Nanofiber-based Delivery of Luliconazole: Fabrication, Characterization, and Therapeutic Performance Assessment.

This study introduces and assesses the potential of a Luliconazole-loaded nanofiber (LUL-NF) patch, fabricated through electrospinning, for enhancing topical drug delivery. The primary objectives involve evaluating the nanofiber structure, characterizing physical properties, determining drug loading and release kinetics, assessing antifungal efficacy, and establishing the long-term stability of the NF patch. LUL-NF patches were fabricated via electrospinning and observed by SEM at approximately 200 nm dimensions. The comprehensive analysis included physical properties (thickness, folding endurance, swelling ratio, weight, moisture content, and drug loading) and UV analysis for drug quantification. In vitro studies explored sustained drug release kinetics, while microbiological assays evaluated antifungal efficacy against Candida albicans and Aspergillus Niger. Stability studies confirmed long-term viability. Comparative analysis with the pure drug, placebo NF patch, LUL-NF patch, and Lulifod gel was conducted using agar diffusion, revealing enhanced performance of the LUL-NF patch. SEM analysis revealed well-defined LUL-NF patches (0.80 mm thickness) with exceptional folding endurance (> 200 folds) and a favorable swelling ratio (12.66 ± 0.73%). The patches exhibited low moisture uptake (3.4 ± 0.09%) and a moisture content of 11.78 ± 0.54%. Drug loading in 1 cm2 section was 1.904 ± 0.086 mg, showing uniform distribution and sustained release kinetics in vitro. The LUL-NF patch demonstrated potent antifungal activity. Stability studies affirmed long-term stability, and comparative analysis highlighted increased inhibition compared to a pure drug, LUL-NF patch, and a commercial gel. The electrospun LUL-NF patch enhances topical drug delivery, promising extended therapy through single-release, one-time application, and innovative drug delivery strategies, supported by thorough analysis.

Dissipation behavior and risk assessment of imidacloprid and its metabolites in apple from field to products.

Pesticides play vital roles in controlling pests and boosting crop yields. Imidacloprid is widely used all over the world and may form in agricultural products. The presence of pesticide residues in apples raises serious health concerns. Understanding the residual fate of imidacloprid is critical for food safety and human health. In this study, the dissipation behavior, metabolism, household processing and risk assessment of imidacloprid and its metabolites in apple were investigated from filed to products. Field experiment results suggested that the half-lives of imidacloprid at 5 times the recommended dosage was 1.5 times that of the standard dosage. And the final residues of imidacloprid were less than the established maximum residue limits (MRLs). Clarification and simmering had little effect on the reduction the residues of imidacloprid and its metabolites. The calculated processing factors were lower than 1 for imidacloprid and its metabolites, implying that the residual ratios of imidacloprid and its metabolites in each steps of the food processing were reduced. The risk quotients were <1 for all Chinese people, indicating that acceptable risks associated with dietary exposure to imidacloprid in apple. However, the higher risks were observed in young people than adults, and females faced higher risks than males. Given high residue levels in pomace, imidacloprid and its metabolites should be further studied in commercial byproducts.

Synthesis, characterization, molecular dynamic simulation, and biological assessment of cinnamates linked to imidazole/benzimidazole as a CYP51 inhibitor.

A class of 2-(1H-imidazol-1-yl)-1-phenylethyl cinnamates 6a-6j and 2-(1H-benzo[d]imidazol-1-yl)-1-phenylethyl cinnamates 7a-7j were synthesized, and their synthesis was validated using various spectroscopic techniques like IR, NMR, and Mass spectrometry. In addition, the compounds were assessed for in-vitro antibacterial against gram-positive and gram-negative strains and in-vitro antifungal against six different fungal strains. Compounds 6 g, 7 b, 7f, and 7 g exhibited significant activity against all bacterial strains ranging from MIC = 12.5-50 µg/mL, and compounds 6 g, 7 b, and 7 g exhibited considerable activity against all fungal strains ranging from MFC = 125-200 µg/mL. A molecular docking study indicated that compounds 6 g, 7 b, 7 g, and 7j could be lodged in the active pocket and inhibit C. albicans Sterol 14α-demethylase (CYP51) protein via various interactions, and these studies validate the antifungal results. Different parameters from the 100 ns MD simulation study are investigated to evaluate the dynamic stability of protein-ligand complexes. According to the MD simulation study, the proposed compounds effectively kept their molecular interaction and structural integrity within the C. albicans Sterol 14-demethylase. Compounds 6 g, 7 b, and 7 g are promising lead compounds in searching for novel antifungal drug-like molecules. Furthermore, in silico ADME indicates that these compounds possess drug-like physicochemical properties to be orally bioavailable.Communicated by Ramaswamy H. Sarma.

