Preparation and functionalization of cellulose nanofibers using a naturally occurring acid and their application in stabilizing linseed oil/water Pickering emulsions.

Finding efficient and environmental-friendly methods to produce and chemically modify cellulose nanofibers (CNFs) remains a challenge. In this study, lactic acid (LA) treatment followed by microfluidization was employed for the isolation and functionalization of CNFs. Small amounts of HCl (0.01, 0.1, and 0.2 M) were used alongside LA to intensify cellulose hydrolysis. FTIR spectroscopy and solid-state 13C NMR confirmed the successful functionalization of CNFs with lactyl groups during isolation, while SEM, AFM, and rheological tests revealed that the addition of HCl governed the fibers' sizes and morphology. Notably, the treatment with LA and 0.2 M HCl resulted in a more efficient defibrillation, yielding smaller nanofibers sizes (62 nm) as compared to the treatment with LA or HCl alone (90 and 108 nm, respectively). The aqueous suspension of CNFs treated with LA and 0.2 M HCl showed the highest viscosity and storage modulus. LA-modified CNFs were tested as stabilizers for linseed oil/water (50/50 v/v) emulsions. Owing to the lactyl groups grafted on their surface and higher aspect ratio, CNFs produced with 0.1 and 0.2 M HCl led to emulsions with increased stability (a creaming index increase of only 3 % and 1 %, respectively, in 30 days) and smaller droplets sizes of 23.4 ± 1.2 and 35.5 ± 0.5 µm, respectively. The results showed that LA-modified CNFs are promising stabilizers for Pickering emulsions.

Developing Innovative Cement Composites Containing Vine Shoot Waste and Superplasticizers.

The expansion of the construction industry requires large quantities of construction materials; therefore, the utilization of alternative raw materials that reduce the environmental impact and enhance the quality of the construction materials has received increasing interest. The comparative performance of 1% Dynamon SR3 or Dynamon SR41 superplasticizers on the properties of cement paste with 1 wt.% vine shoot waste addition (VSW) was investigated after 28 days using Fourier-transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM-EDX), and solid-state 27Al and 29Si nuclear magnetic resonance (NMR) spectroscopy. VSW does not delay the formation of calcium hydroxide and C-S-H and a slight decrease of the -OH band in samples containing superplasticizers, suggesting that free lime is converted to carbonates. The highest degree of crystallinity was remarked for the samples with superplasticizers. The structure of the cement paste with VSW and superplasticizers was corroborated with mechanical properties, showing increased strength in using VSW and superplasticizers. The results showed that adding 1% VSW and superplasticizers does not change the performance of the cement paste but reduces the water-cement ratio. The combination of VSW and superplasticizers led to cement composite with improved structural and mechanical properties suitable for construction.

What Is Wrong with Hyaluronic Acid Chemistry? A 15N/13C Solid-State NMR Re-Evaluation of Its Dopamine Conjugates.

In this work, a systematic 15N/13C solid-state NMR investigation is performed on three dopamine (DA) conjugates of hyaluronic acid, considered in both its native (HA) and NaIO4-oxidized (HAOx) forms. Two of them, here named HAEDC-DA and HAOx-DA, have been previously introduced as covalent conjugates involving DA amine nitrogen: the former by EDC-mediated amide bond formation, and the latter by reaction of the Schiff base with the aldehyde moieties presumed to exist in HAOx. The third conjugate, HA-DA, is reported here for the first time; it is obtained by simply mixing hyaluronan with DA∙HCl at pH 5. The 15N ss-NMR spectra were found to be consistent in all the systems, and the DA molecules were found to be in their charged -NH3+ form, which contradicts the HAEDC-DA/HAOx-DA covalent bonding schemes proposed in the literature. The 13C ss-NMR results add useful new insights into the structure and interaction patterns of the conjugates. All of our findings are relevant for future practical applications, for instance in developing novel HA-based hydrogels. In addition, the present study demonstrates the importance of using the most appropriate analytical tools when investigating composite systems due to the complexity of hyaluronic acid conjugates. Solid-state NMR proved essential to answering the question in the title: actually, there is nothing wrong with hyaluronic acid chemistry; the claimed covalent bonds between DA and the HA(HAOx) chain do not exist in these systems, because the conditions for their formation do not hold in practice.

