. Enchanced biodiversity of the microbial community does not have to be correlated with increase in functional capacity, such as the ability to biodegradation because higher biodiversity corresponded to lower biodegradation. Our findings provide new insights into the effect of NFT contamination on aquatic microbiomes. The study also increases our understanding of the environmental impact of nitrofuran residues and their biodegradation.

Hybrid structures of cobalt-molybdenum bimetallic oxide embedded in flower-like molybdenum disulfide for sensitive detection of the antibiotic drug nitrofurantoin.

Excessive residues of nitrofurantoin (NFT) can cause serious contamination of water bodies and food, and potential harm to ecosystems and food safety. Given that, rapid and efficient detection of NFT in real samples is of particular importance. MoS2 is a promising electrochemical material for this application. Here, MoS2 was modulated by Metal-organic framework through the interfacial microenvironment to enhance the catalytic activity and carbonized to form Co2Mo3O8 nanosheets with high electrical activity. The resulting Co2Mo3O8/MoS2 hybrid structure can be used to prepare highly sensitive NFT electrochemical sensor. The Co2Mo3O8/MoS2@CC electrochemical sensor exhibits strong electrochemical properties due to its fast electron transfer, excellent electrical conductivity, abundant defect sites, and high redox response. Based on this, this electrochemical sensor exhibited excellent electrocatalytic activity for NFT with a wide linear detection range, low detection limit, and high sensitivity. Moreover, the electrode was successfully applied to detect NFT in milk, honey, and tap water, strongly confirming its potential in real samples. This work could furnish the evidence for interfacial microenvironmental regulation of MoS2, and also offer a novel candidate material for NFT sensing.

Molecular Basis of Interactions between the Antibiotic Nitrofurantoin and Human Serum Albumin: A Mechanism for the Rapid Drug Blood Transportation.

Nitrofurantoin is an antimicrobial agent obtained through the addition of a nitro group and a side chain containing hydantoin to a furan ring. The interactions of the antibiotic with human serum albumin (HSA) have been investigated by fluorescence, UV-VIS, Fourier transform infrared spectroscopy (FTIR) spectroscopy, and protein-ligand docking studies. The fluorescence studies indicate that the binding site of the additive involves modifications of the environment around Trp214 at the level of subdomain IIA. Fluorescence and UV-VIS spectroscopy, displacement studies, and FTIR experiments show the association mode of nitrofurantoin to HSA, suggesting that the primary binding site of the antibiotic is located in Sudlow's site I. Molecular modeling suggests that nitrofurantoin is involved in the formation of hydrogen bonds with Trp214, Arg218, and Ser454, and is located in the hydrophobic cavity of subdomain IIA. Moreover, the curve-fitting results of the infrared Amide I' band indicate that the binding of nitrofurantoin induces little change in the protein secondary structure. Overall, these data clarify the blood transportation process of nitrofurantoin and its rapid transfer to the kidney for its elimination, hence leading to a better understanding of its biological effects and being able to design other molecules, based on nitrofurantoin, with a higher biological potential.

Solvothermal Preparation of a Lanthanide Metal-Organic Framework for Highly Sensitive Discrimination of Nitrofurantoin and l-Tyrosine.

Metal-organic frameworks (MOFs) have been rapidly developed for their broad applications in many different chemistry and materials fields. In this work, a multi-dentate building block 5-(4-(tetrazol-5-yl)phenyl)-isophthalic acid (H3L) containing tetrazole and carbolxylate moieties was employed for the synthesis of a two-dimensional (2D) lanthanide MOF [La(HL)(DMF)2(NO3)] (DMF = N,N-dimethylformamide) (1) under solvothermal condition. The fluorescent sensing application of 1 was investigated. 1 exhibits high sensitivity recognition for antibiotic nitrofurantoin (Ksv: 3.0 × 103 M-1 and detection limit: 17.0 µM) and amino acid l-tyrosine (Ksv: 1.4 × 104 M-1 and detection limit: 3.6 µM). This work provides a feasible detection platform of 2D MOFs for highly sensitive discrimination of antibiotics and amino acids.

A Combined Experimental and Theoretical Study of Nitrofuran Antibiotics: Crystal Structures, DFT Computations, Sublimation and Solution Thermodynamics.

