Multicomponent solid forms of the uric acid reabsorption inhibitor lesinurad and cocrystal polymorphs with urea: DFT simulation and solubility study

Lesinurad (systematic name: 2‐{[5‐bromo‐4‐(4‐cyclopropylnaphthalen‐1‐yl)‐4H‐1,2,4‐triazol‐3‐yl]sulfanyl}acetic acid, C₁₇H₁₄BrN₃O₂S) is a selective uric acid reabsorption inhibitor related to gout, which exhibits poor aqueous solubility. High‐throughput solid‐form screening was performed to screen for new solid forms with improved pharmaceutically relevant properties. During polymorph screening, we obtained two solvates with methanol (CH₃OH) and ethanol (C₂H₅OH). Binary systems with caffeine (systematic name: 3,7‐dihydro‐1,3,7‐trimethyl‐1H‐purine‐2,6‐dione, C₈H₁₀N₄O₂) and nicotinamide (C₆H₆N₂O), polymorphs with urea (CH₄N₂O) and eutectics with similar drugs, like allopurinol and febuxostat, were prepared using the crystal engineering approach. All these novel solid forms were confirmed by XRD, DSC and FT–IR. The crystal structures were solved by single‐crystal and powder X‐ray diffraction. The crystal structures indicate that the lesinurad molecule is highly flexible and the triazole moiety, along with the rotatable thioacetic acid (side chain) and cyclopropane ring, is almost perpendicular to the planar naphthalene moiety. The carboxylic acid–triazole heterosynthon in the drug is interrupted by the presence of methanol and ethanol molecules in their crystal structures and forms intermolecular macrocyclic rings. The caffeine cocrystal maintains the consistency of the acid–triazole heterosynthons as in the drug and, in addition, they are bound by several auxiliary interactions. In the binary system of nicotinamide and urea, the acid–triazole heterosynthon is replaced by an acid–amide synthon. Among the urea cocrystal polymorphs, Form I (P, 1:1) consists of an acid–amide (urea) heterodimer, whereas in Form II (P2₁/c, 2:2), both acid–amide heterosynthons and urea–urea dimers co‐exist. Density functional theory (DFT) calculations further support the experimentally observed synthon hierarchies in the cocrystals. Aqueous solubility experiments of lesinurad and its binary solids in pH 5 acetate buffer medium indicate the apparent solubility order lesinurad–urea Form I (43‐fold) > lesinurad–caffeine (20‐fold) > lesinurad–allopurinol (12‐fold) ? lesinurad–nicotinamide (11‐fold) > lesinurad, and this order is correlated with the crystal structures.     

Dopamine sensor based on a glassy carbon electrode modified with a reduced graphene oxide and palladium nanoparticles composite

We report on a sensitive electrochemical sensor for dopamine (DA) based on a glassy carbon electrode that was modified with a nanocomposite containing electrochemically reduced graphene oxide (RGO) and palladium nanoparticles (Pd-NPs). The composite was characterized by scanning electron microscopy, energy dispersive spectroscopy, and electrochemical impendence spectroscopy. The electrode can oxidize DA at lower potential (234 mV vs Ag/AgCl) than electrodes modified with RGO or Pd-NPs only. The response of the sensor to DA is linear in the 1–150 μM concentration range, and the detection limit is 0.233 μM. The sensor was applied to the determination of DA in commercial DA injection solutions.

Structure and DNA cleavage properties of two copper(II) complexes of the pyridine-pyrazole-containing ligands mbpzbpy and Hmpzbpya