Polydopamine conjugated SiO2 nanoparticles as potential drug carriers for melanoma treatment.

Silica nanoparticles (SiO2) are increasingly investigated for biomedical applications. Aim: This study aimed to analyze the potential use of a SiO2 nanoparticles coated with biocompatible polydopamine (SiO2@PDA) as a potential chemotherapeutic drug carrier. Materials & methods: SiO2 morphology and PDA adhesion was analyzed by dynamic light scattering, electron microscopy and nuclear magnetic resonance. Cytotoxicity studies and morphology analyses (immunofluorescence, scanning and transmission electron microscopy) were used to assess the cellular reaction to the SiO2@PDA nanoparticles and to identify a biocompatible (safe use) window. Results & conclusion: Concentrations above 10 µg/ml and up to 100 µg/ml SiO2@PDA showed the best biocompatibility on human melanoma cells at 24 h and represent a potential drug carrier template for targeted melanoma cancer treatment.

Tiny particles can be small enough to enter cells. This is why they may be useful in the treatment of cancer. We made particles in a way that is friendly for human cells, then we analyzed their effects on cancer cells. Our tests showed that these particles could be useful for treatment because they do not worsen cancer cells. This is important because sometimes after treatment, cancer cells can become more dangerous. This way, even if the drug did not work, the cancer will not worsen.

Development of a New Eco-Friendly Copolymer Based on Chitosan for Enhanced Removal of Pb and Cd from Water.

Worldwide, concerns about heavy metal contamination from manmade and natural sources have increased in recent decades. Metals released into the environment threaten human health, mostly due to their integration into the food chain and persistence. Nature offers a large range of materials with different functionalities, providing also a source of inspiration for scientists working in the field of material synthesis. In the current study, a new type of copolymer is introduced, which was synthesized for the first time by combining chitosan and poly(benzofurane-co-arylacetic acid), for use in the adsorption of toxic heavy metals. Such naturally derived materials can be easily and inexpensively synthesized and separated by simple filtration, thus becoming an attractive alternative solution for wastewater treatment. The new copolymer was investigated by solid-state nuclear magnetic resonance, thermogravimetric analysis, scanning electron microscopy, Fourier transform infrared spectroscopy, and X-ray photon electron microscopy. Flame atomic absorption spectrometry was utilized to measure heavy metal concentrations in the investigated samples. Equilibrium isotherms, kinetic 3D models, and artificial neural networks were applied to the experimental data to characterize the adsorption process. Additional adsorption experiments were performed using metal-contaminated water samples collected in two seasons (summer and winter) from two former mining areas in Romania (Roșia Montana and Novaț-Borșa). The results demonstrated high (51-97%) adsorption efficiency for Pb and excellent (95-100%) for Cd, after testing on stock solutions and contaminated water samples. The recyclability study of the copolymer indicated that the removal efficiency decreased to 89% for Pb and 58% for Cd after seven adsorption-desorption cycles.

Ketoconazole-p aminobenzoic cocrystal, an improved antimycotic drug formulation, does not induce skin sensitization on the skin of BALBc mice.

