Influence of Hydrophobic and Hydrophilic Chain Length of CiEj Surfactants on the Solubilization of Active Pharmaceutical Ingredients.

Up to 90% of all newly developed active pharmaceutical ingredients (APIs) are poorly water soluble, most likely also showing a low oral bioavailability. In order to increase the aqueous solubility of these APIs, surfactants are promising excipients to increase both solubility and consequently bioavailability (e.g., in lipid- and surfactant-based drug delivery systems). In this work, we investigated the influence of hydrophobic and hydrophilic chain lengths of CiEj surfactants (C8E6, C10E6, and C10E8) toward the solubilization of fenofibrate, naproxen, and lidocaine. Furthermore, we investigated the partitioning of these APIs between the surfactant aggregates and the surrounding aqueous bulk phase. For all APIs considered, we determined the locus of API solubilization as well as the individual aggregation numbers (Nagg) of surfactants and API molecules in an API/surfactant aggregate. We further determined the hydrodynamic radius (Rh) of the API/surfactant aggregates in the absence and presence of the APIs. The size of the API/surfactant aggregates (Nagg, Rh) passes through a minimum upon lidocaine solubilization; it gradually increases upon naproxen solubilization and is almost constant upon fenofibrate solubilization. The results give valuable insights into the solubilization mechanisms of APIs in the CiEj surfactant aggregates. Our results reveal that fenofibrate is solely solubilized in the hydrophobic core of the CiEj surfactant aggregates, as only the hydrophobic chain length of the surfactant influences its solubilization. Naproxen is solubilized in the palisade layer of the surfactant aggregates, as both the hydrophobic and hydrophilic chain lengths are decisive for its solubilization. Lidocaine is mainly solubilized in the rather hydrophilic corona region of the surfactant aggregates, as the hydrophilic chain length of the surfactant governs its solubilization. The results further reveal that the hydrophilic/lipophilic balance is not an appropriate measure to estimate the solubilization capacity of surfactant aggregates.

Synthesis of 2-(Methylthio)-1,3-dithioles from 1,3-Dithiole-2-thiones: Important Building Blocks in Tetrathiafulvalene Chemistry.

2-(Methylthio)-1,3-dithioles are important heterocyclic compounds used for the preparation of redox-active derivatives of tetrathiafulvalene as they serve as precursors for phosphonate esters that can be employed in Horner-Wadsworth-Emmons olefination reactions. Here, we present a mild and less hazardous method than previous methods for converting readily accessible 1,3-dithiole-2-thiones into 2-(methylthio)-1,3-dithioles by methylation with trimethyl orthoformate and HBF4·Et2O and a subsequent reduction with NaBH4.

Solubilization of Aldehydes and Amines in Aqueous CiEj Surfactant Aggregates: Solubilization Capacity and Aggregate Properties.

Hydroformylation of olefins to aldehydes and subsequent reductive amination of aldehydes to amines takes place in an aqueous system using a water-soluble catalyst. It is limited to short-chain molecules due to an insufficient solubility of long-chain molecules in water. A promising approach to increase the solubility of long-chain aldehydes and amines is the addition of surfactants to the aqueous phase. In this work, we thus determined the solubilization capacity (SC) of different nonionic CiEj surfactants (C8E6, C10E6, and C10E8) toward long-chain aldehydes and amines. We used static and dynamic light scattering techniques to investigate the influence of both the surfactant and solute molecular structures on the SC as well as on the aggregation number (Nagg) and hydrodynamic radius (Rh) of mixed aggregates. Our data reveals that an optimum ratio of hydrophobic to hydrophilic chain length of CiEj surfactants exists where the SC toward long-chain aldehydes and amines possesses a maximum. Further, the size of the aggregates (Nagg, Rh) passes through a minimum upon amine solubilization, while upon aldehyde solubilization, the aggregate size increases gradually. The results shown in this work give valuable insights to the solubilization of aldehydes and n-amines into nonionic CiEj surfactants and facilitate the search of suitable surfactants for hydroformylation and reductive amination as "green" solvents based on the detailed knowledge about the aggregate structure.

