Ultra-Sensitive LC-MS/MS Method for the Trace Level Quantification of Six Potential Genotoxic Nitrosamine Impurities in Telmisartan

Nitrosamine impurities are potentially genotoxic which are considered under cohort of concern as per ICH M7 guidelines and need to be controlled at trace levels during quantification in drug substances and drug products for safe human consumption. Recent regulatory requirements also suggest the need to have highly sensitive analytical methods for the accurate quantification of Nitrosamine impurities. In this paper we have presented simple, rapid and ultra-sensitive LC-MS/MS method for six potential genotoxic nitrosamine impurities: N-Nitroso dimethyl amine (NDMA), N-Nitroso diethyl amine (NDEA), N-Nitroso Ethyl Iso propylamine (NEIPA), N-Nitroso-N-methyl-4-aminobutyric acid (NMBA) N-Nitroso diisopropylamino (NDIPA) and N-Nitroso dibutyl amine (NDBA) with a LOQ of 0.004 ppm. Chromatographic separation is achieved using Zorbax SB C18 150 × 3.0 mm, 3.5 μ column with 0.1% formic acid in water as mobile phase A and 0.1% formic acid in methanol as mobile phase B at a flow rate of 0.3 ml/min using gradient mode of elution at a total run time of 18 minutes. Six nitrosamine impurities are successfully ionized and quantified in positive mode of atmospheric pressure chemical ionization (APCI) using multiple reaction monitoring (MRM). Method validation is performed as per ICH guidelines evaluating the limit of quantification and detection and found to give good S/N ratios with good linearity range of 0.002 - 2 ppm with regression coefficient >0.99 for all the six nitrosamine impurities. Method recoveries are established using three-step sample preparation protocol and are found to be satisfactory within 80% - 120%. The method can be used routinely applied for the detection of Nitrosamines in Telmisartan at a concentration of 1.5 ng/ml (0.03 ppm with respect to telmisartan concentration of 50 mg/ml).

A High Sensitive LC-MS/MS Method for the Simultaneous Determination of Potential Genotoxic Impurities Carboxy Phenyl Boronic Acid and Methyl Phenyl Boronic Acid in Lumacaftor

A simple, rapid, and highly sensitive LC-MS/MS method has been developed for the simultaneous and trace level quantification of underivatized boronic acids in lumacaftor active pharmaceutical ingredient. Chromatographic separation of boronic acids and lumacaftor achieved using Agilent Poroshell HPH C18 150 × 4.6 mm 2.7 μ column with 0.1% ammonia in water as mobile phase A and 100% acetonitrile as mobile phase B at a flow rate of 0.25 ml/min. Gradient elution was used with a total method run time of 14 minutes. Boronic acids were successfully ionized and quantified without derivatization using electrospray ionization in negative mode using tandem quadrupole mass spectrometry in multiple reactions monitoring mode. Method validation was performed as per ICH guidelines with good linearity over the concentration range of 0.05 ppm to 5 ppm of Lumacaftor test concentration for both the boronic acids with a correlation coefficient of >0.99. Recoveries were found good at different concentration levels and within the range of 80% - 120%. The developed method can be successfully used for the routine quantification of boronic acids at a concentration level of 20 ng/ml (1 ppm with respect to 20 mg/ml lumacaftor).

Chemical Composition,Antioxidant and Antimicrobial Activity of the Oil and Plant Extract Myrocarpus frondosus Allemao

The objective of this study was to evaluate the chemical profile of extracts (aqueous and ethanol) and the essential oil of Myrocarpus frondosus Allem?o, the sensitivity of strains of Escherichia coli, Staphylococcus aureus, Salmonella typhimurium and Listéria monocytogenes, front the extracts and essential oil, by means of the microdilution method in broth, the antioxidant activity by the ABTS method, and the content of phenolic compounds present in the extracts and oil. For the preparation of extracts from plant leaves used with ethanol and water, then separated, the chemical identification of compounds was performed by high-performance liquid chromatography (CLAE-DAD) and gas chromatography coupled to mass spectrum (CG/MS). With the chemical analysis of the extracts obtained the presence of the major compound rutin, and oil major compound was found germacrene B. In the microdilution method in broth, oil and extracts showed inhibition against all the bacteria tested in the concentrations 1 mg/ml to 0.25 mg/ml, except for Staphylococcus aureus at a concentration of 0.25 mg/ml of the essential oil and trans-caryophyllene. The results of Minimum Bactericidal Concentration showed that the essential oil had bactericidal activity at a concentration of 1mg/ml for all bacteria tested and trans-caryophyllene at the same concentration only for Listeria monocytogenes. In relation to the essential oil, antioxidant activity showed higher radical reduction capacity of 40.92% and the content of phenolic compounds ethanol extract showed more 12.72%. The in vitro results support the conclusion that the essential oil is very promising both in antimicrobial action as antioxidant activity and the leaf extracts on antioxidant activity.