Design and Synthesis of Non-Covalent Imidazo[1,2-a]quinoxaline-Based Inhibitors of EGFR and Their Anti-Cancer Assessment.

A series of 30 non-covalent imidazo[1,2-a]quinoxaline-based inhibitors of epidermal growth factor receptor (EGFR) were designed and synthesized. EGFR inhibitory assessment (against wild type) data of compounds revealed 6b, 7h, 7j, 9a and 9c as potent EGFRWT inhibitors with IC50 values of 211.22, 222.21, 193.18, 223.32 and 221.53 nM, respectively, which were comparable to erlotinib (221.03 nM), a positive control. Furthermore, compounds exhibited excellent antiproliferative activity when tested against cancer cell lines harboring EGFRWT; A549, a non-small cell lung cancer (NSCLC), HCT-116 (colon), MDA-MB-231 (breast) and gefitinib-resistant NSCLC cell line H1975 harboring EGFRL858R/T790M. In particular, compound 6b demonstrated significant inhibitory potential against gefitinib-resistant H1975 cells (IC50 = 3.65 µM) as compared to gefitinib (IC50 > 20 µM). Moreover, molecular docking disclosed the binding mode of the 6b to the domain of EGFR (wild type and mutant type), indicating the basis of inhibition. Furthermore, its effects on redox modulation, mitochondrial membrane potential, cell cycle analysis and cell death mode in A549 lung cancer cells were also reported.

Highly Efficient Reusable Carboxy Group Functionalized Imidazolium Salts for a Simple and Cost-effective Preparation of pyrano[2,3-d]pyrimidinone Derivatives.

AIMS AND OBJECTIVE: In the current study, environmentally benign and cost-effective procedures were suggested for the preparation of carboxy group functionalized imidazolium salts, including [Cmmim]BF4 - or [Cmmim]Br- as a new, reusable Brønsted acidic ionic liquid (BAIL) catalyst. Then, the catalytic performance of [Cmmim]BF4 - or [Cmmim]Br- were successfully inspected towards the three---components one---pot preparation of pyrano[2,3-d]pyrimidinone derivatives 4a-4q. The mentioned procedures show short reaction times, easy work-up procedure, green conditions, high yields of the products, high potent of recovering, and reusing capability. The current study is useful and adequate for the application and development of imidazolium salts on the basis of green chemistry principles. MATERIALS AND METHODS: An aromatic aldehyde (1 mmol), barbituric acid (1 mmol), and malononitrile (1 mmol) were placed in a round---bottomed flask containing ethanol (5 mL). BAILs A and B (0.1 mmol, 10 mol%) were added to the mixture. The suspension was magnetically stirred at room temperature for an appropriate time (Table 2). After completion of the reaction, which was monitored by TLC (n---hexane:ethyl acetate = 3:1), the pure product was filtered off to separate the catalyst, washed with water, and recrystallized from ethanol to afford the pure compound. After separation of the product, the catalyst was recovered by evaporation of water, washed with Et2O, dried under vacuum for 2 h, and reused for the same reaction. RESULTS: The mentioned procedure shows short reaction times, easy work-up procedure, green conditions, high yields of the products, and high potent of recovering and reusing capability. CONCLUSION: In this study, we unveiled the synthesis of a new acetic acid functionalized ionic liquids [Cmmim]BF4 - BAIL A or [Cmmim]Br- BAIL B and their application for the preparation of pyrano[2,3-d]pyrimidinone derivatives via a three-component reaction among various aromatic aldehydes, barbituric acid, and malononitrile under mild and metal-free conditions. A wide range of pyrano[2,3-d]pyrimidinone derivatives bearing diverse functional groups was obtained in short reaction and excellent yields. Operational simplicity, recoverability, and reusability of catalysts, cheap and chemically stable reagents, high catalytic activity, easy work-up, and the eco-friendly procedure, make this method environmentally benign and cost-effective.