Differential hysteresis scanning of non-templated monomodal amorphous aerogels.

We perform Differential Hysteresis Scanning (DHS) Porosimetry of amorphous silicon oxycarbide aerogels to quantify hierarchical connectivity in these porous materials. We contrast high-resolution argon sorption scanning isotherms of samples obtained through a non-templated synthesis using different solvents, and characterize respective changes after calcination at 1000 °C. The multi-scan DHS data sets are analyzed through non-negative least-squares deconvolution using a kernel of theoretically derived isotherms for a selection of hierarchical geometries using non-local density functional theory (NL-DFT). We obtain two-dimensional contour plots that characterize mesopores according to the ratio between pore diameter and its connecting window. Combined information from DHS and complementary BET and BJH approaches reveals one system with monomodal distribution both in pore diameters and in window diameters. Hence, this amorphous material exhibits a uniformity usually only observed for crystalline systems. We demonstrate that DHS analysis provides quantitative data analyzing the hierarchical structure of mesoporous materials and unlocks pathways towards tailored materials with control of surface heterogeneity, localization, and sequential accessibility - even for amorphous systems.

Combined Tumor Environment Triggered Self-Assembling Peptide Nanofibers and Inducible Multivalent Ligand Display for Cancer Cell Targeting with Enhanced Sensitivity and Specificity.

Many new technologies, such as cancer microenvironment-induced nanoparticle targeting and multivalent ligand approach for cell surface receptors, are developed for active targeting in cancer therapy. While the principle of each technology is well illustrated, most systems suffer from low targeting specificity and sensitivity. To fill the gap, this work demonstrates a successful attempt to combine both technologies to simultaneously improve cancer cell targeting sensitivity and specificity. Specifically, the main component is a targeting ligand conjugated self-assembling monomer precursor (SAM-P), which, at the tumor site, undergoes tumor-triggered cleavage to release the active form of self-assembling monomer capable of forming supramolecular nanostructures. Biophysical characterization confirms the chemical and physical transformation of SAM-P from unimers or oligomers with low ligand valency to supramolecular assemblies with high ligand valency under a tumor-mimicking reductive microenvironment. The in vitro fluorescence assay shows the importance of supramolecular morphology in mediating ligand-receptor interactions and targeting sensitivity. Enhanced targeting specificity and sensitivity can be achieved via tumor-triggered supramolecular assembly and induces multivalent ligand presentation toward cell surface receptors, respectively. The results support this combined tumor microenvironment-induced cell targeting and multivalent ligand display approach, and have great potential for use as cell-specific molecular imaging and therapeutic agents with high sensitivity and specificity.

A Novel High-Pressure Tin Oxynitride Sn2 N2 O.

We report the first oxynitride of tin, Sn2 N2 O (SNO), exhibiting a Rh2 S3 -type crystal structure with space group Pbcn. All Sn atoms are in six-fold coordination, in contrast to Si in silicon oxynitride (Si2 N2 O) and Ge in the isostructural germanium oxynitride (Ge2 N2 O), which appear in four-fold coordination. SNO was synthesized at 20 GPa and 1200-1500 °C in a large volume press. The recovered samples were characterized by synchrotron powder X-ray diffraction and single-crystal electron diffraction in the TEM using the automated diffraction tomography (ADT) technique. The isothermal bulk modulus was determined as Bo =193(5) GPa by using in-situ synchrotron X-ray diffraction in a diamond anvil cell. The structure model is supported by DFT calculations. The enthalpy of formation, the bulk modulus, and the band structure have been calculated.

Silicon monoxide at 1 atm and elevated pressures: crystalline or amorphous?

