Green AOT reverse micelles as nanoreactors for alkaline phosphatase. The hydrogen bond "dances" between water and the enzyme, the reaction product, and the reverse micelles interface.

In this work, we present an investigation of the influence of water encapsulated in 1,4-bis-2-ethylhexylsulfosuccinate/methyl laurate and 1,4-bis-2-ethylhexylsulfosuccinate/isopropyl myristate reverse micelles on the enzymatic hydrolysis of 1-naphthyl phosphate by alkaline phosphatase. Our results show that the enzyme is active in the biocompatible reverse micelles studied and that the Michaelis-Menten kinetic model is valid in all systems. We found that both micellar systems studied have a particular behavior toward pH and that the penetration of external solvents into the interfaces is crucial to understanding the effect. Methyl laurate does not disrupt the interface and is not necessary to control the pH value since alkaline phosphatase in the center of the micelles is always solvated similarly. In contrast, isopropyl myristate disrupts the interfaces so that the water and 1-naphthol molecules cannot form hydrogen bond interactions with the polar head of the surfactant. Then, when the water is at pH = 7, the 1-naphthol moves away to the interfaces inhibiting alkaline phosphatase which is not observable when the water is at pH = 10. Our study shows that the concept of pH cannot be used directly in a confined environment. In addition, our research is of great importance in the field of reactions that occur in reverse micelles, catalyzed by enzymes.

Speciation and Proton Conductivity of Phosphoric Acid Confined in Mesoporous Silica.

Phosphoric acid (PA) confined in a commercial mesoporous silica (CARIACT G) with porous size in the range of 3 to 10 nm was studied in relation to its coordination with the silanol groups on the silica surface as a function of temperature, up to 180 °C, using 31P and 29Si MAS NMR spectroscopy. As the temperature increases, the coordination of Si and P in the mesopores depends on the pore size, that is, on the area/volume ratio of the silica matrix. In the mesoporous silica with the higher pore size (10 nm), a considerable fraction of PA is nonbonded to the silanol groups on the surface, and it seems to be responsible for its higher conductivity at temperatures above 120 °C as compared to the samples with a smaller pore size. The electrical conductivity of the functionalized mesoporous silica was higher than that reported for other silico-phosphoric composites synthesized by sol-gel methods using soft templates, which require high-temperature calcination and high-cost reagents and are close to that of the best PA-doped polybenzimidazole membranes used in high-temperature proton exchange membrane fuel cells (HT-PEMFCs). The rate of PA release from the mesoporous silica matrix when the system is exposed to water has been measured, and it was found to be strongly dependent on the pore size. The low cost and simplicity of the PA-functionalized mesoporous silica preparation method makes this material a promising candidate to be used as an electrolyte in HT-PEMFCs.

Comparison of experimental times in T1-D and D-T2 correlation experiments in single-sided NMR.

Diffusion-relaxation correlation experiments in nuclear magnetic resonance are a powerful technique for the characterization of fluid dynamics in confined geometries or soft matter, in which relaxation may be either spin-spin (T2) or spin-lattice (T1). The general approach is to acquire a set of bidimensional data in which diffusion is codified by the evolution of the magnetization with either Hahn or stimulated echoes (STE) in the presence of a constant magnetic field gradient. While T2 is codified by a Carr-Purcell-Meiboom-Gil (CPMG) sequence, T1 is either encoded by saturation or inversion-recovery methods. In this work, we analyse the measurement time of diffusion-relaxation times in single-sided NMR and show that T1-D acquisition is always shorter than D-T2. Depending on the hardware characteristics, this time reduction can be up to an order of magnitude. We present analytical calculations and examples in model porous media saturated with water and in a dairy product.

Unveiling the stability of Sn/Si/graphite composites for Li-ion storage by physical, electrochemical and computational tools.

Complex materials composed of two and three elements with high Li-ion storage capacity are investigated and tested as lithium-ion battery (LiB) negative electrodes. Namely, anodes containing tin, silicon, and graphite show very good performance because of the large gravimetric and volumetric capacity of silicon and structural support provided by tin and graphite. The performance of the composites during the first cycles was studied using ex situ magic angle spinning (MAS) 7Li Nuclear Magnetic Resonance (NMR), density functional theory (DFT) calculations, and electrochemical techniques. The best performance was obtained for Sn/Si/graphite in a 1 : 1 : 1 proportion, due to an emergent effect of the interaction between Sn and Si. The results suggest a stabilization effect of Sn over Si, providing a physical constraint that prevents Si pulverization. This mechanism ensures good cyclability over more than one hundred cycles, low capacity fading and high specific capacity.