Enabling superior electrochemical performance of NCA cathode in Li_(5.5)PS_(4.5)Cl_(1.5)-based solid-state batteries with a dual-electrolyte layer

LiNi_(0.8)Co_(0.15)Al_(0.05)O_(2)(NCA) is a promising cathode for sulfide-based solid-state lithium batteries(ASSLBs)profiting from its high specific capacity and voltage plateau, which yielding high energy density. However, the inferior interfacial stability between the bare NCA and sulfides limits its electrochemical performance. Hereien, the dual-electrolyte layer is proposed to mitigate this effect and enhance the battery performances of NCA-based ASSLIBs. The Li_(3)InCl_6 wih high conductivity and excellent electrochemcial stability act both as an ion additives to promote Li-ion diffusion across the interface in the cathode and as a buffer layer between the cathode layer and the solid electrolyte layer to avoid side reactions and improve the interface stability. The corresponding battery exhibits high discharge capacities and superior cyclabilities at both room and elevated temperatures. It exhibits discharge performance of 237.04 and216.07 m Ah/g at 0.1 and 0.5 C, respectively, when cycled at 60 ℃, and sustains 95.9% of the capacity after100 cycles at 0.5 C. The work demonstrates a simple strategy to ensure the superior performances of NCA in sulfide-based ASSLBs.

Neural Network Accelerated Investigation of the Dynamic Structure-Performance Relations of Electrochemical CO_(2) Reduction over SnO_(x),Surfaces

Heterogeneous catalysts,especially metal oxides,play a curial role in improving energy conversion efficiency and production of valuable chemicals.However,the surface structure at the atomic level and the nature of active sites are still ambiguous due to the dynamism of surface structure and difficulty in structure characterization under electrochemical conditions.

Simultaneous and Trace Level Quantification of Five Potential Genotoxic Impurities in Ranolazine Active Pharmaceutical Ingredient Using LC-MS/MS

Highly sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed for the simultaneous determination of five potential genotoxic impurities in ranolazine active pharmaceutical ingredient. Chromatographic separation achieved using Poroshell C18 PFP 150 × 3.0 mm 2.7 μ column and 0.1% formic acid in water as Mobile phase A and 0.1% formic acid in methanol as mobile phase B using gradient elution and a flow rate of 0.4 ml/min with a run time of 18 minutes. Mass spectrometric conditions were optimized using electrospray ionization in positive mode. Method shows excellent linearity from 0.05 - 5.0 ppm of the ranolazine test concentration for all the five impurities. The correlation coefficient was observed greater than 0.99. Satisfactory recoveries were observed for all the five impurities within the range of 102.9% - 112.3%. Method has been validated as per ICH recommended guidelines with a LOQ of 0.15 ppm achieved. The developed method was able to quantify all the five impurities at a concentration level of 1 ng/ml (0.5 ppm with respect to 2 mg/ml ranolazine).

Synthesis of Multifunctionalised 2-Substituted Benzimidazoles Using Copper (II) Hydroxide as Efficient Solid Catalyst

Here we demonstrate the synthesis of multifunctionalised benzimidazoles through the coupling of o-phenylenediamine with aldehydes by using Copper (II) hydroxide as an efficient solid catalyst in methanol at room temperature. The Copper (II) hydroxide solid catalyst gave better yields (80%-99%) in short reaction time (4-8 h). These commercially available cheap catalysts are more active than many reported expensive heterogeneous catalysts. Using the Copper hydroxide fresh catalyst, the yield of product 3a was 98%, while the recovered catalyst in the three subsequent cycles gave the yield of 94%, 90% and 88% respectively.

