Nasal residence time and rheological properties of a new bentonite-based thixotropic gel emulsion nasal spray - AM-301.

OBJECTIVE: The present work provides characterization of rheological properties of a new bentonite-based thixotropic gel emulsion nasal spray (AM-301), its nasal residence time, distribution, safety and tolerability. SIGNIFICANCE: The nasal epithelium is a portal of entry for allergens and primary infection by airborne pathogens. Non-pharmacological interventions, which enhance physical and biological barriers, protect against allergens and pathogens without drug-related side effects. AM-301 has shown promising efficacy and safety in the nasal epithelium against viruses (in vitro) and pollen (clinical). METHODS: Technical part (i) spray characterization was performed with a validated droplet size distribution method; evaluation of the rheological properties of the formulation was performed by a validated amplitude sweep method and a validated oscillation, rotation, oscillation; Clinical part (ii) nasal and oropharyngeal endoscopy were used to provide a semi-quantitative evaluation of distribution and residence time of fluorescein-labelled AM-301 in the nose and oropharynx of healthy volunteers; (iii) tolerability and safety. RESULTS: (i) The non-Newtonian rheological properties of the formulation allow AM-301 to be sprayed and then to revert to a gel to prevent run-off from the nasal cavity; (ii) the formulation remains on the inferior turbinate, septum and oropharynx of volunteers for up to 210 min and on the middle turbinate for up to 60 min; two nasal sprays provide no substantial benefit over a single application with regards to coverage or retention; (iii) the spray is well tolerated. CONCLUSIONS: Single dose spray delivery of AM-301 provides extended coverage of the nasal mucosa up to the inferior turbinates.

On the Formation Mechanism of Column Damage Within Modular Taper Junctions.

BACKGROUND: Column damage is a unique degradation pattern observed in cobalt-chromium-molybdenum (CoCrMo) femoral head taper surfaces that resemble column-like troughs in the proximal-distal direction. We investigate the metallurgical origin of this phenomenon. METHODS: Thirty-two severely damaged CoCrMo femoral head retrievals from 7 different manufacturers were investigated for the presence of column damage and chemical inhomogeneities within the alloy microstructure via metallographic evaluation of samples sectioned off from the femoral heads. RESULTS: Column damage was found to affect 37.5% of the CoCrMo femoral heads in this study. All the column-damaged femoral heads exhibited chemical inhomogeneities within their microstructures, which comprised of regions enriched or depleted in molybdenum and chromium. Column damage appears as a dissolution of the entire surface with preferential corrosion along the molybdenum and chromium depleted regions. CONCLUSION: Molybdenum and chromium depleted zones serve as initiation sites for in vivo corrosion of the taper surface. Through crevice corrosion, the degradation spreads to the adjacent non-compositionally depleted areas of the alloy as well. Future improved alloy and processing recipes are required to ensure no chemical inhomogeneity due to segregation of solute elements are present in CoCrMo femoral heads.

Nanoglass-Nanocrystal Composite-a Novel Material Class for Enhanced Strength-Plasticity Synergy.

The properties of a material can be engineered by manipulating its atomic and chemical architecture. Nanoglasses which have been recently invented and comprise nanosized glassy particles separated by amorphous interfaces, have shown promising properties. A potential way to exploit the structural benefits of nanoglasses and of nanocrystalline materials is to optimize the composition to obtain crystals forming within the glassy particles. Here, a metastable Fe-10 at% Sc nanoglass is synthesized. A complex hierarchical microstructure is evidenced experimentally at the atomic scale. This bulk material comprises grains of a Fe90 Sc10 amorphous matrix separated by an amorphous interfacial network enriched and likely stabilized by hydrogen, and property-enhancing pure-Fe nanocrystals self-assembled within the matrix. This composite structure leads a yield strength above 2.5 GPa with an exceptional quasi-homogeneous plastic flow of more than 60% in compression. This work opens new pathways to design materials with even superior properties.