Accurate location of hydrogen atoms in hydrogen bonds of tizoxanide from the combination of experimental and theoretical models.

To obtain detailed information about the position of hydrogen atoms in hydrogen bonds, HBs, of crystalline organic molecular compounds is not an easy task. In this work we propose a combination of ssNMR experimental data with theoretical procedures to get such information. Furthermore, the combination of experimental and theoretical models provides us with well-defined grounds to analyse the strength of π-stacking interactions between layers of hydrogen bonded molecules. Two different theoretical models were considered, both approaches being quite different. The first one is a solid-state model, so that the periodicity of a crystalline system underlies calculations of the electronic energy, the electronic density and NMR parameters. The other one is a molecular model in which molecules are taken as isolated monomers, dimers and tetramers. These two models were applied to the tizoxanide, TIZ, molecular crystal though it can widely be applied to any other molecular crystal. By the application of the quantum molecular model it was possible to learn about the way the intermolecular HBs affect the position of hydrogen atoms that belong to HBs in TIZ. This molecule has two intermolecular HBs that stabilize the structure of a basic dimer, but it also has an intramolecular HB in each monomer whose position should be optimized together with the other ones. We found that by doing this it is possible to obtain reliable results of calculations of NMR spectroscopic parameters. Working with the solid-state model we found that any local variation of the TIZ crystalline structure is correlated with the variation of the values of the NMR parameters of each nucleus. The excellent agreement between experimental and calculated chemical shifts leads to the conclusion that the N10-H10 bond distance should be (1.00 ± 0.02) Å.

Water-soluble gold nanoparticles: recyclable catalysts for the reduction of aromatic nitro compounds in water.

A structure/catalytic activity study of water-soluble gold nanoparticles, stabilized by zwitterionic ligands derived from imidazolium salts, in the reduction of aromatic nitro compounds in pure water at different temperature, as well as their recyclability, was performed. Our studies indicate that the nanoparticles synthesized by an easy, fast and reproducible process, need a short characteristic induction time to restructure the surfaces and make them active. The differences observed in the catalytic activity of the nanoparticles, determined by using the typical Langmuir-Hinshelwood model, are strongly based on the degree of coverage and spatial arrangement of the imidazolium salts on them. Finally, we demonstrate that gold nanoparticles stabilized by non-traditional ligands can be an excellent choice for nitro compound degradation.

Challenging identification of polymorphic mixture: Polymorphs I, II and III in olanzapine raw materials.

Olanzapine (OLZ), a drug for the treatment of schizophrenia, presents in more than 60 crystal forms. Polymorphs I, II and III were reported, however, the preparation conditions for pure II and III have not been reported. Polymorph IV was reported but this form is actually polymorph II described at different temperature. The diversity of solid forms of OLZ, the change in the nomenclature found in the literature and the presence of polymorphic mixture in samples, increase the difficulty for a correct solid state characterization. Therefore, the goal was the polymorphic identification of three OLZ raw materials, highlighting the limitation of conventional techniques (typically used in analytical control) and the necessity to use a combination of advanced ones to solve this challenge. The samples were studied by conventional techniques such as powder X-ray diffraction, thermoanalytical techniques, infrared spectroscopy. In apart from that, synchrotron powder X-ray diffraction (SPXRD) and solid state nuclear magnetic resonance (ss-NMR) were used. All samples were in accordance with the pharmacopoeia criteria. However, the conventional techniques were not specific for the complete polymorphic identification. Therefore, a combination of advanced techniques (SPXRD and ss-NMR) was necessary to identify the mixture of polymorphs (I, II and III) in all samples.

Probing numerical Laplace inversion methods for two and three-site molecular exchange between interconnected pore structures.

Two-dimension (2D) Nuclear Magnetic Resonance relaxometry experiments are a powerful tool extensively used to probe the interaction among different pore structures, mostly in inorganic systems. The analysis of the collected experimental data generally consists of a 2D numerical inversion of time-domain data where T2-T2 maps are generated. Through the years, different algorithms for the numerical inversion have been proposed. In this paper, two different algorithms for numerical inversion are tested and compared under different conditions of exchange dynamics; the method based on Butler-Reeds-Dawson (BRD) algorithm and the fast-iterative shrinkage-thresholding algorithm (FISTA) method. By constructing a theoretical model, the algorithms were tested for a two- and three-site porous media, varying the exchange rates parameters, the pore sizes and the signal to noise ratio. In order to test the methods under realistic experimental conditions, a challenging organic system was chosen. The molecular exchange rates of water confined in hierarchical porous polymeric networks were obtained, for a two- and three-site porous media. Data processed with the BRD method was found to be accurate only under certain conditions of the exchange parameters, while data processed with the FISTA method is precise for all the studied parameters, except when SNR conditions are extreme.