Fungal infections are a growing global health problem. Therefore, our group has synthetized and characterized an improved antimycotic by co-crystallization of ketoconazole and para-amino benzoic acid, named KET-PABA. The aim was to increase bioavailability, biocompatibility, and efficiency of the parent drug-ketoconazole. Based on our previous results showing the cocrystal improved physical properties, such as stability in suspension, solubility, as well as antimycotic efficiency compared to ketoconazole, the current study investigated the local possible side effects induced on the skin of BALBc mice by the application of KET-PABA cocrystal, in view of a further use as a topically applied antimycotic drug. A specific test (mouse ear-swelling test) was used, combined with the histopathological examination and the measurement of pro and anti-inflammatory cytokines and inflammation mediators. KET-PABA application was safe, without signs of skin sensitization shown by the mouse ear sensitization test, or histopathology. KET-PABA strongly inhibited proinflammatory cytokines such as IL1 α, IL1 ß, IL6 and TNF α, and other proinflammatory inducers such as NRF2, compared to vehicle. KET-PABA had no effect on the levels of the anti-inflammatory cytokine IL10, or proinflammatory enzyme COX2 and had minimal effects on the activation of the NF-κB pathway. Overall, KET-PABA application induced no sensitization, moreover, it decreased the skin levels of proinflammatory molecules. The lack of skin sensitization effects on BALBc mice skin along with the inhibition of the proinflammatory markers show a good safety profile for topical applications of KET-PABA and show promise for a further clinical use in the treatment of cutaneous mycosis.

Hydrogen-Mediated Noncovalent Interactions in Solids: What Can NMR Crystallography Tell About?

Hydrogen atoms play a crucial role in the aggregation of organic (bio)molecules through diverse number of noncovalent interactions that they mediate, such as electrostatic in proton transfer systems, hydrogen bonding, and CH-π interactions, to mention only the most prominent. To identify and adequately describe such low-energy interactions, increasingly sensitive methods have been developed over time, among which quantum chemical computations have witnessed impressive advances in recent years. For reaching the present state-of-the-art, computations had to rely on a pool of relevant experimental data, needed at least for validation, if not also for other purposes. In the case of molecular crystals, the best illustration for the synergy between computations and experiment is given by the so-called NMR crystallography approach. Originally designed to increase the confidence level in crystal structure determination of organic compounds from powders, NMR crystallography is able now to offer also a wealth of information regarding the noncovalent interactions that drive molecules to pack in a given crystalline pattern or another. This is particularly true for the noncovalent interactions which depend on the exact location of labile hydrogen atoms in the system: in such cases, NMR crystallography represents a valuable characterization tool, in some cases complementing even the standard single-crystal X-ray diffraction technique. A concise introduction in the field is made in this mini-review, which is aimed at providing a comprehensive picture with respect to the current accuracy level reached by NMR crystallography in the characterization of hydrogen-mediated noncovalent interactions in organic solids. Different types of practical applications are illustrated with the example of molecular crystals studied by our research group, but references to other representative developments reported in the literature are also made. By summarizing the major concepts and methodological progresses, the present work is also intended to be a guide to the practical potential of this relatively recent analytical tool for the scientists working in areas where crystal engineering represents the main approach for rational design of novel materials.

Ketoconazole-p-aminobenzoic Acid Cocrystal: Revival of an Old Drug by Crystal Engineering.

The 1:1 cocrystal of the antifungal agent ketoconazole with p-aminobenzoic acid was successfully crystallized and systematically characterized by a physical and pharmacological point of view. Crystal structure determination confirmed the cocrystal identity, giving full insight in its crystal packing and degree of disorder. Powder dissolution measurements revealed a 10-fold aqueous solubility increase that induces a 6.7-fold oral bioavailability improvement compared to ketoconazole. In vitro cell assays showed a good toxicity profile of the cocrystal with lower oxidative stress and inflammation and enhanced antifungal activity against several Candida species. The in vivo study of the cocrystal indicated similar pharmacokinetic profiles and liver toxicity with increased transaminases, as reported for ketoconazole. Notably, besides minor signs of inflammation, no morphological changes in liver parenchyma or signs of fibrosis and necrosis were detected. The enhanced solubility and oral bioavailability of the cocrystal over ketoconazole, together with the improved antifungal activity and good in vitro/in vivo toxicity, indicate its potential use as an alternative antifungal agent to the parent drug. Our results bring evidence of cocrystallization as a successful approach for bioavailability improvement of poorly soluble drugs.

Optimized multi-step NMR-crystallography approach for structural characterization of a stable quercetin solvate.