Pretreatment of rice straw with recycled ionic liquids by phase-separation process for low-cost biorefinery.

An efficient ionic liquids (ILs) recycle technology will increase the economic viability of lignocellulosic biorefinery. The availability of recycling 1-butyl-3-methylimidazolium chloride for rice straw (RS) pretreatment was conducted. The kosmotropic salt K3 PO4 (TKP) solution was used as antisolvent for cellulose precipitation and forming a three-phase system consisting of biomass, ILs-rich, and salt-rich phases. The upper ILs phase and the bottom TKP phase were recycled without additional purification, which significantly simplifies the process for recovering ILs. Subsequently, the RS pretreated with multiple reusing ILs (RPRS) were investigated by components analysis, structure evolution, enzymatic hydrolysis, and fermentation experiments. The results showed that unpurified reusing ILs led to further delignification and improvement of enzyme accessibility of the pretreated RS. The reducing sugar yield of RS pretreated with 8th reusing IL (8th RPRS) could still reach 98.9%, and the ethanol and succinic acid concentrations achieved 91.9 and 29.3 g/L by simultaneous saccharification and cofermentation. The present study demonstrated that the ILs recovered by phase-separation process could be used for RS pretreatment, and achieving high titer ethanol fermentation.

Luliconazole loaded lyotropic liquid crystalline nanoparticles for topical delivery: QbD driven optimization, in-vitro characterization and dermatokinetic assessment.

Fungal infections are an important cause of morbidity and pose a serious health concern especially in immunocompromised patients. Luliconazole (LUL) is a topical imidazole antifungal drug with a broad spectrum of activity. To overcome the limitations of conventional dosage forms, LUL loaded lyotropic liquid crystalline nanoparticles (LCNP) were formulated and characterized using a three-factor, five-level Central Composite Design of Response Surface Methodology. LUL loaded LCNP showed particle size of 181 ± 12.3 nm with an entrapment efficiency of 91.49 ± 1.61 %. The LUL-LCNP dispersion in-vitro drug release showed extended release up to 54 h. Ex-vivo skin permeation studies revealed transdermal flux value (J) of LUL-LCNP gel (7.582 µg/h/cm2) 2 folds higher compared to marketed cream (3.3706 µg/h/cm2). The retention of LUL in the stratum corneum was ∼1.5 folds higher and ∼2 folds higher in the epidermis and other deeper layers in comparison to the marketed cream. The total amount of drug penetrated (AUC0-∞) with LCNP formulation was 4.7 folds higher in epidermis and 6.5 folds higher in dermis than marketed cream. The study's findings vouch that LCNP can be a promising and effective carrier system for the delivery of antifungal drugs with enhanced skin permeation.

Cellulose Dissolution in Mixtures of Ionic Liquids and Dimethyl Sulfoxide: A Quantitative Assessment of the Relative Importance of Temperature and Composition of the Binary Solvent.

