Studying particle discharge rates in fluidized bed technology is important for optimizing continuous processes and improving product quality. This study investigates particle discharge, specifically the mass outflow rate, from a pilot-scale fluidized bed by means of experimental methods and mathematical modeling. The modeling uses various algebraic equations to predict the mass outflow rate and the time evolution of bed mass. Experiments in which these quantities were measured were conducted under different conditions, including varying mass inflow rates and process modes such as continuous and semi-batch. The results indicate that the mass outflow rate can be effectively modeled using existing equations from the literature, as well as a newly introduced equation, providing a comprehensive understanding of the holdup and discharge behavior of the fluidized bed. The newly introduced equation seems to perform better under transient conditions, being most appropriate for automatic control.

This study focused on representing the three-dimensional (3D) structure of individual aggregates based on their two-dimensional (2D) images. This starts with the determination of 2D box-counting fractal dimension (D-f,D- BC,D-2D), uses a previously derived empirical correlation to obtain 3D power law fractal dimension (D-f,D-PL), and then builds the aggregate on the basis of D-f,D- PL by an existing algorithm. Validation of this procedure can be done in forward or backward manner. Forward validation requires the existence of tomographic measurements of D-f,D-PL. It has been conducted on aggregates of large primary particles produced to this purpose in a spray fluidized bed and analyzed by X-ray micro-computed tomography (mu-CT). For the same agglomerates backward validation has also been exercised, starting the representation from 2D projections of the 3D objects and repeating the same procedure on the represented aggregates to see, how accurately the fractal dimensions of the original objects are reproduced. When the primary particles are too small in size to be resolved by X-ray mu-CT, only 2D imaging data by electron microscopy are usually available. Such images have been taken from literature for aggregates composed of submicron particles or nanoparticles and used for aggregate representation in 3D. Subsequently, backward validation of the procedure has been conducted. Both forward validation and backward validation results indicate a high level of consistency between the fractal characteristics and morphological structures of the represented aggregates and those of the original ones. Additionally, this study shows that the method is effective for aggregates of bidisperse and polydisperse particles.

This work investigates catalyst shaping in top spray fluidized beds and its impact on properties at different levels: particle growth stages, zeolite dispersion within the catalyst particles, and their combined effects on active site accessibility and activity in methanol to hydrocarbons (MTH) reaction. We examine the influence of process parameters such as viscosity, atomization, fluidization, temperature, slurry flow, and initial bed mass on particle size distribution and morphology. Dimensionless number analysis clarifies the dominant growth stage for a given set of process parameters. We elaborate more on optimizing the conditions that maximize zeolite, linked to smaller zeolite size, faster diffusion of probes such as 2, 2-dimethylbutane, and slightly higher activity (without violating the reaction mechanism). By optimizing the dispersion of zeolite through catalyst shaping conditions, we achieved 100 % zeolite utilization, compared to 70 % under non-optimized conditions. This improvement would have a significant impact on scaling this shaping technology.

Spray fluidized bed agglomeration (SFBA) is an essential process in particle engineering, widely applied to improve the flowability, dispersibility, and handling characteristics of fine powders. This study investigates the effects of gas inlet temperature and binder content on agglomerate formation, growth dynamics, and morphology in a continuous SFBA system. The results show that higher gas inlet temperatures lead to smaller agglomerates and lower growth rates due to rapid drying, while increased binder content enhances liquid bridge formation, promoting larger agglomerates with higher growth rates. Steady-state conditions were achieved, confirming process stability. Morphological analysis revealed that higher temperatures resulted in looser structures with reduced inter-particle connectivity, whereas higher binder content produced denser and more cohesive agglomerates. Comparisons with previous studies indicate opposite trends in morphology, highlighting the influence of operating conditions and material properties on agglomerate formation. The study also notes limitations in agglomerate size, which affected structural descriptors and growth behavior. These findings provide valuable insights for optimizing SFBA processes in various industries, including pharmaceuticals, food, and specialty chemicals, and emphasize the need for further research to better understand agglomeration mechanisms in continuous systems.

This work aims to elucidate the particle growth mechanism during agglomeration using a bottom -spray fluidized bed process to produce technical catalysts. The influences of the fundamental operating parameters of the granulation process were investigated through (i) experiments in a newly designed small-scale bottom -spray fluidized bed reactor, (ii) morphological characterization of the catalytic particles produced, (iii) dimensionless number analysis, and (iv) principal component analysis. These results could define the growth stage as dust formation, seed formation, agglomeration, and dust integration or layering. The particle growth mechanism results from the complex interplay of several effects and forces (mass transfer, viscous force, inertial force, surface tension, and gravity), and the prevailing growth stage can be linked with the Weber ( We ) and capillary ( Ca ) numbers (i.e., low values of We = 5.7 and Ca = 1.4 leads to layering growth and high values of We = 19.1 and Ca = 7.1 results in dust formation).