Subnanometric bimetallic Pt-Pd clusters in zeolites for efficient hydrogen production and selective tandem hydrogenation of nitroarenes

The solvolysis of ammonia borane(AB)and the hydrogenation of nitroarenes represent significant reactions for hydrogen generation and value-added chemical synthesis.The strategic engineering of the catalysts is imperative for surmounting obstacles associated with their stability and catalytic efficiency.In this work,subnanometric bimetallic Pt–Pd clusters were encapsulated within silicalite-1(S-1)zeolites through a ligand-protected in-situ hydrothermal synthesis method.The synergetic effect of bimetallic composition and zeolite confinement markedly enhances the catalytic performance of representative Pt_(0.5)Pd_(0.5)@S-1-H catalyst,affording exceptional turnover frequency(TOF)values of 1,043 and 573 mol_(H_(2))mol_(metal)^(-1)min^(-1)for AB hydrolysis and methanolysis at ambient conditions,respectively,surpassing most of the state-of-the-art Pt-based catalysts.Kinetic and isotopic experiments reveal that the bimetallic catalytic system remarkably boosts the O-H cleavage of water,thereby facilitating the H_(2) production from AB hydrolysis.Remarkably,a conspicuous synergistic effect is demonstrated in the shape-selective tandem hydrogenation of nitroarenes,with the bimetallic catalyst facilitating both AB hydrolysis and nitroarene hydrogenation,giving a high TOF value of 1,260 h^(-1)under atmospheric pressure.This study not only demonstrates the effectiveness of bimetallic nanocatalysts encapsulated in zeolites for hydrogen production from chemical hydrogen storage materials,but also paves the way for the design of catalysts with multifunctional active sites capable of synergistically promoting tandem catalytic processes.

Methods to Make Conductive Covalent Organic Frameworks for Electrocatalytic Applications

Covalent organic frameworks(COFs) represent a new class of crystalline organic polymer materials with the characteristics of high specific surface area, uniform pore distribution, high porosity, low density, devisable chain structures and good structural stability. These collective features play an important role in creating highly efficient electrocatalysts for energy conversion and fuel generation. Recent years have witnessed considerable advances in COF-based electrocatalysts for major electrocatalytic reactions such as oxygen reduction, oxygen evolution, hydrogen evolution, and reduction of carbon dioxide and nitrogen. However, it has been widely accepted that the poor electrical conductivity of most pristine COFs limits the further progress in electrocatalytic field. In this review, recent structural engineering strategies are summarized toward improving the electrical conductivity of COFs for achieving high performance. The researches of conductive COFs and their derivatives are described in detail. The structure-activity relationship between molecular structures of COFs and their electrocatalytic performance is emphasized. Lastly, current challenges and future perspectives on fabricating COFs as promising electrocatalysts are discussed. The purpose of this review is to provide guidelines for the preparation of highly efficient COF-based electrocatalytic materials with a view to replacing the commercially available noble metal-based electrocatalysts.

Zeolite-encaged Ultrasmall Pt-Zn Species with Trace Amount of Pt for Efficient Propane Dehydrogenation

Propane dehydrogenation(PDH)has become a globe-welcoming technology to meet the massive demand for propylene,but the most commonly used Pt-based catalysts suffer from quick sintering,poor selectivity for propylene,and unsatisfied Pt utilization.Herein,a series of Silicalite-1(S-1)zeolite-encaged ultrasmall Pt-Zn clusters with a trace amount of Pt[40—180 ppm(parts per million)]were developed by using a one-pot ligand-protected direct H_(2) reduction method.Interestingly,the extremely low amount of Pt can significantly promote the activity of zeolite-encaged Zn catalysts in PDH reactions.Thanks to the high Pt dispersion,the synergy between Pt and Zn species,and the confinement effect of zeolites,the optimized PtZn@S-1 catalyst with 180 ppm Pt and 1.88%(mass fraction)Zn,exhibited an extraordinarily high propane conversion(33.9%)and propylene selectivity(99.5%)at 550℃with a weight hourly space velocity(WHSV)of 8 h^(-1),affording an extremely high propylene formation rate of 340.7 mol_(C_(3)H_(6))·g_(Pt^(-1))·h^(-1).This work provides a reference for the preparation of zeolite-encaged metal catalysts with high activity and noble metal utilization in PDH reactions.

Superhydrophobicity-mediated enhanced enzymatic kinetics and high-performance bioassays

As a typical superwettability behavior,superhydrophobicity can provide an appropriate strategy to enhance the mass transport in multiphase chemical reactions.In the oxidase-based enzymatic reactions,the elaborately regulating of reactant oxygen are critical to the development of an oxidase-based high-performance biosensor.In solid–liquid diphase condition,however,the kinetics of oxidase-catalyzed reactions is inhibited by delayed mass transport and poor solubility of oxygen.To address this limitation,the design of the solid–liquid–air triphase interface is proposed according to the binary cooperation of superhydrophobicity and hydrophilicity.On the triphase joint interface,oxygen required for the oxidase-catalyzed reactions can diffuse directly to the reaction center from the air phase through the micro/nanostructured superhydrophobic substrate,thus improving the kinetics of the oxidase-catalyzed reactions.In this minireview,we summarize recent advances in the fabrication of triphase reaction system based on different superhydrophobic substrate for oxidase-based biosensors.Common substrates including fibrous network,nanowire arrays,3D porous framework,and hollow sphere structures are outlined in categories.