The absence of a crystalline SiO phase under ordinary conditions is an anomaly in the sequence of group 14 monoxides. We explore theoretically ordered ground-state and amorphous structures for SiO at P = 1 atm, and crystalline phases also at pressures up to 200 GPa. Several competitive ground-state P = 1 atm structures are found, perforce with Si-Si bonds, and possessing Si-O-Si bridges similar to those in silica (SiO2) polymorphs. The most stable of these static structures is enthalpically just a little more stable than a calculated random bond model of amorphous SiO. In that model we find no segregation into regions of amorphous Si and amorphous SiO2. The P = 1 atm structures are all semiconducting. As the pressure is increased, intriguing new crystalline structures evolve, incorporating Si triangular nets or strips and stishovite-like regions. A heat of formation of crystalline SiO is computed; it is found to be the most negative of all the group 14 monoxides. Yet, given the stability of SiO2, the disproportionation 2SiO(s) → Si(s)+SiO2(s) is exothermic, falling right into the series of group 14 monoxides, and ranging from a highly negative ΔH of disproportionation for CO to highly positive for PbO. There is no major change in the heat of disproportionation with pressure, i.e., no range of stability of SiO with respect to SiO2. The high-pressure SiO phases are metallic.

Vacuum ultraviolet detector for gas chromatography.

Analytical performance characteristics of a new vacuum ultraviolet (VUV) detector for gas chromatography (GC) are reported. GC-VUV was applied to hydrocarbons, fixed gases, polyaromatic hydrocarbons, fatty acids, pesticides, drugs, and estrogens. Applications were chosen to feature the sensitivity and universal detection capabilities of the VUV detector, especially for cases where mass spectrometry performance has been limited. Virtually all chemical species absorb and have unique gas phase absorption cross sections in the approximately 120-240 nm wavelength range monitored. Spectra are presented, along with the ability to use software for deconvolution of overlapping signals. Some comparisons with experimental synchrotron data and computed theoretical spectra show good agreement, although more work is needed on appropriate computational methods to match the simultaneous broadband electronic and vibronic excitation initiated by the deuterium lamp. Quantitative analysis is governed by Beer-Lambert Law relationships. Mass on-column detection limits reported for representatives of different classes of analytes ranged from 15 (benzene) to 246 pg (water). Linear range measured at peak absorption for benzene was 3-4 orders of magnitude. Importantly, where absorption cross sections are known for analytes, the VUV detector is capable of absolute determination (without calibration) of the number of molecules present in the flow cell in the absence of chemical interferences. This study sets the stage for application of GC-VUV technology across a wide breadth of research areas.

Crystal structures of two new high-pressure oxynitrides with composition SnGe4N4O4, from single-crystal electron diffraction.

SnGe4N4O4 was synthesized at high pressure (16 and 20 GPa) and high temperature (1200 and 1500°C) in a large-volume press. Powder X-ray diffraction experiments using synchrotron radiation indicate that the derived samples are mixtures of known and unknown phases. However, the powder X-ray diffraction patterns are not sufficient for structural characterization. Transmission electron microscopy studies reveal crystals of several hundreds of nanometres in size with different chemical composition. Among them, crystals of a previously unknown phase with stoichiometry SnGe4N4O4 were detected and investigated using automated diffraction tomography (ADT), a three-dimensional electron diffraction method. Via ADT, the crystal structure could be determined from single nanocrystals in space group P63mc, exhibiting a nolanite-type structure. This was confirmed by density functional theory calculations and atomic resolution scanning transmission electron microscopy images. In one of the syntheses runs a rhombohedral 6R polytype of SnGe4N4O4 could be found together with the nolanite-type SnGe4N4O4. The structure of this polymorph was solved as well using ADT.

Influence of Temperature and Concentration on the Self-Assembly of Nonionic CiEj Surfactants: A Light Scattering Study.

Nonionic poly(ethylene oxide) alkyl ether (CiEj) surfactants self-assemble into aggregates of various sizes and shapes above their critical micelle concentration (CMC). Knowledge on solution attributes such as CMC as well as aggregate characteristics is crucial to choose the appropriate surfactant for a given application, e.g., as a micellar solvent system. In this work, we used static and dynamic light scattering to measure the CMC, aggregation number (N agg), and hydrodynamic radius (R h) of four different CiEj surfactants (C8E5, C8E6, C10E6, and C10E8). We examined the influence of temperature, concentration, and molecular structure on the self-assembly in the vicinity of the CMC. A minimum in the CMC vs temperature curve was identified for all surfactants investigated. Further, extending the hydrophilic and hydrophobic chain lengths leads to an increase and decrease of the CMC, respectively. The size of the aggregates strongly depends on temperature. N agg and R h increase with increasing temperature for all surfactants investigated. Additionally, N agg and R h both increase with increasing surfactant concentration. The data obtained in this work further improve the understanding of the influence of temperature and molecular structure on the self-assembly of CiEj surfactants and will further foster their use in micellar solvent systems.