Mixing nanoparticles is critical in various industries, including pharmaceuticals, solar, and nanotechnology. When different nanopowders are mixed, hetero-aggregates consisting of hetero-contacts are formed, facilitating the exchange of charge, mass and moments between particles of different materials. This research paper presents a novel approach for mixing nanoparticles using special spouted bed equipment to produce hetero-aggregates. The paper explores the potential of special spouted bed equipment for mixing nanoparticles. High-velocity opposed inlet air streams in this equipment result in high gas-solid contact efficiency and enhanced particle circulation, which contribute to the breakage of aggregates and promote the mixing process. The study investigates the aggregate breakage and mixing quality in produced hetero-aggregates. Experimental results demonstrate that the special spouted bed equipment enables efficient mixing of nanoparticles, leading to higher dispersion in hetero-aggregates with many hetero-contacts. The modified homogeneity of mixing method is utilized to quantify the mixing inside the single hetero-aggregates. Visual confirmation of the assessed values of mixing quality is provided by EDX spectral mapping.

Aerosol droplets are used to coat fluidized particles in this work. Coating experiments utilizing aerosol droplets (with a mean diameter of around 1μm) were performed under different process conditions to explore their impact on process yield, as well as on coating coverage. Core materials were glass and porous γ-Al2O3, which had mean diameters of 653μm and 610μm, respectively. Sodium benzoate (NaB) solution and silicon dioxide (SiO2) nanosuspension were used as the coating liquid. After sampling, particle pictures were taken by a scanning electron microscope and analyzed using image processing to determine the coating coverage. To simulate the coating process and determine, for each experiment, a factor for preferential deposition on already occupied positions, Monte Carlo simulations were used. Also, some particles were cut in the middle to measure coating layer thickness. Intraparticle coating thickness distribution from Monte Carlo simulations coarsely matches the measured thickness from cut particles. Results show that the process yield, coating coverage, and preference factor are affected by experimental conditions such as expanded bed height, fluidization air temperature, atomizing pressure, the number of aerosol inlets, as well as the surface potential of core particles. This study is first to examine the impact of surface charge of different core materials on droplet deposition. In an experiment with SiO2 nanosuspension, γ-Al2O3 cores could be coated quite uniformly with SiO2 nanoparticles with a layer thickness of ca. 1.1μm. This shows the potential of aerosol droplet deposition as a novel semi-wet method for coating large particles with nanoparticles without using any binders.

In this study, an aerosol fluidized bed is used to coat particles. A new aerosol generator is used to obtain coating solution droplets with a diameter of around 1 μm or smaller. Glass particles, which have a mean diameter of 653 μm, were the non-porous core material and the coating solution was sodium benzoate. Scanning electron microscope pictures were analyzed by MATLAB image processing for evaluating the coverage with the curvature effect. Monte Carlo simulation was used to describe the coating of fluidized particles by aerosol droplets. The purpose of this work was the determination of possible island growth on particles, and investigation of the reasons of it by comparing the experimental and simulation results. The preferential deposition of droplets on already occupied positions is seen as the main possible reason for island growth.

OBJECTIVE:Dextromethorphan (DXM) is a commonly used antitussive medication with positive effects in people with type 2 diabetes mellitus, since it increases glucose tolerance and protects pancreatic islets from cell death. However, its use as an antidiabetic medication is limited due to its central nervous side effects and potential use as a recreational drug. Therefore, we recently modified DXM chemically to reduce its blood-brain barrier (BBB) penetration and central side effects. However, our best compound interacted with the cardiac potassium channel hERG (human ether-à-go-go-related gene product) and the μ-opioid receptor (MOR). Thus, the goal of this study was to reduce the interaction of our compound with these targets, while maintaining its beneficial properties. METHODS:Receptor and channel binding assays were conducted to evaluate the drug safety of our DXM derivative. Pancreatic islets were used to investigate the effect of the compound on insulin secretion and islet cell survival. Via liquor collection from the brain and a behavioral assay, we analyzed the BBB permeability. By performing intraperitoneal and oral glucose tolerance tests as well as pharmacokinetic analyses, the antidiabetic potential and elimination half-life were investigated, respectively. To analyze the islet cell-protective effect, we used fluorescence microscopy as well as flow cytometric analyses. RESULTS:Here, we report the design and synthesis of an optimized, orally available BBB-impermeable DXM derivative with lesser binding to hERG and MOR than previous ones. We also show that the new compound substantially enhances glucose-stimulated insulin secretion (GSIS) from mouse and human islets and glucose tolerance in mice as well as protects pancreatic islets from cell death induced by reactive oxygen species and that it amplifies the effects of tirzepatide on GSIS and islet cell viability. CONCLUSIONS:We succeeded to design and synthesize a novel morphinan derivative that is BBB-impermeable, glucose-lowering and islet cell-protective and has good drug safety despite its morphinan and imidazole structures.