The DNA-cleavage properties of the two copper(II) complexes, [Cu(mbpzbpy)Br(2)](H(2)O)(2.5) (1) and [Cu(mpzbpya)Cl](CH(3)OH) (2), obtained from the ligands 6,6'-bis(3,5-dimethyl-N-pyrazolmethyl)-2,2'-bipyridine) (mbpzbpy) and 6'-(3,5-dimethyl-N-pyrazolmethyl)-2,2'-bipyridine-6-carboxylic acid) (Hmpzbpya), respectively, are reported. Upon coordination to Cu(II) chloride in methanol, one arm of the ligand mbpzbpy is hydrolyzed to form mpzbpya. Under the same experimental conditions, the reaction of mbpzbpy with CuBr(2) does not lead to ligand hydrolysis. The ligand mpzbpya is coordinated to a copper(ii) ion generating a CuN(3)OCl chromophore, resulting in a distorted square-pyramidal environment, whereas with the N(4) mbpzbpy ligand, the Cu(II) ion is four-coordinated in a distorted square planar geometry. Both complexes promote the oxidative DNA cleavage of phiX174 phage DNA in the absence of reductant. The oxidative nature of the DNA cleavage reaction has been confirmed by religation and cell-transformation experiments. Studies using standard radical scavengers suggest the involvement of hydroxyl radicals in the oxidative cleavage of DNA. Although both compounds do convert form I (supercoiled) DNA to form II (nicked, relaxed form), only complex 1 is able to produce small amounts of form III (linearized DNA). This observation may be explained either by the attack of the copper(ii) complexes to only one single strand of DNA, or by a single cleavage event. Statistical analysis of relative DNA quantities present after the treatment with both copper(ii) complexes supports a random mode of DNA cleavage.     

Non-enzymatic sensing of hydrogen peroxide using a glassy carbon electrode modified with a composite consisting of chitosan‐encapsulated graphite and platinum nanoparticles

We report on a non-enzymatic hydrogen peroxide (H₂O₂) sensor which makes use of a nanocomposite consisting of platinum nanoparticles (PtNPs) and chitosan-encapsulated graphite (graphite-CS). The composite was prepared by sonication of pristine graphite in chitosan (CS) in 5 % acetic acid. The PtNP decorated graphite-CS (graphite-CS/PtNPs) composite was prepared by electrodeposition of PtNPs on the graphite-CS modified glassy carbon electrode. The graphite-CS/PtNP composite was characterized by scanning electron microscopy, elemental analysis and FTIR spectroscopy. The modified electrode displays an enhanced reduction peak current for H₂O₂ when compared with electrodes modified with graphite/PtNPs and PtNPs. The modified electrode exhibits excellent electrocatalytic activity towards the reduction of H₂O₂, and the amperometric response is linear over the concentration range from 0.25 to 2890 μM. The sensitivity and the detection limit are 0.465 μA?μM￣¹ ? cm￣² and 66 nM, respectively. The sensor shows fast response (3 s) in detecting H₂O₂. It is also highly selective in the presence of potentially interfering compounds, and may therefore be used as a feasible platform for sensing H₂O₂ in real samples.

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Graphical abstract Preparation of graphite-CS/PtNP composite, and its application to electrochemical reduction of H₂O₂.

     

Lack of linear free energy relationship: Tungsten(VI) catalyzed perborate oxidation of anilines

The rates of tungsten(VI) catalyzed perborate oxidation of 29 para‐, meta‐ and ortho‐substituted anilines in aqueous acetic acid at 35–55°C conform to the Exner relationship, also the activation parameters to the isokinetic relationship but not to any of the linear free energy relationships. The results are rationalized. © 1999 John Wiley & Sons, Inc. Int J Chem Kinet 31: 571–575, 1999     

Direct Electrochemistry of Glucose Oxidase at Reduced Graphene Oxide and β‐Cyclodextrin Composite Modified Electrode and Application for Glucose Biosensing

A simple glucose biosensor has been developed based on direct electrochemistry of glucose oxidase (GOx) immobilized on the reduced graphene oxide (RGO) and β‐cyclodextrin (CD) composite. A well‐defined redox couple of GOx appears with a formal potential of ～?0.459 V at RGO/CD composite. A heterogeneous electron transfer rate constant (K_s) has been calculated for GOx at RGO/CD as 3.8 s^?1. The fabricated biosensor displays a wide response to glucose in the linear concentrations range from 50 µM to 3.0 mM. The sensitivity and limit of detection of the biosensor is estimated as 59.74 µA mM^?1 cm^?2 and 12 µM, respectively.     