We studied the dissolution of microcrystalline cellulose (MCC) in binary mixtures of dimethyl sulfoxide (DMSO) and the ionic liquids: allylbenzyldimethylammonium acetate; 1-(2-methoxyethyl)-3-methylimidazolium acetate; 1,8-diazabicyclo [5.4.0]undec-7-ene-8-ium acetate; tetramethylguanidinium acetate. Using chemometrics, we determined the dependence of the mass fraction (in %) of dissolved cellulose (MCC-m%) on the temperature, T = 40, 60, and 80 °C, and the mole fraction of DMSO, χDMSO = 0.4, 0.6, and 0.8. We derived equations that quantified the dependence of MCC-m% on T and χDMSO. Cellulose dissolution increased as a function of increasing both variables; the contribution of χDMSO was larger than that of T in some cases. Solvent empirical polarity was qualitatively employed to rationalize the cellulose dissolution efficiency of the solvent. Using the solvatochromic probe 2,6-dichloro-4-(2,4,6-triphenylpyridinium-1-yl)phenolate (WB), we calculated the empirical polarity ET(WB) of cellobiose (a model for MCC) in ionic liquid (IL)-DMSO mixtures. The ET(WB) correlated perfectly with T (fixed χDMSO) and with χDMSO (fixed T). These results show that there is ground for using medium empirical polarity to assess cellulose dissolution efficiency. We calculated values of MCC-m% under conditions other than those employed to generate the statistical model and determined the corresponding MCC-m% experimentally. The excellent agreement between both values shows the robustness of the statistical model and the usefulness of our approach to predict cellulose dissolution, thus saving time, labor, and material.

In Silico Food-Drug Interaction: A Case Study of Eluxadoline and Fatty Meal.

Food-drug interaction is an infrequently considered aspect in clinical practice. Usually, drugs are taken together with meals and what follows may adversely affect pharmacokinetic and pharmacodynamic properties, and hence, the therapeutic effects. In this study, a computational protocol was proposed to explain the different assimilations of two µ-receptors agonists, eluxadoline and loperamide, with a peculiar pharmacokinetic profile. Compared to loperamide, eluxadoline is absorbed less after the intake of a fatty meal, and the LogP values do not explain this event. Firstly, keeping in mind the different pH in the intestinal tract, the protonation states of both compounds were calculated. Then, all structures were subjected to a conformational search by using MonteCarlo and Molecular Dynamics methods, with solvation terms mimicking the water and weak polar solvent (octanol). Both computational results showed that eluxadoline has less conformational freedom in octanol, unlike loperamide, which exhibits constant behavior in both solvents. Therefore, we hypothesize that fatty meal causes the "closure" of the eluxadoline molecule to prevent the exposure of the polar groups and their interaction with water, necessary for the drug absorption. Based on our results, this work could be a reasonable "case study", useful for future investigation of the drug pharmacokinetic profile.

Assessment of effective imidazole derivatives against SARS-CoV-2 main protease through computational approach.

Because of the fast increase in deaths due to Corona Viral Infection in majority region in the world, the detection of drugs potent of this infection is a major need. With this idea, docking study was executed on eighteen imidazole derivatives based on 7-chloro-4-aminoquinoline against novel Coronavirus (SARS-CoV-2). In this study, we carried out a docking study of these molecules in the active site of SARS-CoV-2 main protease. The result indicate that Molecules N° 3, 7 and 14 have more binding energy with SARS-CoV-2 main protease recently crystallized (pdb code 6LU7) in comparison with the other imidazole derivatives and the two drug; Chloroquine and hydroxychloroquine. Because of the best energy of interaction, these three molecules could have the most potential antiviral treatment of COVID-19 than the other studied compounds. The structures with best affinity in the binding site of the protease have more than 3 cycles and electronegative atoms in the structure. This may increase the binding affinity of these molecules because of formation of π-bonds, halogen interactions and/or Hydrogen bond interactions between compounds and the enzyme. So, compounds with more cycles and electronegative atoms could have a potent inhibition of SARS-CoV-2 main protease.

A simpler potentiometric method for histamine assessment in blood sera.