Building a Library of Simulated Atom Probe Data for Different Crystal Structures and Tip Orientations Using TAPSim.

The process of building an open source library of simulated field desorption maps for differently oriented synthetic tips of the face-centered cubic, body-centered cubic, and hexagonal-close-packed crystal structures using the open source software TAPSim is reported. Specifically, the field evaporation of a total set of 4 × 101 single-crystalline tips was simulated. Their lattices were oriented randomly to sample economically the fundamental zone of crystal orientations. Such data are intended to facilitate the interpretation of low-density zone lines and poles that are observed on detector hit maps during Atom Probe Tomography (APT) experiments. The datasets and corresponding tools have been made publicly available to the APT community in an effort to provide better access to simulated atom probe datasets. In addition, a computational performance analysis was conducted, from which recommendations are made as to which key tasks should be optimized in the future to improve the parallel efficiency of TAPSim.

Investigation of the Compatibility of the Skin PAMPA Model with Topical Formulation and Acceptor Media Additives Using Different Assay Setups.

The Skin Parallel Artificial Membrane Permeability Assay (PAMPA) is a 96-well plate-based skin model with an artificial membrane containing free fatty acid, cholesterol, and synthetic ceramide analogs to mimic the stratum corneum (SC) barrier. The current study evaluates the compatibility of lipophilic solvents/penetration enhancer, topical emulsions containing different emulsifier systems, and organic acceptor media additives with the artificial membrane of the assay. Additionally, different assay setups (standard setup: donor in bottom plate versus modified setup: donor in top plate) were compared. Methylparaben (MP), ethylparaben (EP), and propylparaben (PP) were used as model permeants and internal standards for proper assay execution. The permeation order of the parabens (MP > EP > PP) remained the same with different lipophilic solvents, and the ranking of lipophilic solvents was comparable under standard and modified conditions (isopropyl myristate, IPM > dimethyl isosorbide, DMI ≥ propylene glycol, PG > diisopropyl adipate, DIPA). Pre-incubation of the Skin PAMPA plates with IPM, DIPA, and DMI, as well as with formulations that contain non-ionic emulsifiers, and acceptor solutions containing DMSO or EtOH (≤ 50%) for 4 h did not increase the percentage of permeated parabens in the main experiment, suggesting that those compounds do not make the artificial membrane more permeable. High-resolution mass spectrometry confirmed that acceptor solutions with ≤ 50% DMSO or EtOH do not extract stearic acid, cholesterol, and certramides at standard assay conditions. Hence, if certain constraints are considered, the Skin PAMPA model can be used as a pre-screening tool for topical formulation selection.

Segregation stabilizes nanocrystalline bulk steel with near theoretical strength.

Grain refinement through severe plastic deformation enables synthesis of ultrahigh-strength nanostructured materials. Two challenges exist in that context: First, deformation-driven grain refinement is limited by dynamic dislocation recovery and crystal coarsening due to capillary driving forces; second, grain boundary sliding and hence softening occur when the grain size approaches several nanometers. Here, both challenges have been overcome by severe drawing of a pearlitic steel wire (pearlite: lamellar structure of alternating iron and iron carbide layers). First, at large strains the carbide phase dissolves via mechanical alloying, rendering the initially two-phase pearlite structure into a carbon-supersaturated iron phase. This carbon-rich iron phase evolves into a columnar nanoscaled subgrain structure which topologically prevents grain boundary sliding. Second, Gibbs segregation of the supersaturated carbon to the iron subgrain boundaries reduces their interface energy, hence reducing the driving force for dynamic recovery and crystal coarsening. Thus, a stable cross-sectional subgrain size <10 nm is achieved. These two effects lead to a stable columnar nanosized grain structure that impedes dislocation motion and enables an extreme tensile strength of 7 GPa, making this alloy the strongest ductile bulk material known.