Herein we report the preparation and solid state structural investigation of the 1,4-dioxane-quercetin solvate. NMR crystallography methods were employed for crystal structure determination of the solvate from microcrystalline powder. The stability of the compound relative to other reported quercetin solvates is discussed and found to be in perfect agreement with the hydrogen bonding networks/supra-molecular architectures formed in each case. It is also clearly shown that NMR crystallography represents an ideal analytical tool in such cases when hydrogen-bonding networks are required to be constrained at a high accuracy level.

Highly sensitive solid forms discrimination on the whole tablet of the active ingredients in quercetin dietary supplements by NMR crystallography approaches.

Similarly to synthetic drugs, the exact crystalline form of active ingredients in solid formulations of dietary supplements may directly influence the dissolution rate, bioavailability, and stability of the final product, but this information is usually not provided by manufacturers. Working on the examples of two commercial quercetin dietary supplements a quick, reliable, and sensitive method is introduced for quercetin solid forms discrimination directly on the marketed products, without the need for prior sample preparation. It exploits the complementarity between solid-state Nuclear Magnetic Resonance (ss-NMR) and Powder X-Ray Diffraction (PXRD), which proved essential for performing a complete and accurate solid-state characterization of the two commercial products, and for obtaining new insights into the complex quercetin solid-forms landscape. The method can be readily generalized also to other dietary supplements based on bio-flavonoids/polyphenols.

Cytotoxicity assessment of graphene-based nanomaterials on human dental follicle stem cells.

Graphene-oxide (GO) and its most encountered derivatives, thermally reduced graphene oxide (TRGO) and nitrogen-doped graphene (N-Gr), were synthesized and structurally characterized by spectroscopic techniques, like Raman and (13)C MAS solid state NMR. Several biological effects (cytotoxicity, oxidative stress induction, and cellular and mithocondrial membrane alterations) induced by such graphene-based materials on human dental follicle stem cells were investigated. Graphene oxide shows the lowest cytotoxic effect, followed by the nitrogen-doped graphene, while thermally reduced graphene oxide exhibits high cytotoxic effects. Graphene oxide induces oxidative stress without causing cell membrane damage. Nitrogen-doped graphene shows a slight antioxidant activity; however, at high doses (20 and 40 µg/ml) it causes membrane damage. Both graphene oxide and nitrogen-doped graphene seem to be valuable candidates for usage in dental nanocomposites.

Crystal Structure and Desolvation Behaviour of the Tadalafil Monosolvates with Acetone and Methyl Ethyl Ketone.

Crystal structures of Tadalafil (TDF) monosolvated forms with acetone (ACE) and methyl ethyl ketone (MEK) were determined by single-crystal X-ray diffraction in which same persistent chains of TDF molecules are present as in the reported structures. The solvates crystallize in a higher orthorhombic symmetry than the known forms with monoclinic structures. Weak interactions between TDF and solvent molecules are present in both solvates, leading to slight conformational distortions of TDF molecules. The MEK solvate showed slightly higher stability than the ACE solvate, regardless of their highly similar molecular conformations and crystal packing. Desolvation into anhydrous TDF was achieved by heating, exposure to temperature and relative humidity and by mechanical stress. The high solubility of TDF in ACE and MEK solvents combined with the ease of desolvation of the resulting solvated forms indicates the viability of the solvates use as intermediates in the TDF crystallization process.

Can the conformation of flexible hydroxyl groups be constrained by simple NMR crystallography approaches? The case of the quercetin solid forms.