Single crystal of furazolidone (FZL) has been successfully obtained, and its crystal structure has been determined. Common and distinctive features of furazolidone and nitrofurantoin (NFT) crystal packing have been discussed. Combined use of QTAIMC and Hirshfeld surface analysis allowed characterizing the non-covalent interactions in both crystals. Thermophysical characteristics and decomposition of NFT and FZL have been studied by differential scanning calorimetry (DSC), thermogravimetric analysis (TG) and mass-spectrometry. The saturated vapor pressures of the compounds have been measured using the transpiration method, and the standard thermodynamic functions of sublimation were calculated. It was revealed that the sublimation enthalpy and Gibbs energy of NFT are both higher than those for FZL, but a gain in the crystal lattice energy of NFT is leveled by an entropy increase. The solubility processes of the studied compounds in buffer solutions with pH 2.0, 7.4 and in 1-octanol was investigated at four temperatures from 298.15 to 313.15 K by the saturation shake-flask method. The thermodynamic functions of the dissolution and solvation processes of the studied compounds have been calculated based on the experimental data. Due to the fact that NFT is unstable in buffer solutions and undergoes a solution-mediated transformation from an anhydrate form to monohydrate in the solid state, the thermophysical characteristics and dissolution thermodynamics of the monohydrate were also investigated. It was demonstrated that a combination of experimental and theoretical methods allows performing an in-depth study of the relationships between the molecular and crystal structure and pharmaceutically relevant properties of nitrofuran antibiotics.

The structures of E. coli NfsA bound to the antibiotic nitrofurantoin; to 1,4-benzoquinone and to FMN.

NfsA is a dimeric flavoprotein that catalyses the reduction in nitroaromatics and quinones by NADPH. This reduction is required for the activity of nitrofuran antibiotics. The crystal structure of free Escherichia coli NfsA and several homologues have been determined previously, but there is no structure of the enzyme with ligands. We present here crystal structures of oxidised E. coli NfsA in the presence of several ligands, including the antibiotic nitrofurantoin. Nitrofurantoin binds with the furan ring, rather than the nitro group that is reduced, near the N5 of the FMN. Molecular dynamics simulations show that this orientation is only favourable in the oxidised enzyme, while potentiometry suggests that little semiquinone is formed in the free protein. This suggests that the reduction occurs by direct hydride transfer from FMNH- to nitrofurantoin bound in the reverse orientation to that in the crystal structure. We present a model of nitrofurantoin bound to reduced NfsA in a viable hydride transfer orientation. The substrate 1,4-benzoquinone and the product hydroquinone are positioned close to the FMN N5 in the respective crystal structures with NfsA, suitable for reaction, but are mobile within the active site. The structure with a second FMN, bound as a ligand, shows that a mobile loop in the free protein forms a phosphate-binding pocket. NfsA is specific for NADPH and a similar conformational change, forming a phosphate-binding pocket, is likely to also occur with the natural cofactor.

Drug-Drug Binary Solids of Nitrofurantoin and Trimethoprim: Crystal Engineering and Pharmaceutical Properties.

With the aim of developing multidrug solids through a tuned crystal engineering approach, we have selected two antiurinary infective drugs, namely, nitrofurantoin (NF) and trimethoprim (TMP) and isolated eight binary drug-drug solid solvates along with a nonsolvated cocrystal. Crystal structure analyses were performed for eight of these solids and rationalized in terms of known supramolecular synthons formed by pyrimidine, imide, and amine functionalities. Notably, the TMP-NF anhydrous cocrystal and its ionic cocrystal hydrate exhibit enhanced equilibrium solubilities compared to pure NF or the simple NF hydrate. Furthermore, the ionic cocrystal hydrate exhibits greater antibacterial activity against the Gram-negative bacteria, E. coli, compared to the parent TMP and NF at the lowest concentration of 3.9 µg/mL. This study indicates initial pathways using the cocrystal methodology that would help to eventually arrive at an antiurinary cocrystal with optimal properties.

Combined Effect of Nitrofurantoin and Plant Surfactant on Bacteria Phospholipid Membrane.