Multi-scale correlative microscopy investigation of both structure and chemistry of deformation twin bundles in Fe-Mn-C steel.

A multi-scale investigation of twin bundles in Fe-22Mn-0.6C (wt%) twinning-induced plasticity steel after tensile deformation has been carried out by truly correlative means; using electron channelling contrast imaging combined with electron backscatter diffraction, high-resolution secondary ion mass spectrometry, scanning transmission electron microscopy, and atom probe tomography on the exact same region of interest in the sample. It was revealed that there was no significant segregation of Mn or C to the twin boundary interfaces.

Rational Design of Topical Semi-Solid Dosage Forms-How Far Are We?

Specific aspects of semi-solid dosage forms for topical application include the nature of the barrier to be overcome, aspects of susceptibility to physical and chemical instability, and a greater influence of sensory perception. Advances in understanding the driving forces of skin penetration as well as the design principles and inner structure of formulations, provide a good basis for the more rational design of such dosage forms, which still often follow more traditional design approaches. This review analyses the opportunities and constraints of rational formulation design approaches in the industrial development of new topical drugs. As the selection of drug candidates with favorable physicochemical properties increases the speed and probability of success, models for drug selection based on theoretical and experimental approaches are discussed. This paper reviews how progress in the scientific understanding of mechanisms and vehicle-influence of skin penetration can be used for rational formulation design. The characterization of semi-solid formulations is discussed with a special focus on modern rheological approaches and analytical methods for investigating and optimizing the chemical stability of active ingredients in consideration of applicable guidelines. In conclusion, the combination of a good understanding of scientific principles combined with early consideration of regulatory requirements for product quality are enablers for the successful development of innovative and robust semi-solid formulations for topical application.

Topical Film-Forming Solid Solutions for Enhanced Dermal Delivery of the Retinoid Tazarotene.

Topical film-forming solutions (FFSs) show considerable potential for dermal delivery of an API. Through a mechanism of in situ film formation upon solvent evaporation, they may improve skin delivery by prolonging substantivity on the skin, by establishing a transient supersaturation, and/or by enhancing solubility through the formation of a solid dispersion in the resulting film. This work aimed at developing an FFS for topical application with enhanced skin delivery. The tested FFSs were composed of the lipophilic retinoid tazarotene and the hydrophobic polyamide-3 polymers. The residual films cast from FFSs were examined by DSC and their release mechanism was investigated. Additionally, ex vivo skin penetration of tazarotene was explored. In comparison to a physical mixture, the glass transition (Tg) was significantly increased (p < 0.01) in in-situ generated polyamide-3 (11,500 Da)/tazarotene films with ratios 5:1 and 10:1, indicating a molecular distribution of tazarotene within the polymer. Stress testing at 32°C and 40°C further indicated that these films were kinetically stabilized for at least two weeks. Tazarotene release from solid solution films was notably increased as compared to the crystalline and the amorphous tazarotene. A ten-times higher skin penetration of the ratio 10:1 film (containing 0.1% tazarotene) was observed as compared to a commercial 0.1% tazarotene cream. Hence, topical solid solutions may represent an option for improved dermal API delivery.

Reconstructing dual-phase nanometer scale grains within a pearlitic steel tip in 3D through 4D-scanning precession electron diffraction tomography and automated crystal orientation mapping.

The properties of polycrystalline materials are related to their microstructures and hence a complete description, including size, shape, and orientation of the grains, is necessary to understand the behavior of materials. Here, we use Scanning Precession Electron Diffraction (SPED) in the Transmission Electron Microscope (TEM) combined with a tilt series to reconstruct individual grains in 3D within a polycrystalline dual-phase cold wire-drawn pearlitic steel sample. Nanoscale ferrite grains and intragranular cementite particles were indexed using an Automated Crystallographic Orientation Mapping (ACOM) tool for each tilt dataset. The grain orientations were tracked through the tilt datasets and projections of the individual grains were reconstructed from the diffraction data using an orientation-specific Virtual Dark Field (VDF) approach for tomographic reconstruction. The algorithms used to process and reconstruct such datasets are presented. These algorithms represent an extension to the ACOM approach that may be straightforwardly applied to other multi-phase polycrystalline materials to enable 3D spatial and orientation reconstructions.