Hydrogen atoms in systems with many flexible hydroxyl side-groups are difficult to be exactly located from experimental X-Ray diffraction and/or solid-state NMR data, thus often leading to wrong conclusions with respect to the hydrogen bonding network established in crystal lattice. A simple computational method is proposed in the present work to tackle this problem, which may be readily incorporated in conventional NMR crystallography protocols. The method is based on ranking all possible conformations of the flexible hydroxyls according to their lattice energy in crystalline environments. Its effectiveness is investigated on two distinct solid forms of quercetin, for which only two out of the five hydroxyl side-groups can be well constrained from experimental/theoretical data. For this purpose, first-principle quantum-mechanical computations were combined with calculations at the molecular mechanics (MM) level of theory, and previous ss-NMR and X-Ray diffraction data. To assess accuracy in ranking the identified conformers, tests have been performed first on quercetin dihydrate, for which an X-Ray single-crystal structure is available. The possibility of applying this method in a real NMR crystallography context has been investigated finally on anhydrous quercetin, for which only powder X-Ray crystal structure has been reported so far.

Testing the limits of sensitivity in a solid-state structural investigation by combined X-ray powder diffraction, solid-state NMR, and molecular modelling.

A solid state structural investigation of ethoxzolamide is performed on microcrystalline powder by using a multi-technique approach that combines X-ray powder diffraction (XRPD) data analysis based on direct space methods with information from (13)C((15)N) solid-state Nuclear Magnetic Resonance (SS-NMR) and molecular modeling. Quantum chemical computations of the crystal were employed for geometry optimization and chemical shift calculations based on the Gauge Including Projector Augmented-Wave (GIPAW) method, whereas a systematic search in the conformational space was performed on the isolated molecule using a molecular mechanics (MM) approach. The applied methodology proved useful for: (i) removing ambiguities in the XRPD crystal structure determination process and further refining the derived structure solutions, and (ii) getting important insights into the relationship between the complex network of non-covalent interactions and the induced supra-molecular architectures/crystal packing patterns. It was found that ethoxzolamide provides an ideal case study for testing the accuracy with which this methodology allows to distinguish between various structural features emerging from the analysis of the powder diffraction data.

Structure of N-(5-ethyl-[1,3,4]-thiadiazole-2-yl)toluenesulfonamide by combined X-ray powder diffraction, 13C solid-state NMR and molecular modelling.

The crystal structure solution of the title compound is determined from microcrystalline powder using a multi-technique approach that combines X-ray powder diffraction (XRPD) data analysis based on direct-space methods with information from (13)C solid-state NMR (SSNMR), and molecular modelling using the GIPAW (gauge including projector augmented-wave) method. The space group is Pbca with one molecule in the asymmetric unit. The proposed methodology proves very useful for unambiguously characterizing the supramolecular arrangement adopted by the N-(5-ethyl-[1,3,4]-thiadiazole-2-yl)toluenesulfonamide molecules in the crystal, which consists of extended double strands held together by C-H···π non-covalent interactions.

SD-CAS: Spin Dynamics by Computer Algebra System.

A computer algebra tool for describing the Liouville-space quantum evolution of nuclear 1/2-spins is introduced and implemented within a computational framework named Spin Dynamics by Computer Algebra System (SD-CAS). A distinctive feature compared with numerical and previous computer algebra approaches to solving spin dynamics problems results from the fact that no matrix representation for spin operators is used in SD-CAS, which determines a full symbolic character to the performed computations. Spin correlations are stored in SD-CAS as four-entry nested lists of which size increases linearly with the number of spins into the system and are easily mapped into analytical expressions in terms of spin operator products. For the so defined SD-CAS spin correlations a set of specialized functions and procedures is introduced that are essential for implementing basic spin algebra operations, such as the spin operator products, commutators, and scalar products. They provide results in an abstract algebraic form: specific procedures to quantitatively evaluate such symbolic expressions with respect to the involved spin interaction parameters and experimental conditions are also discussed. Although the main focus in the present work is on laying the foundation for spin dynamics symbolic computation in NMR based on a non-matrix formalism, practical aspects are also considered throughout the theoretical development process. In particular, specific SD-CAS routines have been implemented using the YACAS computer algebra package (http://yacas.sourceforge.net), and their functionality was demonstrated on a few illustrative examples.

CHHC and (1)H-(1)H magnetization exchange: analysis by experimental solid-state NMR and 11-spin density-matrix simulations.