Histamine intolerance results from a disequilibrium of accumulated histamine and the capacity for histamine degradation. An impaired histamine degradation based on reduced DAO activity and the resulting histamine excess may cause numerous symptoms mimicking an allergic reaction. For that, the determination of histamine in blood or in food products has great importance to identify risk factors. A new histamine-selective electrode is proposed using cucurbit[6]uril (CB[6]), as ionophore, in the analysis of biological samples. The selection of this smart supramolecular organic framework was based on its apparent stability constant of histamine-CB[6] (log ß) of 4.33. The optimized electrode based on a polymeric membrane (PVC) combines the histamine-selective ionophore with 2-nitrophenyl octyl ether as solvent mediator and potassium tetrakis(4-chlorophenyl)borate as anionic additive. Furthermore, multi-walled carbon nanotubes particles were included in the membrane composition to partly lower the detection limit of the method, while improving stability and lowering the response drift (± 4 mV). The electrodes showed a rapid response (≃ 13 s) in the pH operational range of 2.7-5.4, with a Nernstian slope of 30.9 ± 1.2 mV/dec, a detection limit of (3.00 ± 0.61) × 10-7 mol/L, and a lower limit of the linear range of (3.00 ± 0.00) × 10-7 mol/L. After miniaturization, the electrode was used as a detector in a sequential-injection lab-on-valve flow setup. The optimized flow conditions were achieved for sample injection volumes of 197 µL propelled towards the cell under detection, at a flow rate of 30 µL/s during 100 s, making the analysis of 30 samples per hour possible. The developed system was used to analyze spiked blood serum samples previously cleaned by using solid-phase extraction. The sample pretreatment of the serum samples using Oasis MCX cartridges showed outstanding efficiency for histamine determination. The recovery values for three different levels of histamine concentration (1 × 10-4 mol/L, 1 × 10-5 mol/L, and 1 × 10-6 mol/L) were (97 ± 6)%, (103 ± 1)%, and (118 ± 9)%, respectively, showing that this method was suitable for biological samples.

One-pot fabrication of multifunctional catechin@ZIF-L nanocomposite: Assessment of antibiofilm, larvicidal and photocatalytic activities.

Zeolitic imidazole framework (ZIF) is an emerging class of metal organic frameworks exhibiting unique features such as crystalline nature with tunable pore size, large surface area and biocompatible nature. Exceptional thermal and chemical stabilities of ZIF-L make it a suitable candidate for biomedical applications. The present study has focused on the single step fabrication of catechin encapsulated ZIF-L and evaluation of its antibiofilm efficiency, larvicidal activity and dye degradation ability. The as- prepared CA@ZIF-L nanocomposite was characterized by spectroscopic and microscopic techniques. The results revealed that the CA@ZIF-L showed significant toxicity against mosquito larvae in a dose dependent manner with the IC50 63.43±1.25 µg/mL. CA@ZIF-L showed dose dependent reduction of biofilm formation in both ATCC and clinical MRSA strains. In addition, CA@ZIF-L exhibited excellent photocatalytic activity with around 92% degradation of methylene blue under direct sunlight. Overall, the present work highlights the possibility of employing the multifunctional CA@ZIF-L nanocomposite as a suitable material for biomedical and photocatalytic applications.

Optimization of a liquid chromatography method for the analysis of related substances in daclatasvir tablets using design of experiments integrated with the steepest ascent method and Monte Carlo simulation.

Analytical method for the determination of related substances (RS) in Daclatasvir tablets was optimised using quality by design (QbD) approach. Seven degradants (each more than 1.0%) generated during oxidation study, adversely affected the selectivity of the method. Coelution of the degradant peaks with API and known impurities, suggested failure in developing a stability indicating method. To overcome the shortcomings and develop a robust method, QbD principles were incorporated. Resolution was the critical quality attribute (CQA) and buffer pH, column oven temperature, gradient slope and flow rate were the critical method variables (CMVs) studied through design of experiments (DoE). Discovery of an unknown impurity (named as impurity D, about1.0%) was a key finding from this DoE study. The most crucial responses viz. Resolution between impurity D and the main peak and resolution between the main peak and impurity E demanded contradictory pH requirements. To select the right pH, responses were prioritised and eventually to attain the desired resolution between Daclatasvir and impurity E the value for pH was fixed to 3.0. Next, to improve resolution between impurity D and Daclatasvir, method of steepest ascent was applied to locate an apt value for column oven temperature. Accordingly, experiments were performed at different temperatures along the path of rapid increase in response. Finally, at 45 °C (pH :3.0), both the critical pairs were well resolved. The global optimum was determined through a Response surface methodology (RSM) design with pH and column oven temperature as critical factors. pH 3.0, column oven temperature 44 °C, % MP. B 45% and flow rate 1.0 mL min-1 was found to be the optimum condition. Further, the design space was complimented by establishment of a robust zone through Monte Carlo simulation and capability analysis. An analytical control strategy (ACS) was set up to ensure that the method repeatedly meets its acceptance criteria. The optimised method was successfully validated within the factor ranges mentioned in the ACS. Despite various intricacies, the QbD approach facilitated systematic optimisation of a stability indicating robust method.