Nanostructured heteroaggregates provide improved or new functionalities over homoaggregates due to the formation of heterocontacts. For a high number of heterocontacts, intense mixing of the primary particles and their reaggregation is required. This work presents results using the principle of fluidization for formulation of nanostructured heteroaggregates. Intraaggregate mixing of constituents is evaluated by SEM-EDX. The feasibility of two technologies, spouted bed and opposed jet fluidized bed, is demonstrated, also showing the variety of structures that can be achieved by the technologies.

Pyroglutamate - 3Aβ (N3pE), a toxic Aβ variant formed by the activity of glutaminyl gyclase (QPCT) has been shown to play a pivotal role in the development and progression of Alzheimer’s disease (AD). Recently, we demonstrated that a combination of the QPCT inhibitor varoglutamstat (PQ912) with the N3pE-specific antibody m6 has an additive effect on lowering of N3pE in vivo . Here, we analyzed whether a similar additive effect could be achieved when combining varoglutamstat with the Aβ-aggregate-specific antibody aducanumab. Nine-months old APPxhQC mice were treated with either varoglutamstat (1.6 g/kg chow, ad libitum), chimeric aducanumab (chAdu, ≈10 mg/kg i.p. weekly) or a combination of both for 16 weeks. Brain Aβ accumulation (ELISA and immunohistochemistry) and AD biomarkers in the water-soluble brain fractions (neurogranin, BACE-1, YKL-40; ELISA) were analyzed and compared to a vehicle-treated group. Treatment with either varoglutamstat or chAdu significantly reduced the accumulation of both total Aβ and N3pE in the brain. The effect of chAdu was more pronounced for total Aβ (-35% vs. -21% for varoglutamstat), while varoglutamstat treatment resulted in a stronger decrease of N3pE (-28% vs. -19% for chAdu). The combination treatment generally led to a stronger decrease of Aβ vs. single agent treatment (Bliss combination index (CI) = 0.88 for soluble Aβ42 and 1.23 for insoluble Aβ42). For insoluble N3pE, the observed effect was nearly additive (CI = 1.09). Treatment with chAdu, varoglutamstat or both had different effects on the analyzed AD biomarkers. chAdu treatment significantly decreased BACE-1 protein levels (-30%), while varoglutamstat treatment significantly reduced levels of the brain inflammation marker YKL-40 (-27%), which is in line with earlier clinical Phase 2a study results. Our data indicate that a combination of agents with different modes of action such as aducanumab, an Aβ aggregate-specific antibody and varoglutamstat, a small molecule designed to block formation of toxic, aggregation-prone N3pE, can act additively to decrease total Aβ and N3pE levels in the brain. Our results also provide a rationale for investigating different potential combination regimens, including an initial antibody-mediated Aβ clearance followed by long-term suppression of N3pE formation and inflammation by varoglutamstat (“treat and maintain”).

Protein–protein modulation has emerged as a proven approach to drug discovery. While significant progress has been gained in developing protein–protein interaction (PPI) inhibitors, the orthogonal approach of PPI stabilization lacks established methodologies for drug design. Here, we report the systematic ″bottom-up″ development of a reversible covalent PPI stabilizer. An imine bond was employed to anchor the stabilizer at the interface of the 14-3-3/p65 complex, leading to a molecular glue that elicited an 81-fold increase in complex stabilization. Utilizing protein crystallography and biophysical assays, we deconvoluted how chemical properties of a stabilizer translate to structural changes in the ternary 14-3-3/p65/molecular glue complex. Furthermore, we explore how this leads to high cooperativity and increased stability of the complex.

Compelling evidence suggests that pyroglutamate-modified Aβ (pGlu3-Aβ; AβN3pG) peptides play a pivotal role in the development and progression of Alzheimer’s disease (AD). Approaches targeting pGlu3-Aβ by glutaminyl cyclase (QC) inhibition (Varoglutamstat) or monoclonal antibodies (Donanemab) are currently in clinical development. Here, we aimed at an assessment of combination therapy of Varoglutamstat (PQ912) and a pGlu3-Aβ-specific antibody (m6) in transgenic mice. Whereas the single treatments at subtherapeutic doses show moderate (16–41%) but statistically insignificant reduction of Aβ42 and pGlu-Aβ42 in mice brain, the combination of both treatments resulted in significant reductions of Aβ by 45–65%. Evaluation of these data using the Bliss independence model revealed a combination index of ≈1, which is indicative for an additive effect of the compounds. The data are interpreted in terms of different pathways, in which the two drugs act. While PQ912 prevents the formation of pGlu3-Aβ in different compartments, the antibody is able to clear existing pGlu3-Aβ deposits. The results suggest that combination of the small molecule Varoglutamstat and a pE3Aβ-directed monoclonal antibody may allow a reduction of the individual compound doses while maintaining the therapeutic effect.