Gold nanoparticles stabilized with sulphonated imidazolium salts in water and reverse micelles.

Herein we describe the synthesis of gold nanoparticles (Au-NPs) in presence of sulphonated imidazolium salts [1,3-bis(2,6-diisopropyl-4-sodiumsulfonatophenyl)imidazolium (L1), 1-mesityl-3-(3-sulfonatopropyl)imidazolium (L2) and 1-(3-sulfonatopropyl)imidazolium (L3)] in water and in a confinement environment created by reverse micelles (RMs). The Au-NPs were characterized-with an excellent agreement between different techniques-by UV-vis spectroscopy, transmission electron microscopy (TEM), dynamic light scattering (DLS) and zeta potential. In homogeneous media, the Au-NPs interact with the imidazolium ring and the sulphonate groups were directed away from the NPs' surface. This fact is responsible for the Au-NPs' stability-over three months-in water. Based on the obtained zeta potential values we assume the degree of coverage of the Au-NPs by the imidazolium salts. In n-heptane/sodium 1,4-bis (2-ethylhexyl) sulfosuccinate (AOT)/water RMs, the Au-NPs formed in presence of sulphonated imidazolium salts present different patterns depending on the ligand used as stabilizer. Interestingly, the Au-NPs are more stable in time when the salts are present in AOT RMs (three weeks) in comparison with the same RMs system but in absence of ligands (less than an hour). Clearly, the sulphonated imidazolium salts are very effective Au-NPs stabilizers in a different medium and this generates a plus to be able to use them for multiple purposes.

Application of 1-Dimensional and 2-Dimensional Solid-State Nuclear Magnetic Resonance Spectroscopy to the Characterization of Morphine, Morphine Hydrochloride, and Their Hydrates.

The detailed knowledge of the solid forms of a drug is a key element in pharmaceutical development. Morphine (MOR) is an opiate alkaloid widely used to treat severe acute and chronic pain. Much of the available information on its solid state dates from several decades ago. In order to obtain updated and reliable information, 1-dimensional (1D) and 2-dimensional solid-state nuclear magnetic resonance spectroscopy were used and complemented with powder X-ray diffraction, FTIR, and Raman spectroscopy and thermal analysis. 13C cross-polarization with magic angle spinning 1D spectra accomplish a complete identification of the related forms of MOR. Remarkably, 1H-13C heteronuclear correlation spectra together with FTIR results gave clear evidence that neither MOR nor its hydrate crystallizes as a zwitterion. Our results indicate that the hydrogen bonds in the anhydrate forms have a different nature or strength than in their respective hydrates. The unique information obtained would be useful for the characterization of MOR as a bulk drug, dosage forms, and future developments.

Preparation of Chloramphenicol/Amino Acid Combinations Exhibiting Enhanced Dissolution Rates and Reduced Drug-Induced Oxidative Stress.

Chloramphenicol is an old antibiotic agent that is re-emerging as a valuable alternative for the treatment of multidrug-resistant pathogens. However, it exhibits suboptimal biopharmaceutical properties and toxicity profiles. In this work, chloramphenicol was combined with essential amino acids (arginine, cysteine, glycine, and leucine) with the aim of improving its dissolution rate and reduce its toxicity towards leukocytes. The chloramphenicol/amino acid solid samples were prepared by freeze-drying method and characterized in the solid state by using Fourier transform infrared spectroscopy, powder X-ray diffraction, differential scanning calorimetry, scanning electron microscopy, and solid-state nuclear magnetic resonance. The dissolution properties, antimicrobial activity, reactive oxygen species production, and stability of the different samples were studied. The dissolution rate of all combinations was significantly increased in comparison to that of the pure active pharmaceutical ingredient. Additionally, oxidative stress production in human leukocytes caused by chloramphenicol was decreased in the chloramphenicol/amino acid combinations, while the antimicrobial activity of the antibiotic was maintained. The CAP:Leu binary combination resulted in the most outstanding solid system makes it suitable candidate for the development of pharmaceutical formulations of this antimicrobial agent with an improved safety profile.

Very fast dissolving acid carboxymethylcellulose-rifampicin matrix: Development and solid-state characterization.