Dissipation behavior, residue distribution and risk assessment of three fungicides in pears.

BACKGROUND: Fungicides are often applied to pears before they are kept in storage facilities. The scientific application of pesticides can reduce unnecessary exposure, which in turn could benefit both humans and the environment. RESULTS: We investigated dissipation behavior and residue distribution, and conducted risk assessments for prochloraz, pyraclostrobin, and tebuconazole in pears stored under different conditions using ultra-performance liquid chromatography (UPLC). The recoveries of the three fungicides ranged from 76.5% to 114.5%, and the coefficients of variation were 1.0%-8.5%. The half-life (t1/2 ) ranges for degradation of the three fungicides in Dangshan Su pear peel were 8.8-13.9 days after storage at 25 °C and 99.0-346.6 days after storage at 2 °C. Among the three fungicides, tebuconazole had the lowest residue concentration in pear pulp (maximum of 0.226 mg·kg-1 ) and the longest half-life (≥ 231.0 days). Accordingly, among these fungicides, tebuconazole is the most suitable for the preservation of Dangshan Su pears during storage. Finally, we analyzed samples of six pear varieties from markets in China and found that the residue concentrations of the three fungicides in pear pulp and fruit met Chinese standards. CONCLUSION: The results provide a scientific basis for rationalizing the use of prochloraz, pyraclostrobin, and tebuconazole, and improving the safety of pears for eating. © 2019 Society of Chemical Industry.

Dissipation and Risk Assessment of Multiresidual Fungicides in Grapes under Field Conditions.

Grapes are among the most popular fruits globally, and various fungicides are widely applied to grape crops. As such, the presence of multiple fungicide residues and dietary risks in grapes has become the focus of significant attention. In this study, an easy-to-implement and sensitive UPLC-MS/MS approach was developed to simultaneously determine pyraclostrobin, dimethomorph, cymoxanil, cyazofamid and its metabolite CCIM in grapes via QuEChERS. This approach achieved 78.1-106.0% recovery and a 0.01 mg kg-1 limit of quantitation (LOQ). Field trials revealed that these compounds had degradation half-lives ranging from 0.9 to 13.3 days. And their terminal residues ranging from < LOQ to 1.36 mg kg-1 were below the official maximum residue limit (MRL) in China. The short-term risk for each tested fungicide was below 54%. The long-term risk of individual chemicals ranged from 0.0086% to 3.1%, and their cumulative risk was 4.4%. Results indicated that the dietary risk of these fungicides in grapes was minor.

Toxicity and inhibition assessment of ionic liquids by activated sludge.