A protocol is presented for correcting the effect of non-specific cross-polarization in CHHC solid-state MAS NMR experiments, thus allowing the recovery of the (1)H-(1)H magnetization exchange functions from the mixing-time dependent buildup of experimental CHHC peak intensity. The presented protocol also incorporates a scaling procedure to take into account the effect of multiplicity of a CH(2) or CH(3) moiety. Experimental CHHC buildup curves are presented for l-tyrosine.HCl samples where either all or only one in 10 molecules are U-(13)C labeled. Good agreement between experiment and 11-spin SPINEVOLUTION simulation (including only isotropic (1)H chemical shifts) is demonstrated for the initial buildup (t(mix)<100micros) of CHHC peak intensity corresponding to an intramolecular close (2.5A) H-H proximity. Differences in the initial CHHC buildup are observed between the one in 10 dilute and 100% samples for cases where there is a close intermolecular H-H proximity in addition to a close intramolecular H-H proximity. For the dilute sample, CHHC cross-peak intensities tended to significantly lower values for long mixing times (500micros) as compared to the 100% sample. This difference is explained as being due to the dependence of the limiting total magnetization on the ratio N(obs)/N(tot) between the number of protons that are directly attached to a (13)C nucleus and hence contribute significantly to the observed (13)C CHHC NMR signal, and the total number of (1)H spins into the system. (1)H-(1)H magnetization exchange curves extracted from CHHC spectra for the 100% l-tyrosine.HCl sample exhibit a clear sensitivity to the root sum squared dipolar coupling, with fast buildup being observed for the shortest intramolecular distances (2.5A) and slower, yet observable buildup for the longer intermolecular distances (up to 5A).

WITHDRAWN: CHHC and (1)H-(1)H magnetization exchange: Analysis by experimental solid-state NMR and 11-spin density-matrix simulations.

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Polarization transfer from remote protons in 13C CP/MAS.

An experimental procedure for CP/MAS polarization transfer from remote 1H nuclear spins is introduced, which is applicable to protonated carbons in organic solids. It is based on preparing a state of non-uniform polarization, where directly bonded 13C-1H nuclei are de-polarized prior to recording the CP buildup curve. This curve is then expected to quantify the polarization transfer from remote protons only. The ability of the cross-polarization/polarization-inversion (CPPI) sequence to generate an initial state suitable for remote 1H CP/MAS scheme is analyzed both theoretically and experimentally. Confining to aliphatic groups, it was found that complete de-polarization of bonded proton is possible in the case of CH, whereas for CH2 and CH3 moieties only a partial de-polarization can be achieved. The theoretical predictions have been verified in practice for the particular case of L-alanine. The significance of the results from fundamental, as well as practical point of view, is also discussed. In particular, it is shown that: (i) the coherent description of polarization transfer under CP/MAS, including 1H polarization redistribution, is valid over time-scales longer than commonly assumed in many treatments of cross-polarization, and (ii) the remote protons polarization transfer curve can be used in combination with the conventional CP/MAS curve to get additional structural and dynamical information in organic systems.

Heteronuclear decoupling under fast MAS by a rotor-synchronized Hahn-echo pulse train.

A new heteronuclear decoupling mechanism under fast magic-angle spinning MAS is introduced. It is based on refocusing the coherences responsible for the dephase of low-gamma nuclei ((13)C, (15)N) transverse spin-polarization in the presence of strongly dipolar-coupled protons, and has the advantage that can be implemented by pulsed techniques, with all the benefits resulting from a reduced duty cycle compared with conventional decoupling by continuous rf irradiation. The decoupling efficiency of a simple rotor-synchronized Hahn-echo pulse train is analyzed both theoretically and experimentally. It was found that a substantial improvement in sensitivity and resolution can be achieved in compounds with small (1)H chemical shielding parameters even at moderate sample spinning, and some interesting applications are shown. It is also shown that much faster spinning frequencies, or alternative refocusing sequences, are needed for applications on rigid organic solids, i.e., in systems with larger (1)H chemical shifts.