Development of a new, fully automated system for electron backscatter diffraction (EBSD)-based large volume three-dimensional microstructure mapping using serial sectioning by mechanical polishing, and its application to the analysis of special boundaries in 316L stainless steel.

We report the development of a fully automatic large-volume 3D electron backscatter diffraction (EBSD) system (ELAVO 3D), consisting of a scanning electron microscope (ZEISS crossbeam XB 1540) with a dedicated sample holder, an adapted polishing automaton (Saphir X-change, QATM), a collaborative robotic arm (Universal Robots UR5), and several in-house built devices. The whole system is orchestrated by an in-house designed software, which is also able to track the process and report errors. Except for the case of error, the system runs without any user interference. For the measurement of removal thickness, the samples are featured with markers put on the perpendicular lateral surface, cut by plasma focused ion beam (PFIB) milling. The individual effects of both 1 µm diamond suspension and oxide polishing suspension polishing were studied in detail. Coherent twin grain boundaries (GBs) were used as an internal standard to check the removal rates measured by the side markers. The two methods for Z-spacing measurements disagreed by about 10%, and the inaccurate calibration of the PFIB system was found to be the most probable reason for this discrepancy. The angular accuracy of the system was determined to be ∼2.5°, which can be significantly improved with more accurate Z-spacing measurements. When reconstructed grain boundary meshes are sufficiently smoothed, an angular resolution of ±4° is achieved. In a 3D EBSD dataset of a size of 587 × 476 × 72 µm3, we focused on the investigation of coincidence site lattice ∑9 GBs. While bearing predominantly a pure tilt character, ∑9 GBs can be categorized into three groups based on correlative 3D morphologies and crystallography.

Removal of hydrocarbon contamination and oxide films from atom probe specimens.

Many materials science phenomena require joint structural and chemical characterization at the nanometer scale to be understood. This can be achieved by correlating electron microscopy (EM) and atom probe tomography (APT) subsequently on the same specimen. For this approach, specimen yield during APT is of particular importance, as significantly more instrument time per specimen is invested as compared to conventional APT measurements. However, electron microscopy causes hydrocarbon contamination on the surface of atom probe specimens. Also, oxide layers grow during specimen transport between instruments and storage. Both effects lower the chances for long and smooth runs in the ensuing APT experiment. This represents a crucial bottleneck of the method correlative EM/APT. Here, we present a simple and reliable method based on argon ion polishing that is able to remove hydrocarbon contamination and oxide layers, thereby significantly improving APT specimen yield, particularly after EM.

Reactive wear protection through strong and deformable oxide nanocomposite surfaces.

Wear-related energy and material loss cost over 2500 Billion Euro per year. Traditional wisdom suggests that high-strength materials reveal low wear rates, yet, their plastic deformation mechanisms also influence their wear performance. High strength and homogeneous deformation behavior, which allow accommodating plastic strain without cracking or localized brittle fracture, are crucial for developing wear-resistant metals. Here, we present an approach to achieve superior wear resistance via in-situ formation of a strong and deformable oxide nanocomposite surface during wear, by reaction of the metal surface with its oxidative environment, a principle that we refer to as 'reactive wear protection'. We design a TiNbZr-Ag alloy that forms an amorphous-crystalline oxidic nanocomposite surface layer upon dry sliding. The strong (2.4 GPa yield strength) and deformable (homogeneous deformation to 20% strain) nanocomposite surface reduces the wear rate of the TiNbZr-Ag alloy by an order of magnitude. The reactive wear protection strategy offers a pathway for designing ultra-wear resistant alloys, where otherwise brittle oxides are turned to be strong and deformable for improving wear resistance.