Due to the increasing use of antibiotics, measures are being taken to improve their removal from the natural environment. The support of biodegradation with natural surfactants that increase the bioavailability of impurities for microorganisms that degrade them, raises questions about their effect on bacterial cells. In this paper we present analysis of the interaction of nitrofurantoin (NFT) and saponins from the Saponaria officinalis on the environmental bacteria membrane and the model phospholipid membrane mimicking it. A wide perspective of the process is provided with the Langmuir monolayer technique and membrane permeability test with bacteria. The obtained results showed that above critical micelle concentration (CMC), saponin molecules are incorporated into the POPE monolayer, but the NFT impact was ambiguous. What is more, differences in membrane permeability between the cells exposed to NFT in comparison to that of the non-exposed cells were observed above 1.0 CMC for Achromobacter sp. KW1 or above 0.5 CMC for Pseudomonas sp. MChB. In both cases, NFT presence lowered the membrane permeability. Moreover, the Congo red adhesion to the cell membrane also decreased in the presence of a high concentration of surfactants and NFT. The results suggest that saponins are incorporated into the bacteria membrane, but their sugar hydrophilic part remains outside, which modifies the adsorption properties of the cell surface as well as the membrane permeability.

Stability of Azathioprine, Clonidine Hydrochloride, Clopidogrel Bisulfate, Ethambutol Hydrochloride, Griseofulvin, Hydralazine Hydrochloride, Nitrofurantoin, and Thioguanine Oral Suspensions Compounded with SyrSpend SF pH4.

To allow for tailored dosing and overcome swallowing difficulties, compounded liquid medication is often required in pediatric patients. The objective of this study was to evaluate the stability of oral suspensions compounded with SyrSpend SF PH4 and the commonly used active pharmaceutical ingredients azathioprine (powder) 50 mg/mL, azathioprine (from tablets) 50 mg/mL, clonidine hydrochloride (powder) 0.1 mg/mL, clopidogrel bisulfate (from tablets) 5 mg/mL, ethambutol hydrochloride (powder) 50 mg/mL, ethambutol hydrochloride (from tablets) 50 mg/mL, ethambutol hydrochloride (powder) 100 mg/mL, griseofulvin (powder) 25 mg/mL, hydralazine hydrochloride (powder) 4 mg/mL, nitrofurantoin (powder) 10 mg/mL, and thioguanine (powder) 2.5 mg/mL. Suspensions were compounded at the concentrations listed above and stored at controlled room and refrigerated temperatures. Stability was assessed by measuring the percentage recovery at 0 day (baseline), and at 7 days, 14 days, 30 days, 60 days, and 90 days. Active pharmaceutical ingredients quantification was performed by high-performance liquid chromatography, via a stability-indicating method. The following oral suspensions compounded using SyrSpend SF PH4 as the vehicle showed a beyond-use date of 90 days when stored both at room or refrigerated temperatures: clonidine hydrochloride 0.1 mg/mL, ethambutol hydrochloride 50 mg/mL and 100 mg/mL, griseofulvin 25 mg/mL, nitrofurantoin 10 mg/mL, and thioguanine 2.5 mg/mL, all compounded from the active pharmaceutical ingredients in powder form. Suspensions compounded using the active pharmaceutical ingredients from tablets presented a lower beyond-use date: 30 days for ethambutol hydrochloride 50 mg/mL and hydralazine hydrochloride 4 mg/mL, stored at both temperatures, and for clopidogrel bisulfate 5 mg/mL when stored only at refrigerated temperature. Azathioprine suspensions showed a beyond-use date of 14 days when compounded using active pharmaceutical ingredients in powder form at both temperatures. This suggests that SyrSpend SF PH4 is suitable for compounding active pharmaceutical ingredients from different pharmacological classes.

Exposure to sub-inhibitory ciprofloxacin and nitrofurantoin concentrations increases recA gene expression in uropathogenic Escherichia coli: The role of RecA protein as a drug target.

Sub-inhibitory concentrations (sub-MIC) of antimicrobial agents can lead to genetic changes in bacteria, modulating the expression of genes related to bacterial stress and leading to drug resistance. Herein we describe the impact of sub-MIC of ciprofloxacin and nitrofurantoin on three uropathogenic Escherichia coli strains. Disk-diffusion assays with different antimicrobial agents were tested to detect phenotype alterations, and quantitative real-time PCR (qRT-PCR) was performed to analyze the expression of ompF and recA genes. Significant reduction on the susceptibility to ciprofloxacin and nitrofurantoin was detected on disk diffusion test. The qRT-PCR results revealed a 1.2-4.7 increase in recA expression in all E. coli studied, while the ompF expression varied. Because RecA was pointed as an important component to the development of drug resistance, molecular docking studies were performed with three experimentally known inhibitors of this enzyme. These studies aimed to understand the inhibitory binding mode of such compounds. The results confirmed the ADP/ATP binding site as a potential site of inhibitor recognition and a binding mode based on π-stacking interactions with Tyr103 and hydrogen bonds with Tyr264. These findings can be useful for guiding the search and design of new antimicrobial agents, mainly concerning the treatment of infections with resistant bacterial strains.