One of the main obstacles to the successful treatment of tuberculosis is the poor and variable oral bioavailability of rifampicin (RIF), which is mainly due to its low hydrophilicity and dissolution rate. The aim of this work was to obtain a hydrophilic new material that allows a very fast dissolution rate of RIF and therefore is potentially useful in the development of oral solid dosage forms. The acid form of carboxymethylcellulose (CMC) was co-processed with RIF by solvent impregnation to obtain CMC-RIF powder, which was characterized by polarized optical microscopy, powder x-ray diffraction, DSC-TGA, hot stage microscopy, 13C and 15N solid-state NMR and FT-IR spectroscopy. In addition, the CMC-RIF matrices were subjected to water uptake and dissolution studies to assess hydrophilicity and release kinetics. CMC-RIF is a crystalline solid dispersion. Solid-state characterization indicated that no ionic interaction occurred between the components, but RIF crystallized as a zwitterion over the surface of CMC, which drastically increased the hydrophilicity of the solid. The CMC-RIF matrices significantly improved the water uptake of RIF and disintegrated in a very short period immediately releasing RIF. As CMC improves the hydrophilicity and delivery properties of RIF, CMC-RIF is very useful in the design of oral solid dosage forms with very fast dissolution of RIF, either alone or in combination with other antitubercular drugs.

Enhanced Surface Interaction of Water Confined in Hierarchical Porous Polymers Induced by Hydrogen Bonding.

Hierarchical porous polymer systems are increasingly applied to catalysis, bioengineering, or separation technology because of the versatility provided by the connection of mesopores with percolating macroporous structures. Nuclear magnetic resonance (NMR) is a suitable technique for the study of such systems as it can detect signals stemming from the confined liquid and translate this information into pore size, molecular mobility, and liquid-surface interactions. We focus on the properties of water confined in macroporous polymers of ethylene glycol dimethacrylate and 2-hydroxyethyl methacrylate [poly(EGDMA-co-HEMA)] with different amounts of cross-linkers, in which a substantial variation of hydroxyl groups is achieved. As soft polymer scaffolds may swell upon saturation with determined liquids, the use of NMR is particularly important as it measures the system in its operational state. This study combines different NMR techniques to obtain information on surface interactions of water with hydrophilic polymer chains. A transition from a surface-induced relaxation in which relaxivity depends on the pore size to a regime where the organic pore surface strongly restricts water diffusion is observed. Surface affinities are defined through the molecular residence times near the network surface.

Evaporation kinetics in swollen porous polymeric networks.

NMR is a fast, nondestructive, and noninvasive technique that can provide information about the pore structure of macroporous polymer beads and the dynamics of liquids confined in them. In this work, we describe the study of the pore structure of the macroporous polymer of ethylene glycol dimethacrylate and 2-hydroxyethyl methacrylate [poly(EGDMA-co-HEMA)] in the dry but also in the swollen state by measuring relaxation times of liquids contained in the polymer network. The results show that the pore architecture differs from the dry to the soaked state. The behavior of polar liquids during evaporation and deswelling dynamics is monitored and described. An internal migration of water from the swollen polymer mesh into expanding pores takes place. With this procedure it is possible to obtain information about the microscopic morphology behavior of the matrix during evaporation and deswelling. This information is of great interest with the aspect of possible and future applications for these types of materials.

Solid-state evaluation and polymorphic quantification of venlafaxine hydrochloride raw materials using the Rietveld method.

Venlafaxine hydrochloride (VEN) is an antidepressant drug widely used for the treatment of depression. The purpose of this study was to carry out the preparation and solid state characterization of the pure polymorphs (Forms 1 and 2) and the polymorphic identification and quantification of four commercially-available VEN raw materials. These two polymorphic forms were obtained from different crystallization methods and characterized by X-ray Powder Diffraction (XRPD), Diffuse Reflectance Infrared Fourier Transform (DRIFT), Raman Spectroscopy (RS), liquid and solid state Nuclear Magnetic Resonance (NMR and ssNMR) spectroscopies, Differential Scanning Calorimetry (DSC), and Scanning Electron Microscopy (SEM) techniques. The main differences were observed by DSC and XRPD and the latter was chosen as the standard technique for the identification and quantification studies in combination with the Rietveld method for the commercial raw materials (VEN1-VEN4) acquired from different manufacturers. Additionally Form 1 and Form 2 can be clearly distinguished from their (13)C ssNMR spectra. Through the analysis, it was possible to conclude that VEN1 and VEN2 were composed only of Form 1, while VEN3 and VEN4 were a mixture of Forms 1 and 2. Additionally, the Rietveld refinement was successfully applied to quantify the polymorphic ratio for VEN3 and VEN4.

Studies of pilocarpine:carbomer intermolecular interactions.