Concurrent genesis of color and electrical conductivity in leathers through in‐situ polymerization of aniline for smart product applications

We present a simple method to produce self‐colored and conducting leathers using in‐situ polymerization of aniline with ammonium persulfate as oxidant and hydrochloric acid as dopant. The structural and morphological features of treated leathers were examined using Fourier transformed infra‐red spectroscopy, X‐ray diffraction and scanning electron microscopic analyses. Results suggest the deposition of conducting emeraldine salt form of polyaniline on the leather substrate rather than other poorly conducting states. We also show that the treated leathers are bluish green through reflectance measurements thereby suggesting that the use of toxic and expensive dyes can be avoided for coloration process. Further, we demonstrate that a maximum electrical conductivity of 0.15 S/cm is obtained for the leather treated with optimal experimental conditions, which aids its application to operate touch‐screen devices. Copyright © 2015 John Wiley & Sons, Ltd.     

Structure, cytotoxicity, and DNA-cleavage properties of the complex [Cu(II)(pbt)Br2

The reactions of the ligand 2-(2-pyridyl)benzthiazole (pbt) with CuBr 2 and ZnCl 2 in acetonitrile produce the complexes [Cu(pbt)Br 2] ( 1) and [Zn(pbt)Cl 2] ( 3), respectively. When complex 1 is dissolved in DMF, complex 2 is obtained as light-green crystals. The reaction of pbt with CuBr 2 in DMF also yields the complex [Cu(pbt)Br 2(dmf)] ( 2) (dmf = dimethylformamide). Complexes 1- 3 were characterized by X-ray crystallography. Complexes 1 and 3 have distorted tetrahedral coordination environments, and complex 2 is constituted of two slightly different copper centers, both exhibiting distorted trigonal bipyramidal geometries. Complexes 1 and 2 cleave phiX174 phage DNA, both in the presence and the absence of reductant. The free ligand pbt does not show any DNA-cleaving abilities. The poor solubility of complex 3 makes it not applicable for biological tests. The occurrence of DNA breaks in the presence of various radical scavengers suggests that no diffusible radicals are involved in the DNA cleavage by complex 1, as none of the scavengers inhibit the cleavage reaction. The DNA-cleavage products are not religated with the enzyme T4 DNA ligase, which is an additional proof that the cleavage is nonhydrolytic. Most probably the cleaving reaction involves reactive oxygen species, which could not be trapped, leading to an oxidative mechanism. An easy oxidation of Cu (II)(pbt)Br 2 to Cu (III) in DMF and the reduction of the same to Cu (I), under similar electrochemical conditions may lead to the in situ activation of molecular oxygen, resulting in the formation of metal solvated nondiffusible radicals able to prompt the oxidative cleavage of DNA. Complex 1 and the pure ligand exhibit remarkable cytotoxic effects against the cancer cell lines L1210 and A2780 and also against the corresponding cisplatin-resistant mutants of these cell lines.     

Nanoscale surface modification via scanning electrochemical probe microscopy

Micro- and nanoscale surface modification using scanning probe microscopy techniques in combination with electrochemically induced surface structuring provides a maskless in situ fabrication strategy enabling deposition or etching of three-dimensional nanostructures. This current opinion article focuses on scanning electrochemical probe microscopy techniques highlighting recent progress in nanoscale 3D surface modification along with a spotlight on approaches of practical relevance.     

Electrical and optical properties of pulse plated CdS<Subscript><Emphasis Type="BoldItalic">x</Emphasis></Subscript>Te<Subscript>1-<Emphasis Type="BoldItalic">x</Emphasis></Subscript> films

Thin films of CdS_xTe_1-x were deposited by the pulse electrodeposition technique using cadmium sulfate, sodium thiosulfate, and tellurium dioxide on titanium and conducting glass substrates. Structural studies indicated the formation of polycrystalline films possessing hexagonal structure. The resistivity varies from 53 Ω cm to 8 Ω cm as the stochiometric coefficient “x” value decreases from 1 to 0. The carrier concentration increases with CdTe concentration. It is observed that as the post-heat treatment temperature increases, the photosensitivity also increases. It is observed that a post-heat treatment temperature of 550 °C results in high photosensitivity as well as low light resistance. The optical constants, refractive index (n) and extinction coefficient (k) were evaluated from the transmission spectra of the films of different composition.