Interaction of nitrofurantoin with lipid langmuir monolayers as cellular membrane models distinguished with tensiometry and infrared spectroscopy.

Knowing how a drug interacts with cell membranes is important to understand and predict its effects at the molecular level. Therefore, we aimed to study the interaction of nitrofurantoin (NFT), a compound with potential antibiotic and antitumor properties, with lipidic biological interfaces using Langmuir monolayers. We employed the phospholipids 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dipalmitoyl-sn-glycero-3-phospho-l-serine (DPPS), which were spread on the surface of water to form Langmuir films, to investigate the membrane-drug interactions. The interaction of the drug with the lipid monolayers was evaluated by using surface pressure-area isotherms, surface pressure-time kinetic curves, Brewster angle microscopy (BAM), and polarization-modulated infrared reflection-absorption spectroscopy (PM-IRRAS). Nitrofurantoin shifted the isotherms to lower DPPC molecular areas, indicating monolayer condensation, and to higher DPPS molecular areas, indicating monolayer expansion. Meanwhile, BAM images showed the appearance of interfacial aggregates for DPPS, but not for DPPC, in the presence of NFT. PM-IRRAS spectra showed that bands related to methylene stretches changed their relative intensities and maximum position related to their asymmetric and symmetric modes for both lipids. This suggested an alteration of the monolayer packing degree and the conformational order of the lipid alkyl chains, which were related to an increase in configurational order for DPPS, but disorder for DPPC. In conclusion, NFT caused distinctive changes in the thermodynamic, morphological, and structural properties of DPPC and DPPS monolayers, which may be associated with its bioactivity in cellular membranes and other lipidic interfaces of pharmaceutical interest.

Robust and selective electrochemical detection of antibiotic residues: The case of integrated lutetium vanadate/graphene sheets architectures.

Lutetium vanadate (LuVO4) 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 LuVO4/ graphene sheet (GRS) nanocomposite where LuVO4 is encapsulated with an ultrathin GRS to form a hierarchical structure (LuVO4/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 LuVO4/GRS nanocomposite is due to their excellent electrical conductivity, suitable surface area, high redox reaction and large number of electron transport. In addition, the LuVO4/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 LuVO4/GRS nanocomposite presented here can serve as a favorable candidate for developing electrochemical sensor and plays an important role in widespread fields.

A mechanical stability enhanced luminescence lanthanide MOF test strip encapsulated with polymer net for detecting picric acid and macrodantin.

The improper use of organic explosives and antibiotics have brought serious threats to the public health and the environmental safety, exploiting cost-effective and handy luminescent sensors with water stability and high selectivity in monitoring and detecting these hazardous substances are of utmost importance. Herein, we developed a simple yet powerful luminescent test strip sensor in a facile way. As for fabricating this test strip, the filter paper used for filtering lanthanide MOF (Ln-MOF) of [Tb(HIP)(H2O)5]·(H2O)·(HIP)1/2 (Tb-HIP, where HIP is 5-hydroxyisophthalate) powders was firstly recycled, and encapsulated with poly(methyl methacrylate) (PMMA) polymer net. The as-fabricated Tb-HIP test strips exhibit enhanced mechanical stability than the un-encapsulated ones, and show characteristic green emission of Tb3+. These test strips can behave as promising highly selective luminescent probes for picric acid (PA) and macrodantin (MDT) even existence of relevant potentially competing analytes. The detection limit for PA is 0.26 µM, and for MDT is 0.21 µM. In addition, the sensors can be successfully applied to detect PA in the river water samples as well as MDT in serum samples with satisfactory results. More importantly, the Tb-HIP test strips are highly efficient, recyclable luminescence sensors to detect PA and MDT.

Formulation strategy of nitrofurantoin: co-crystal or solid dispersion?