A multicenter, randomized, double-blind, placebo-controlled trial of intravenous ibuprofen (i.v.-ibuprofen) in the management of postoperative pain following abdominal hysterectomy.

BACKGROUND: Ibuprofen and other nonsteroidal anti-inflammatory drugs are widely used to block pain and inflammation in a variety of settings. Contrarily, opioid analgesia does not block the inflammatory component of pain and the use of these agents can be accompanied by serious side effects. We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of intravenous ibuprofen (i.v.-ibuprofen) as a postoperative analgesic. METHODS: A total of 319 patients were randomly assigned in a 1:1 ratio to receive 800 i.v.-ibuprofen or placebo every 6 hours; in addition patients had access to morphine at a dose of 1-2 mg every 5 minutes. The primary outcome measure was median morphine consumption within the first 24 hours following surgery. RESULTS: During the first 24 hours of treatment, the median morphine requirement was reduced by 19% (P ≤ 0.001) and resulted in a significant reduction in pain at rest (AUC, 6 to 24 hours and 12 to 24 hours, P < 0.001) and pain with movement (AUC, 6 to 24 hours, P = 0.010 and 12 to 24 hours, P ≤ 0.001) as measured by the visual analog scale (VAS) in patients receiving 800 mg i.v.-ibuprofen compared to placebo. Time to ambulation was significantly faster (P = 0.018) in the i.v.-ibuprofen treated group, as well. Similar treatment-emergent adverse events occurred across both study groups and there was no difference in the overall incidence of these events. CONCLUSION: This study demonstrated that i.v.-ibuprofen is an effective analgesic medication that is safe and well tolerated when administered as an 800 mg dose every 6 hours in patients undergoing total abdominal hysterectomy surgery.

Predicting the API partitioning between lipid-based drug delivery systems and water.

Partitioning tests in water are early-stage standard experiments during the development of pharmaceutical formulations, e.g. of lipid-based drug delivery system (LBDDS). The partitioning behavior of the active pharmaceutical ingredient (API) between the fatty phase and the aqueous phase is a key property, which is supposed to be determined by those tests. In this work, we investigated the API partitioning between LBDDS and water by in-silico predictions applying the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) and validated these predictions experimentally. The API partitioning was investigated for LBDDS comprising up to four components (cinnarizine or ibuprofen with tricaprylin, caprylic acid, and ethanol). The influence of LBDDS/water mixing ratios from 1/1 up to 1/200 (w/w) as well as the influence of excipients on the API partitioning was studied. Moreover, possible API crystallization upon mixing the LBDDS with water was predicted. This work showed that PC-SAFT is a strong tool for predicting the API partitioning behavior during in-vitro tests. Thus, it allows rapidly assessing whether or not a specific LBDDS might be a promising candidate for further in-vitro tests and identifying the API load up to which API crystallization can be avoided.

Compressing the most hydrogen-rich inorganic ion.

Motivated by the potential high-temperature superconductivity of "chemically precompressed" hydrogen-rich compounds, the high pressure phases of the ionic salt BaReH(9) are explored theoretically. We find that the compound adapts to compression not only by structural distortions or increase of coordination number, but also through evolution of discrete H(2) units which fill up interspace gaps. This last structural change is associated with a dramatic lowering of metallization pressure, so that BaReH(9) can be expected to turn metallic at the onset of the H(2)-containing phase (51 GPa).

Simulation of Vacuum Ultraviolet Absorption Spectra: Paraffin, Isoparaffin, Olefin, Naphthene, and Aromatic Hydrocarbon Class Compounds.