Fine particles are widely used in many industrial fields, and there are many techniques applied for these particles, like electroplating, and chemical and physical vapor deposition. However, in the food and pharmaceutical industries, most coating processes conducted with fluidized bed use core particles with a diameter larger than 200 μm, otherwise agglomerates are formed. This study contributes to the development of a new coating process for fine particles with diameters of around 50 μm. The innovation lies in the combined use of a Wurster fluidized bed and a novel aerosol atomizer. The feasibility of the operation is based on the application of the aerosol atomizer, which generates droplets smaller than 1 μm in diameter. A series of experiments with different coating solutions and glass beads in a 150 mm fluidized bed fed with droplet aerosol supplied from the cone chamber bottom is presented. The quality of the coating product is analyzed by scanning electron microscopy and CAMSIZER®. In this way, the influence of different conditions and core material properties on the product quality were determined. Experimental results showed the coating layer quality getting worse as coating solution viscosity became lower, meanwhile moderate process temperature was found to enhance coating layer formation and quality of that. It was also observed that lower aerosol feed rates help improve the yield of the process.

AbstractSmall‐molecule stabilization of protein–protein interactions (PPIs) is a promising concept in drug discovery, however the question how to identify or design chemical starting points in a “bottom‐up” approach is largely unanswered. We report a novel concept for identifying initial chemical matter for PPI stabilization based on imine‐forming fragments. The imine bond offers a covalent anchor for site‐directed fragment targeting, whereas its transient nature enables efficient analysis of structure–activity relationships. This bond enables fragment identification and optimisation using protein crystallography. We report novel fragments that bind specifically to a lysine at the PPI interface of the p65‐subunit‐derived peptide of NF‐κB with the adapter protein 14‐3‐3. Those fragments that subsequently establish contacts with the p65‐derived peptide, rather than with 14‐3‐3, efficiently stabilize the 14‐3‐3/p65 complex and offer novel starting points for molecular glues.

Recent innovations have brought pharmacophore-driven methods for navigating virtual chemical spaces, the size of which can reach into the billions of molecules, to the fingertips of every chemist. There has been a paradigm shift in the underlying computational chemistry that drives chemical space search applications, incorporating intelligent reaction knowledge into their core so that they can readily deliver commercially available molecules as nearest neighbor hits from within giant virtual spaces. These vast resources enable medicinal chemists to execute rapid scaffold-hopping experiments, rapid hit expansion, and structure-activity relationship (SAR) exploitation in largely intellectual property (IP)-free territory and at unparalleled low cost.

Pyroglutamyl-Aβ (pE3Aβ) is a post-translationally modified form of Aβ showing increased stability, aggregation propensity and neurotoxicity. The formation of pEA3β is catalyzed by the enzyme glutaminyl cyclase (QC). PQ912, a QC-inhibitor in Phase 2 clinical development, has been shown to inhibit pE3Aβ formation and attenuate AD-like symptoms in animals. Similarly, we have shown that PBD-mC06, a pE3Aβ specific antibody, is efficacious in AD-like mouse models without inducing microhemorrhage. Here, we tested the effect of a combination of PQ912 and PBD-m06 in the double transgenic Alzheimer animal model APPswLxhQC. APPswl/hQC mice were treated with the single agent (PQ912 or PBD-mC06 antibody) or a combination of both starting at 8 to 9 months of age and continued for 16 weeks. PQ912 was applied orally by freely available chow (0.8 g/kg chow) and m06 was applied by intra-peritoneal injection (150 μg) once a week. An Ig isotype antibody (IgG2a) was used as control. Brain levels of soluble and insoluble pEAβ and total Aβ were captured by ELISA and by immunohistochemistry. ELISA analysis of brain homogenates showed a modest reduction in pE3Aβ (27 to 41 %) and total Aβ (22 to 38 %) following treatment with each single agent. The combination resulted in a significant (α = 0.05) reduction in pE3Aβ (46 to 53 %) and total Aβ (38 to 45%). Bliss combination indices between 1 and 1.3 for the different Aβ fractions indicate an additive effect. These ELISA results were underscored by results from quantitative immunohistochemistry where each single agent led to an ≈ 40 % reduction in hippocampal pE3Aβ plaque load whereas the combination treatment significantly reduced plaque load by 65 %. The results suggest that QC inhibitor and anti-pE3Aβ antibody act independently on formation and removal of pEAβ providing a rational for a combination therapy in AD.