Poor solubility and bioavailability of drugs are often affected by its microscopic structural properties. Nitrofurantoin (NF), a Biopharmaceutics Classification System class II item, has a low water solubility with low plasma concentrations. To improve its therapeutic efficacy, formulation strategy of solid dispersion (SD) and co-crystallization are compared herein. The co-crystal is prepared with citric acid in 1:1 stoichiometric ratio while SD consists of 30% w/w nitrofurantoin and 70% w/w hydroxypropyl methylcellulose (HPMC) as the carrier system. As a control, the physical mixture of NF and HPMC was prepared. All the preparations were characterized with differential scanning calorimetry (DSC), attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), microscopy analysis, solubility, and dissolution studies. The formation of co-crystal, solvent evaporated, and spray-dried SD are confirmed by the ATR-FTIR where peaks shifting of several functional groups indicate the formation of the hydrogen bond. Dissolution studies showed a greater initial dissolution rate in co-crystal than SD despite the possible presence of amorphous content in the SD system. Overall, co-crystal is concluded to be a better approach than SD for an effective dissolution.

Novel 5-Nitrofuran-Activating Reductase in Escherichia coli.

The global spread of multidrug-resistant enterobacteria warrants new strategies to combat these pathogens. One possible approach is the reconsideration of "old" antimicrobials, which remain effective after decades of use. Synthetic 5-nitrofurans such as furazolidone, nitrofurantoin, and nitrofurazone are such a class of antimicrobial drugs. Recent epidemiological data showed a very low prevalence of resistance to this antimicrobial class among clinical Escherichia coli isolates in various parts of the world, forecasting the increasing importance of its uses to battle antibiotic-resistant enterobacteria. However, although they have had a long history of clinical use, a detailed understanding of the 5-nitrofurans' mechanisms of action remains limited. Nitrofurans are known as prodrugs that are activated in E. coli by reduction catalyzed by two redundant nitroreductases, NfsA and NfsB. Furazolidone, nevertheless, retains relatively significant antibacterial activity in the nitroreductase-deficient ΔnfsA ΔnfsBE. coli strain, indicating the presence of additional activating enzymes and/or antibacterial activity of the unreduced form. Using genome sequencing, genetic, biochemical, and bioinformatic approaches, we discovered a novel 5-nitrofuran-activating enzyme, AhpF, in E. coli The discovery of a new nitrofuran-reducing enzyme opens new avenues for overcoming 5-nitrofuran resistance, such as designing nitrofuran analogues with higher affinity for AhpF or screening for adjuvants that enhance AhpF expression.

Nitrofurantoin-melamine monohydrate (cocrystal hydrate): Probing the role of H-bonding on the structure and properties using quantum chemical calculations and vibrational spectroscopy.

Cocrystal monohydrate of nitrofurantoin (NF) with melamine (MELA) has been studied as NF is an antibacterial drug used for the treatment of urinary tract infections. The structure of nitrofurantoin-melamine-monohydrate (NF-MELA-H2O) is characterized by FT-IR and FT-Raman spectroscopy. The energies and vibrational frequencies of the optimized structures calculated using quantum chemical calculations. Supported by normal coordinate analyses and potential energy distributions (PEDs), the complete vibrational assignments recommended for the observed fundamentals of cocrystal hydrate. With the aim of inclusion of all the H-bond interactions, dimer of NF-MELA-H2O has been studied as only two molecules of cocrystal hydrate are present in the unit cell. By the study of dimeric model consistent assignment of the FT-IR and FT-Raman spectrum obtained. H-bonds are of essential importance in an extensive range of molecular sciences. The vibrational analyses depict existence of H-bonding (O-H⋯N) between water O-H and pyridyl N atom of MELA in both monomer and dimer. To probe the strength and nature of H-bonding in monomer and dimer, topological parameters such as electron density (ρBCP), Laplacian of electron density (∇2ρBCP), total electron energy density (HBCP) and H-bond energy (EHB) at bond critical points (BCP) are evaluated by quantum theory of atoms in molecules (QTAIM). Natural bond orbitals (NBOs) analyses are carried out to study especially the intra and intermolecular H-bonding and their second order stabilization energy (E(2)). The value of HOMO-LUMO energy band gap for NF-MELA-H2O (monomer and dimer both) is less than NF, showing more chemical reactivity for NF-MELA-H2O. Chemical reactivity has been described with the assistance of electronic descriptors. Global electrophilicity index (ω = 7.3992 eV) shows that NF-MELA-H2O behaves as a strong electrophile than NF. The local reactivity descriptors analyses such as Fukui functions, local softnesses and electrophilicity indices performed to determine the reactive sites within NF-MELA-H2O. In MEP map of NF-MELA (monomer and dimer) electronegative regions are about NO2 and C=O group of NF, although the electropositive regions are around NH2, N-H group and H2O molecule. Molar refractivity (MR) value of NF-MELA-H2O (monomer and dimer) lies within the range set by Lipinski's modified rules. This study could set as an example to study the H-bond interactions in pharmaceutical cocrystals.