Toxicity of 13 ionic liquids (ILs) corresponding to different families were studied by inhibition respiration assays (15 min) using activated sludge. Toxicity increased as increasing the number of carbons in the alkyl-chain of imidazolium-based ILs, with EC50 values from 4.19 to 0.17 for 1-ethyl-3-methylimidazolium chloride ([Emim][Cl]) and 1-octyl-3-methylimidazolium chloride ([Omim][Cl]), respectively. An increase in toxicity was observed for aromatic-based ILs (pyridinium- and imidazolium-based ILs) due to the hydrophobic character of the head groups in comparison with linear structures as phosphonium and ammonium cations. Among to the anions studied fixing [Emim]+ as cation, [HSO4]- and [NTf2]- presented low EC50 values (0.34 mM and 1.69 mM, respectively) while [Cl]- and [EtSO4]- were considered harmless anions due to the hydrophilic character of chloride and the organic nature of [EtSO4]-. ILs toxicity/inhibition was determined by adding a biodegradable compound and measuring the sludge response after being in contact with the ILs for at least 15 h. The exposure of sewage sludge to ILs for more than 15 min used in short inhibition assays caused more toxic effect on microorganisms, even for [Choline][NTf2], previously defined as practically harmless (EC50 = 2.79 mM). Biodegradability assays confirmed the biodegradable nature of choline cation, related with TOC conversion of 40%, only due to cation consumption. No oxygen consumption or even lysis of microbial cells was observed for Tetrabutylammonium bis(trifluoromethylsulfonyl)imide and for 1-Ethyl-3-methylimidazolium hydrogensulphate due to the presence of anions previously defined as hazardous ([NTf2]- and [HSO4]-), maintaining their recalcitrant character to sewage systems.

Integrative Assessment of Mixture Toxicity of Three Ionic Liquids on Acetylcholinesterase Using a Progressive Approach from 1D Point, 2D Curve, to 3D Surface.

The joint toxicities of [BMIM]BF4, [BMIM]PF6, and [HMIM]BF4 on acetylcholinesterase (AChE) were systematically investigated by using a progressive approach from 1D single effect point, 2D concentration-response curve (CRC), to 3D equivalent-surface (ES) level. The equipartition equivalent-surface design (EESD) method was used to design 10 ternary mixtures, and the direct equipartition ray (EquRay) design was used to design 15 binary mixtures. The toxicities of ionic liquids (ILs) and their mixtures were determined using the microplate toxicity analysis (MTA) method. The concentration addition (CA), independent action (IA), and co-toxicity coefficient (CTC) were used as the additive reference model to analyze the toxic interaction of these mixtures. The results showed that the Weibull function fitted well the CRCs of the three ILs and their mixtures with the coefficient of determination (R2) greater than 0.99 and root-mean-square error (RMSE) less than 0.04. According to the CTC integrated with confidence interval (CI) method (CTCICI) developed in this study, the 25 mixtures were almost all additive action at 20% and 80% effect point levels. At 50% effect, at least half of the 25 mixtures were slightly synergistic action, and the remaining mixtures were additive action. Furthermore, the ESs and CRCs predicted by CA and IA were all within the CIs of mixture observed ESs and CRCs, respectively. Therefore, the toxic interactions of these 25 mixtures were actually additive action. The joint toxicity of the three ILs can be effectively evaluated by the ES method. We also studied the relationship between the mixture toxicities and component concentration proportions. This study can provide reference data for IL risk assessment of combined pollution.

Validating interfacial behaviour of surface-active ionic liquids (SAILs) with computational study integrated with biocidal and cytotoxic assessment.

Surface-active ionic liquids (SAILs) belonging to the series of N-alkylmethylimidazolium halides [C8mimX] (X = Br, Cl, and BF4) and [CnmimBr] (n = 10, 12, 14, and 16) were employed to understand the influence of hydrophobicity of alkyl chain length and the chaotropicity of counter-ions of SAILs on the micellization, antimicrobial action and cytotoxicity properties. The micellization phenomenon of SAILs in an aqueous environment was examined employing tensiometry and steady-state fluorescence spectrophotometry. The corresponding interfacial parameters viz., critical micelle concentration (CMC), effectiveness (γCMC), surface pressure (ПCMC), maximum surface excess concentration (Гmax), and the minimum area engaged per molecule (Amin) at the air-water interface were evaluated at 303.15 K. These experimental findings were monitored and geometrically optimized theoretically using Gaussian software to highlight the recent advances in this field of theoretical calculations for putative structure. The simulation descriptors correlated the micellization behavior as a function of hydrophobicity which may contribute to obtaining awareness on their ecological behavior and fate. In addition, the biological screening of all the examined SAILs was undertaken with a combined experimental and theoretical (optimized) method against bacteria and fungus. Results revealed that SAILs with the alkyl chain-length greater than C8- act as a fair antimicrobial agent against the selected microbial strain which is attributed to the enhanced degree of SAILs hydrophobicity. The cytotoxicity of these imidazolium-based SAILs was also assessed on the cervical human cell line (HeLa) using the MTT cell viability assay and the data thus obtained were subjected to statistical analysis.