The interactions between pilocarpine (PIL) and the anionic polyelectrolyte carbomer (CBR) were investigated. The effects of the chemical interactions on the chemical stability of the drug also were evaluated. The binary system was characterized by nuclear magnetic resonance techniques, Fourier-transform infrared spectroscopy (FT-IR), X-ray powder diffraction, scanning electron microscopy (SEM) and thermal analysis. The experiments showed that the complex, prepared by freeze-drying, is a solid amorphous form different from its precursors, thereby offering an interesting alternative for the preparation of extended release matrices. The solution stability of PIL was studied at pH 7 and 8, at 70 °C. The PIL solution stability was evaluated alone and in the presence of CBR. Results indicated that the drug in the presence of the polymer is 3.3 and 3.5 times more stable, at pH 7 and pH 8, respectively, than the drug without CBR. The activation energy and the frequency factor, according to Arrhenius plot, were estimated to be 13.9 ± 0.4 and 14.8 ± 0.5 kcalmol(-1), and 6.1 ± 0.3 and 7.6 ± 0.3, with and without the polymer, respectively.

Characterization of the solubility and solid-state properties of saccharin salts of fluoroquinolones.

Saccharinates salts of the fluoroquinolone antibiotics norfloxacin, ciprofloxacin, ofloxacin, and enrofloxacin were obtained as pure crystalline anhydrous solids with sweet taste. The products were characterized by one- ((13)C) and two-dimensional ((1)H-(13)C) dimensions solid state Nuclear Magnetic Resonance and infrared spectroscopy showing ionic interactions between the saccharine amide and the fluoroquinolone piperazine. Several intermolecular bindings were also identified. Thermal behavior and powder X-ray diffraction provided complementary evidences of salt formation. The series of products showed improved properties with respect to water solubility. A solubility model was developed. These salts would be a good way forward to developing more suitable formulations of these APIs.

NMR and IR characterization of the aluminium complexes of norfloxacin and ciprofloxacin fluoroquinolones.

A set of new aluminium complexes of norfloxacin (NOR) and ciprofloxacin (CIP) that show an improvement in their pharmaceutical properties were studied using solution and solid-state nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy. The complexes synthesized with two different methods were compared. One of these methods will allow formulation of the compounds at production scale. High-resolution (13)C spectra were obtained with the cross-polarization and magic angle spinning (CP-MAS) experiment. These spectra were assigned by comparing them with the solution data of the pure drug and by using a quaternary carbon edition technique. The carbon relaxation times in the rotating frame, T(1rhoC), were measured for all the complexes. A two-exponential decay evidences that the complexes are nonhomogeneous. The short T(1rhoC) values are in the range 320-1100 micros and the long values in the range 1.8-7 ms. (27)Al MAS NMR spectra revealed an octahedral coordination between the aluminium ion and oxygens of the pure drug, supporting a 3:1 ligand:metal stoichiometry in both CIP and NOR complexes. The stretching and deformation modes of carboxylic acid and carboxylate and keto groups were analyzed by IR. This technique shows that the same modes are present in the aluminium complexes obtained by the two methods and that the coordination of the fluoroquinolone to aluminium occurs through the 4-keto and 3-carboxylic groups.

Physicochemical characterization of deflazacort: thermal analysis, crystallographic and spectroscopic study.

The solid state properties of deflazacort (1-(1beta,16alpha)-21-(acetyloxy)-11-hydroxy-2'-methyl-5'H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione, 1) were investigated using differential scanning calorimetry (DSC), thermogravimetry (TG), single-crystal X-ray diffraction, solid and liquid nuclear magnetic resonance spectroscopy ((13)C NMR), Fourier transform infrared and Raman spectroscopy (FTIR and FT Raman). From the trends observed in the crystal structure and spectral data some conclusions can be made about hydrogen bonding, molecular conformation and crystal packing. Compound 1 crystallizes in an orthorhombic cell, space group P2(1)2(1)2(1) and the following lattice parameters: a=11.2300(5), b=12.8161(8), c=16.171(1)A, V: 2327.4(2)A(3), D(c): 1.260g/cm(3), R1=0.0479, wR2=0.1012. The crystal structure is stabilized by intra and intermolecular interactions, which provides for a very closely packed form. The NMR data indicated that 1 shows a similar conformation in solid and liquid state; while, thermal data revealed that 1 follows a monophasic pattern with a DSC melting peak at 258.4 degrees C (DeltaH 99.7Jg(-1), n=3), indicating that 1 is thermally stable as solid; but, as liquid is unstable to undergo a thermal decomposition reaction. The reactivity of 1 toward light and moisture was examined via DSC and TLC. The data indicated that 1 do not interact with water to give hydrated forms or decomposition products; however, light degrades 1.