Electron Deficiency of Nitro Group Determines Hepatic Cytotoxicity of Nitrofurantoin.

Nitrofurantoin (NFT) is a widely used antimicrobial agent in the treatment of specific urinary tract infections (UTIs). Many adverse effects associated with NFT use have been reported, including hepatotoxicity. A structure-toxicity relationship study was performed to gain the insight into the mechanisms of toxic action of NFT. The toxic effects of NFT and its nine analogues or constituent moieties (1-9) designed and synthesized by structural manipulation of NFT were evaluated in rat liver microsomes and primary rat hepatocytes. A decrease in ability to deplete glutathione (GSH) was found in the following order: nitrofuran-containing compounds (NFT and 1-3) > nitrobenzene-containing compounds (4 and 5) > nitro-free compounds (6-9). A similar pattern was observed in the cytotoxicity of these compounds as that of GSH depletion. The potential for reduction (electron deficiency) of nitro groups of the nitro-containing test compounds (NFT, 1-5) decreased with the decrease in the ability to deplete GSH and the intensity of their cytotoxicity. The corresponding nitroso and hydroxylamine intermediates resulting from metabolic reduction of NFT were found to be reactive to GSH for the first time. Additionally, nitro-containing compound 4 (a model compound) was much more cytotoxic than the corresponding analine (4a). The findings allowed us not only to define the mechanism of toxic action of NFT but also to provide medicinal chemists with instructive guidance for rational design of nitro-containing pharmaceutical agents.

Ultrasonic energy-assisted preparation of ß-cyclodextrin-carbon nanofiber composite: Application for electrochemical sensing of nitrofurantoin.

A simple ultrasonic energy assisted synthesis of ß-cyclodextrin (ß-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 ß-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 ß-CD over CNF enhance the aqueous dispersion and offer abundant active surface to the ß-CD/CNF composite. Further, the electrocatalytic efficacy of the ß-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 ß-CD/CNF offered outstanding analytical performance in real-world samples with higher reliability.

Application of miniaturized near-infrared spectroscopy for quality control of extemporaneous orodispersible films.

Extemporaneous oral preparations are routinely compounded in the pharmacy due to a lack of suitable formulations for special populations. Such small-scale pharmacy preparations also present an avenue for individualized pharmacotherapy. Orodispersible films (ODF) have increasingly been evaluated as a suitable dosage form for extemporaneous oral preparations. Nevertheless, as with all other extemporaneous preparations, safety and quality remain a concern. Although the United States Pharmacopeia (USP) recommends analytical testing of compounded preparations for quality assurance, pharmaceutical assays are typically not routinely performed for such non-sterile pharmacy preparations, due to the complexity and high cost of conventional assay methods such as high performance liquid chromatography (HPLC). Spectroscopic methods including Raman, infrared and near-infrared spectroscopy have been successfully applied as quality control tools in the industry. The state-of-art benchtop spectrometers used in those studies have the advantage of superior resolution and performance, but are not suitable for use in a small-scale pharmacy setting. In this study, we investigated the application of a miniaturized near infrared (NIR) spectrometer as a quality control tool for identification and quantification of drug content in extemporaneous ODFs. Miniaturized near infrared (NIR) spectroscopy is suitable for small-scale pharmacy applications in view of its small size, portability, simple user interface, rapid measurement and real-time prediction results. Nevertheless, the challenge with miniaturized NIR spectroscopy is its lower resolution compared to state-of-art benchtop equipment. We have successfully developed NIR spectroscopy calibration models for identification of ODFs containing five different drugs, and quantification of drug content in ODFs containing 2-10mg ondansetron (OND). The qualitative model for drug identification produced 100% prediction accuracy. The quantitative model to predict OND drug content in ODFs was divided into two calibrations for improved accuracy: Calibration I and II covered the 2-4mg and 4-10mg ranges respectively. Validation was performed for method accuracy, linearity and precision. In conclusion, this study demonstrates the feasibility of miniaturized NIR spectroscopy as a quality control tool for small-scale, pharmacy preparations. Due to its non-destructive nature, every dosage unit can be tested thus affording positive impact on patient safety.