Residue behaviours, dissipation kinetics and dietary risk assessment of pyaclostrobin, cyazofamid and its metabolite in grape.

BACKGROUND: Grape is an important fruit consumed either fresh or processed, therefore, fungicide misuse of grape has become an issue of global food safety and human health. Pyraclostrobin, and cyazofamid have been applied to grape frequently. RESULTS: Here a simple QuEChERS (quick, easy, cheap, effective, rugged, and safe) liquid chromatography mass spectrometry technique has been developed and validated for the determination of pyraclostrobin, cyazofamid and its metabolite CCIM in open field grape samples. The recoveries of these three in the range of 0.01 to 5 mg kg-1 (n = 5) ranged from 73.1% to 97.9%. The relative standard deviations (RSDs) were below 12% for all cases. The limits of quantitation of each analyte was 0.005 mg kg-1 , which was lower than maximum residue limits of not only pyraclostrobin but also cyazofamid. Not only dissipation kinetics but also residue determination was obtained in grape for those three pesticides. Furthermore, their half-lives in grapes were 10.7-30.1 days, recommending the pre-harvest intervals for these three of 14 days. The calculated hazard quotient and acute hazard index lower than 100% illustrated the safety of intake of grape for the Chinese population for not only long-term but also short-term dietary risk assessment. CONSLUSIONS: The less than 30 day half-life illustrated that pyraclostrobin and cyazofamid could degrade relatively easily in the environment. The long-term and short-term dietary risk assessment also illustrated the intake safety of these three. Thus, a 14 day pre-harvest interval was safe and recommended. The results of this study contributed to environmental protection, food safety and human health. © 2019 Society of Chemical Industry.

Risk assessment and QbD based optimization of an Eprosartan mesylate nanosuspension: In-vitro characterization, PAMPA and in-vivo assessment.

Quality by design (QbD) principles were implemented to understand the product and process variables of sonoprecipitation technique, for preparation of eprosartan mesylate (EM) nanosuspension. Quality risk management approach was utilized to identify and assess high-risk attributes affecting critical quality attributes (CQA's), prioritizing the number of experiments. The effect of critical material attributes (CMA's) and critical process parameters (CPP's) (soluplus concentration, drug concentration ultrasonication amplitude) on z-average particle size and PDI were investigated using a central composite face-centered design (CCF). Further, design space with criteria set of CMA's and CPP's was established to offer assurance of quality. The optimal formulation, identified using numerical optimization method, was further lyophilized and evaluated for redispersibility, solubility saturation, dissolution kinetic and in-vitro dissolution behavior. The EM nanoparticles were in an amorphous state as confirmed by differential scanning calorimetry (DSC) and X-ray diffraction (XRD) studies. The stability study conducted for a span of 6 months attests physical and chemical stability of EM dry nanosuspension in an amorphous state when stored at 4 °C. The enhanced solubility and in-vitro dissolution of EM nanosuspension may be attributed to the reduced particle size and alteration of the physical state from a crystalline to an amorphous state. Further, the optimized formulation was subjected to in-vitro and ex-vivo transport study using parallel artificial membrane permeability assay (PAMPA) and rat everted gut sac model respectively. The transport studies revealed successful permeation enhancement of EM nanoparticle when compared with EM API and physical mixture (PM). The absolute bioavailability of EM API was 7.1% and improved to 39.9% for EM nanosuspension, suggesting that nanoformulation had overcome solubility and permeability limited bioavailability which was observed with EM API.