The advent of a new vacuum ultraviolet (VUV) spectroscopic absorption detector for gas chromatography has enabled applications in many areas. Theoretical simulations of VUV spectra using computational chemistry can aid the new technique in situations where experimental spectra are unavailable. In this study, VUV spectral simulations of paraffin, isoparaffin, olefin, naphthene, and aromatic (PIONA) compounds using time-dependent density functional theory (TDDFT) methods were investigated. Important factors for the simulations, such as functionals/basis sets and formalism of oscillator strength calculations, were examined and parameters for future PIONA compound simulations were obtained by fitting computational results to experimental spectra. The simulations produced satisfactory correlations between experimental observations and theoretical calculations, and enabled potential analysis applications for complex higher distillate fuels, such as diesel fuel. Further improvement of the methods was proposed.

Discovery of Ternary Silicon Titanium Nitride with Spinel-Type Structure.

Here we report on the discovery of a ternary silicon titanium nitride with the general composition (Si1-x,Tix)3N4 with x = 0 < x < 1 and spinel-type crystal structure. The novel nitride is formed from an amorphous silicon titanium nitride (SiTiN) precursor under high-pressure/high-temperature conditions in a large volume high-pressure device. Under the conditions of 15-20 GPa and 1800-2000 °C, spinel-type γ-Si3N4 and rock salt-type c-TiN are formed. In addition, crystals of the discovered nano-sized ternary phase (Si1-x,Tix)3N4 embedded in γ-Si3N4 are identified. The ternary compound is formed due to kinetically-controlled synthesis conditions and is analyzed to exhibit the spinel-type structure with ca. 8 atom% of Ti. The Ti atoms occur in both Ti3+ and Ti4+ oxidation states and are located on the Si sites. The ternary nano-crystals have to be described as (Si,Ti)3N4 with N-vacancies resulting in the general composition (Si4+1-x Ti4+x-δTi3+δ)3N4-δ.

Monomeric copper(I), silver(I), and gold(I) alkyne complexes and the coinage metal family group trends.

A series of thermally stable, easily isolable, monomeric, and isoleptic coinage metal alkyne complexes have been reported. Treatment of [N{(C(3)F(7))C(Dipp)N}(2)]Li (the lithium salt of the 1,3,5-triazapentadiene [N{(C(3)F(7))C(Dipp)N}(2)]H) with AuCl, CF(3)SO(3)Ag or CF(3)SO(3)Cu in the presence of 3-hexyne led to the corresponding coinage metal alkyne complex [N{(C(3)F(7))C(Dipp)N}(2)]M(EtC[triple bond]CEt) in good yield (M = Au, Ag, Cu; Dipp = 2,6-diisopropylphenyl). X-ray crystal structures of the three coinage metal alkynes are remarkably similar, and show the presence of trigonal-planar metal sites with eta(2)-bonded 3-hexyne. The M-C and M-N bond distances vary in the order Cu < Au < Ag. The bending of the C-C[triple bond]C bond angle is largest for the gold, followed by Cu and Ag adducts. The gold adduct also shows the largest decrease in C[triple bond]C stretching frequency in Raman, while the Ag adduct shows the smallest change compared to that of the uncoordinated alkyne. DFT calculations on [N{(CF(3))C(Ph)N}(2)]M(EtC[triple bond]CEt) and the related ClM(EtC[triple bond]CEt) predict that the M-alkyne bond energy varies in the order Ag < Cu < Au. The gold adducts are also predicted to have the longest C[triple bond]C, largest deviation of C-C[triple bond]C bond angle from linearity, and smallest C[triple bond]C stretching frequency, followed by the Cu and Ag adducts. In these triazapentadienyl coinage metal adducts, the sigma-donation from alkyne --> M dominates over the M --> alkyne pi-back-donation.

Gold(I) chloride coordinated 3-hexyne.

A linear gold(I) complex featuring a simple, unstrained alkyne has been synthesized using AuCl and 3-hexyne and characterized using X-ray crystallography. Density functional theory calculations show that sigma donation from alkyne --> Au dominates over the Au --> alkyne pi back-donation.

Magnetism in graphene due to single-atom defects: dependence on the concentration and packing geometry of defects.