In situ correlation between metastable phase-transformation mechanism and kinetics in a metallic glass.

A combination of complementary high-energy X-ray diffraction, containerless solidification during electromagnetic levitation and transmission electron microscopy is used to map in situ the phase evolution in a prototype Cu-Zr-Al glass during flash-annealing imposed at a rate ranging from 102 to 103 K s-1 and during cooling from the liquid state. Such a combination of experimental techniques provides hitherto inaccessible insight into the phase-transformation mechanism and its kinetics with high temporal resolution over the entire temperature range of the existence of the supercooled liquid. On flash-annealing, most of the formed phases represent transient (metastable) states - they crystallographically conform to their equilibrium phases but the compositions, revealed by atom probe tomography, are different. It is only the B2 CuZr phase which is represented by its equilibrium composition, and its growth is facilitated by a kinetic mechanism of Al partitioning; Al-rich precipitates of less than 10 nm in a diameter are revealed. In this work, the kinetic and chemical conditions of the high propensity of the glass for the B2 phase formation are formulated, and the multi-technique approach can be applied to map phase transformations in other metallic-glass-forming systems.

Atomic Scale Origin of Metal Ion Release from Hip Implant Taper Junctions.

Millions worldwide suffer from arthritis of the hips, and total hip replacement is a clinically successful treatment for end-stage arthritis patients. Typical hip implants incorporate a cobalt alloy (Co-Cr-Mo) femoral head fixed on a titanium alloy (Ti-6Al-4V) femoral stem via a Morse taper junction. However, fretting and corrosion at this junction can cause release of wear particles and metal ions from the metallic implant, leading to local and systemic toxicity in patients. This study is a multiscale structural-chemical investigation, ranging from the micrometer down to the atomic scale, of the underlying mechanisms leading to metal ion release from such taper junctions. Correlative transmission electron microscopy and atom probe tomography reveals microstructural and compositional alterations in the subsurface of the titanium alloy subjected to in vitro gross-slip fretting against the cobalt alloy. Even though the cobalt alloy is comparatively more wear-resistant, changes in the titanium alloy promote tribocorrosion and subsequent degradation of the cobalt alloy. These observations regarding the concurrent occurrence of electrochemical and tribological phenomena are vital to further improve the design and performance of taper junctions in similar environments.

Crystal-Glass High-Entropy Nanocomposites with Near Theoretical Compressive Strength and Large Deformability.

High-entropy alloys (HEAs) and metallic glasses (MGs) are two material classes based on the massive mixing of multiple-principal elements. HEAs are single or multiphase crystalline solid solutions with high ductility. MGs with amorphous structure have superior strength but usually poor ductility. Here, the stacking fault energy in the high-entropy nanotwinned crystalline phase and the glass-forming-ability in the MG phase of the same material are controlled, realizing a novel nanocomposite with near theoretical yield strength (G/24, where G is the shear modulus of a material) and homogeneous plastic strain above 45% in compression. The mutually compatible flow behavior of the MG phase and the dislocation flux in the crystals enable homogeneous plastic co-deformation of the two regions. This crystal-glass high-entropy nanocomposite design concept provides a new approach to developing advanced materials with an outstanding combination of strength and ductility.

Influence of emulsifier concentration on partition behavior and chemical stability of betamethasone dipropionate in emulsion gels.