Base-controlled annulation of tryptamine-derived isocyanides with nitrile imines for access to polycyclic spiroindoline derivatives

An annulation reaction of tryptamine-derived isocyanides with hydrazonyl chlorides in the presence of bases was developed.Controlled by different bases,[1+2+3]annulation and[1+2+3]/[2+3]annulation cascade were realized.In the latter reaction,five new chemical bonds as well as three new heterocycles were formed in one step.It showed extremely high efficiency,relatively broad substrate scope,milder reaction conditions,good tolerance of functional groups and good chemoselectivity.

An Isolable Phosphinogermylyne as a Synthon of One-Coordinate GeⅠRadical

Reduction of chlorogermylene MsFluindtBu-GeCl 1 with potassium graphite(KC8)afforded putative germylyne radical MsFluindtBu-Ge 2 as confirmed by electron paramagnetic resonance(EPR)spectroscopy.However,it slowly decayed via C—H bond activation at the fluorenyl moiety to yield a bis(germylene)3 at room temperature.By using a Lewis base to stabilize the unoccupied p orbital at the GeⅠradical center,acyclic two-coordinate GeⅠradicals MsFluindtBu-Ge(IMe4)4(IMe4=1,3,4,5-tetramethyl-imidazolin-2-ylidene),MsFluindtBu-Ge(IiPr)5(IiPr=1,3-diisopropyl-4,5-dimethyl-imidazolin-2-ylidene),MsFluindtBu-Ge(PMe3)6 were isolated in crystalline forms.The unpaired electron in 4-6 mainly resides at the Ge 4p orbital as revealed by EPR spectroscopic studies and theoretical calculations.Interestingly,facile ligand exchange of PMe3 in 6 with IMe4 and IiPr was observed to afford 4 and 5,respectively.Moreover,phosphinogermylyne 6 reacted with PhEEPh(E=S,Se),4-tetrabutylphenylacetylene(Ar'CCH),[CpMo(CO)3]2 and nBu3SnH to furnish germylenes MsFluindtBu-GeEPh(E=S 7,Se 8),MsFluindtBu-GeCH=CHAr'9,a germylyne complex MsFluindtBu-Ge≡Mo(CO)2Cp 10 and a Ge(Ⅳ)compound MsFluindtBu-GeH2SnnBu311,respectively.The reactivity studies demonstrate that 6 can act as a synthon of one-coordinate germylyne radical attributing to labile coordination of trimethylphosphine.

Isolation and characterization of xanthine oxidase inhibitory constituents of Pyrenacantha staudtii

Six compounds have been isolated from the leaves of Pyrenacantha staudtii, two of which are new compounds. The new compounds have been characterized as kaempherol 3-O-β-rhamnopyranosyl (1→6)-β-D-glucopyranoside (1) and 4-β-glucopyranosyl-(2-furyl)-5-methy-l,2-glucopyranoside phenylmethanone (2). The known compounds are 3-pyridinecarboxylic acid (3), β-sitosterol (4), sitosterol 3-O-β-glucopyranoside (5) and taraxerol (6). Their structures were determined by spectroscopic and chemical evidences. The two new compounds together with 3-pyridinecarboxylic acid showed significant in vitro xanthine oxidase inhibitory activity. To the best of our knowledge, this is the first report of these compounds from this plant.

To Break the Limit of Catalytic Site Density of Fe-NCs

Rational design of Fe and N co-doped carbon catalysts(FeNCs), one promising non-precious cathode catalyst, is critical to commercialization of proton exchange membrane fuel cells. The atomic Fe site density of Fe-NCs is critical to improve catalytic currents approaching industrial levels. One recent research proposes a template-guided strategy to break the limit of Fe site density, and greatly promotes the fuel cell performance.

Mechanistic insights into nickel-and goldcatalyzed diastereoselective[4+2+1]cycloadditions between dienynes and diazo compounds:a DFT study

Density functional theory(DFT)calculations were performed to gain an in-depth mechanistic understanding of Ni(0)-and Au(I)-catalyzed diastereoselective[4+2+1]cycloadditions between dienynes and diazo compounds.The computational results indicate that,for both Ni(0)-and Au(I)-catalysis,transition-metal catalysts are more readily available to activate diazo compounds to form transition-metal carbene intermediates prior to the activation of the dienynes.