The magnetism in graphene due to single-atom defects is examined by using spin-polarized density functional theory. The magnetic moment per defect due to substitutional atoms and vacancy defects is dependent on the density of defects, while that due to adatom defects is independent of the density of defects. It reduces to zero with decrease in the density of substitutional atoms. However, it increases with decrease in density of vacancies. The graphene sheet with B adatoms is nonmagnetic, but with C and N adatoms it is magnetic. The adatom defects distort the graphene sheet near the defect perpendicular to the sheet. The distortion in graphene due to C and N adatoms is significant, while the distortion due to B adatoms is very small. The vacancy and substitutional atom (B, N) defects in graphene are planar in the sense that there is in-plane displacement of C atoms near the vacancy and substitutional defects. Upon relaxation the displacement of C atoms and the formation of pentagons near the vacancy site due to Jahn-Teller distortion depends upon the density and packing geometry of vacancies.

A density functional study of the high-pressure chemistry of MSiN(2)(M = Be, Mg, Ca): prediction of high-pressure phases and examination of pressure-induced decomposition.

Normal pressure modifications and tentative high-pressure phases of the nitridosilicates MSiN(2) with M =  Be, Mg, or Ca have been thoroughly studied by density functional methods. At ambient pressure, BeSiN(2) and MgSiN(2) exhibit an ordered wurtzite variant derived from idealized filled ß-cristobalite by a C1-type distortion. At ambient pressure, the structure of CaSiN(2) can also be derived from idealized filled ß-cristobalite by a different type of distortion (D1-type). Energy-volume calculations for all three compounds reveal transition into an NaCl superstructure under pressure, affording sixfold coordination for Si. At 76 GPa BeSiN(2) forms an LiFeO(2)-type structure, corresponding to the stable ambient-pressure modification of LiFeO(2), while MgSiN(2) and CaSiN(2) adopt an LiFeO(2)-type structure, corresponding to a metastable modification (24 and 60 GPa, respectively). For both BeSiN(2) and CaSiN(2) intermediate phases appear (for BeSiN(2) a chalcopyrite-type structure and for CaSiN(2) a CaGeN(2)-type structure). These two tetragonal intermediate structures are closely related, differing mainly in their c/a ratio. As a consequence, chalcopyrite-type structures exhibit tetrahedral coordination for both cations (M and Si), whereas in CaGeN(2)-type structures one cation is tetrahedrally (Si) and one bisdisphenoidally (M) coordinated. Both structure types, chalcopyrite and CaGeN(2), can also be derived from idealized filled ß-cristobalite through a B1-type distortion. The group-subgroup relation of the BeSiN(2)/MgSiN(2), the CaSiN(2), the chalcopyrite, the CaGeN(2) and the idealized filled ß-cristobalite structure is discussed and the displacive phase transformation pathways are illustrated. The zero-pressure bulk moduli were calculated for all phases and have been found to be comparable to compounds such as α- Si(3)N(4), CaIrO(3) and Al(4)C(3). Furthermore, the thermodynamic stability of BeSiN(2), MgSiN(2) and CaSiN(2) against phase agglomerates of the binary nitrides M(3)N(2) and Si(3)N(4) under pressure are examined.

High-pressure phases and transitions of the layered alkaline earth nitridosilicates SrSiN(2) and BaSiN(2).

We investigate the high-pressure phase diagram of SrSiN(2) and BaSiN(2) with density-functional calculation. Searching a manifold of possible candidate structures, we propose new structural modifications of SrSiN(2) and BaSiN(2) attainable in high-pressure experiments. The monoclinic ground state of SrSiN(2) transforms at 3 GPa into an orthorhombic BaSiN(2) type. At 14 GPa a CaSiN(2)-type structure becomes the most stable configuration of SrSiN(2). A hitherto unknown Pbcm modification is adopted at 85 GPa and, finally, at 131 GPa a LiFeO(2)-type structure. The higher homologue BaSiN(2) transforms to a CaSiN(2) type at 41 GPa and further to a Pbcm modification at 105 GPa. Both systems follow the pressure-coordination rule: the coordination environment of Si increases from tetrahedral through trigonal bipyramidal to octahedral. Some high-pressure phases are related in structure through simple group-subgroup mechanisms, indicating displacive phase transformations with low activation barriers.