The partitioning of active pharmaceutical ingredients (API) in emulsions is influenced by various factors, such as composition of the phases, emulsifier type and concentration, and temperature. Therefore, the chemical stability of the API can be influenced by its partitioning into the aqueous phase as degradation is typically facilitated in water. With increasing emulsifier concentration from 0.15% to 5.0%, more betamethasone dipropionate (BDP) was solubilized in polysorbate 80 micelles leading to a small, but increased fraction of BDP exposed to the aqueous phase along with preferential partitioning of BDP to the aqueous phase and thus increased degradation. Similarly, by enhancing solubility and partitioning to the aqueous phase, the addition of polyethylene glycol 400 also led to increased BDP degradation. Due to pH dependent degradation of BDP, increasing emulsifier concentrations resulted in a more pronounced degradation of BDP at pH 8, which is beyond the stability optimum, whereas at pH 5 the API was sufficiently stable and no differences in concentration were detected within 12 weeks even under accelerated conditions. No significant differences were seen with the varying emulsifier concentrations regarding ex vivo skin penetration.

Development of a design of experiments optimized method for quantification of polysorbate 80 based on oleic acid using UHPLC-MS.

The aim was to develop a straightforward UHPLC-MS quantification method for polysorbate 80 using oleic acid as surrogate marker, which was the commonest substance within the emulsifier. However, hydrolysis of polysorbate 80 and subsequent analysis of fatty acids revealed a co-elution of oleic acid and an isomer while all the other fatty acids were successfully separated by varying retention times and mass-to-charge ratios. For identification and separation of the isomer a derivatization method was evaluated. Oxidation to the corresponding dihydroxystearic acids with potassium permanganate resulted in peak separation of cis/trans and structural isomers of the 18:1 fatty acids. Hydrolyzed and derivatized polysorbate 80 was quantified indirectly in the range of 0.046-5.83 µg/mL (R2 > 0.997) with a limit of detection of 11.4 ng/mL. Quantification of polysorbate 80 using oleic acid as a surrogate marker showed good reproducibility and linearity. As all isomers of the 18:1 fatty acids were successfully separated, the previously co-eluting peak was identified as elaidic acid and was found as a component in the mixture of the emulsifier polysorbate 80. Additionally, cis-vaccenic acid was separated as a second co-eluting isomer. Therefore, derivatization led to successful chromatographical separation of cis/trans and structural 18:1 fatty acid isomers.

Correlation of antimicrobial effects of phenoxyethanol with its free concentration in the water phase of o/w-emulsion gels.

Antimicrobial testing is a time consuming and cost-intensive but essential method for evaluation of newly developed pharmaceutical formulations for topical use. In this study the correlation between free preservative concentration in emulsion gels measured by equilibrium dialysis and the successful preservative effectiveness testing for Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans and Aspergillus brasiliensis (analyzed according to Ph. Eur. and USP) was investigated. The higher the lipophilicity of the oil phase and the lower the content of the aqueous phase with regard to dissolved ingredients the more preferably distributed is phenoxyethanol to the water phase and, consequently, the higher was the efficacy against the microbes. Increased emulsifier concentrations reduced the free amount of the preservative due to micellar interactions. Aspergillus brasiliensis was the most resistant and Staphylococcus aureus the most sensitive germ towards phenoxyethanol in o/w-emulsion gels.

Machine-learning-based atom probe crystallographic analysis.

Atom probe tomography is known for its accurate compositional analysis at the nanoscale. However, the patterns created by successive hits on the single particle detector during experiments often contain complementary information about the specimen's crystallography, including structure and orientation. This information remains in most cases unexploited because it is, up to now, retrieved predominantly manually. Here, we propose an approach combining image analysis techniques for feature selection and deep-learning to automatically interpret the patterns. Application of unsupervised machine learning techniques allows to build and train a deep neural network, based on a library generated from theoretically known crystallographic angular relationships. This approach enables direct interpretation of the detector hit maps, as shown here on the example of numerous pure-Al, and is robust enough to function under various conditions of base temperature, pulsing mode and pulse fraction. We benchmark our approach against recent attempts to automate the pattern identification via Hough-transform and discuss the current limitations of our approach. This new automated approach renders crystallographic atom probe tomography analysis more efficient, feature-sensitive, robust, user-independent and reliable. With that, deep-learning algorithms show a great potential to give access to combined atom probe crystallographic and compositional analysis to a large community of users.