Based on the drug repositioning strategy, niclosamide (NCL) has shown potential applications for treating COVID-19. However, the development of new formulations for effective NCL delivery is still challenging. Herein, NCL-embedded dry powder for inhalation (NeDPI) was fabricated by a novel spray freeze drying technology. The addition of Tween-80 together with 1,2-Distearoyl-sn-glycero-3-phosphocholine showed the synergistic effects on improving both the dispersibility of primary NCL nanocrystals suspended in the feed liquid and the spherical structure integrity of the spray freeze dried (SFD) microparticle. The SFD microparticle size, morphology, crystal properties, flowability and aerosol performance were systematically investigated by regulating the feed liquid composition and freezing temperature. The addition of leucine as the aerosol enhancer promoted the microparticle sphericity with greatly improved flowability. The optimal sample (SF D-NLDT) showed the highest fine particle fraction of ∼47.83%, equivalently over 3.8 mg NCL that could reach the deep lung when inhaling 10 mg dry powders.

We have performed Computational Fluid Dynamics-Discrete Element Method (CFD-DEM) simulations of air and particles in a commercial ELLIPTA® inhaler. We simulated the fluidization, deagglomeration and transport of carrier and API particles, with two realistic inhalation profiles that are representative of moderate asthma and very severe COPD patients, and three different mouthpiece designs. In each of the ten cases simulated, we determined the fine particle fraction (FPF) in the stream leaving the mouthpiece, the temporal evolution of the spatial distribution of the particles, the mean air (slip) velocity seen by the carrier particles, and the average numbers and normal impact velocities of carrier-carrier and carrier-wall collisions inside the inhaler. In the cases examined, the air-carrier and carrier-carrier interactions affected the FPF, while the carrier-wall interactions were too infrequent to have a substantial effect. The simulations revealed the benefit of loading both blisters even when only a single medication needs to be delivered.

The coronavirus disease 2019 (COVID-19) pandemic has led to severe social and economic disruption worldwide. Although currently no consent has been reached on a specific therapy that can treat COVID-19 effectively, several inhalation therapy strategies have been proposed to inhibit SARS-CoV-2 infection. These strategies include inhalations of antiviral drugs, anti-inflammatory drugs, and vaccines. To investigate how to enhance the therapeutic effect by increasing the delivery efficiency (DE) of the inhaled aerosolized drug particles, a patient-specific tracheobronchial (TB) tree from the trachea up to generation 6 (G6) with moderate COVID-19 symptoms was selected as a testbed for the in silico trials of targeted drug delivery to the lung regions with pneumonia alba, i.e., the severely affected lung segments (SALS). The 3D TB tree geometry was reconstructed from spiral computed tomography (CT) scanned images. The airflow field and particle trajectories were solved using a computational fluid dynamics (CFD) based Euler-Lagrange model at an inhalation flow rate of 15 L/min. Particle release maps, which record the deposition locations of the released particles, were obtained at the inlet according to the particle trajectories. Simulation results show that particles with different diameters have similar release maps for targeted delivery to SALS. Point-source aerosol release (PSAR) method can significantly enhance the DE into the SALS. A C++ program has been developed to optimize the location of the PSAR tube. The optimized simulations indicate that the PSAR approach can at least increase the DE of the SALS by a factor of 3.2× higher than conventional random-release drug-aerosol inhalation. The presence of the PSAR tube only leads to a 7.12% change in DE of the SALS. This enables the fast design of a patient-specific treatment for reginal lung diseases.

Computational analysis of virus dynamics provides a non-contact environment for the study of the vital object. Cluster modelling is an essential step to investigate the properties of a group of viruses, and an automatic approach is required for massive 3D data processing. The morphological complexity of individual virus limits the application of smooth function algorithms with a regular-shaped assumption. This paper proposed a voxel-based redistribution approach to generate the virus cluster with COVID-19 input automatically. Representative elementary volume analysis was performed to address the statistical influence from the digital sample size. Coordination number analysis and surface density measurement were conducted with COVID-19 input and spherical input for comparison. The proposed approach is in natural compatibility with the lattice Boltzmann method for fluid dynamics analysis. A virtual permeation simulation was performed with the COVID-19 cluster and spherical cluster to demonstrate the necessity to include spike protein structure in the cluster modelling.

The de-agglomeration characteristics of single agglomerate-wall impaction are examined using high-resolution shadowgraph imaging. Experiments are performed to investigate the effects of constituent particle size (D from 3-7 m) and air velocity on the individual size and velocity of de-agglomerated fragments at conditions relevant to dry powder inhalation systems. De-agglomerated fragment area and trajectories were used to differentiate between pseudo-elastic and inelastic collisions during de-agglomeration. Advanced image processing techniques have enabled provision of joint population distributions of fragment area and aspect ratio, which identify a bimodal dispersion of fragments during de-agglomeration. The bimodality is destroyed with increasing air velocity and also generally diminishes with time after impact. The experiment presented forms a platform for the detailed quantitative characterisation of de-agglomeration behaviour and can be useful towards the development and validation of related computational models for pharmaceutical dry powder inhalers.

[This corrects the article PMC8724865.].

The environmental conditions associated with changing the hydration state of active pharmaceutical ingredients (API) are crucial to understanding their stability, bioperformance, and manufacturability. Identifying the dehydration event using < 1μg of material is an increasingly important challenge. Atomic Force Microscopy indentation mapping is implemented at controlled temperatures between 25-100°C, for nanoscale volumes of hydrated APIs exhibiting distinct dehydration behavior and anhydrous APIs as controls. For caffeine hydrate and azithromycin dihydrate, the relative mechanical modulus increases ~10-fold at dehydration temperatures. These are confirmed by conventional macroscopic measurements including Variable Temperature Powder X-ray Diffraction, Thermogravimetric Analysis, and Differential Scanning Calorimetry. Conversely, no such mechanical transition is observed for anhydrous ibuprofen or a proprietary anhydrous compound. AFM-based mechanical mapping is therefore demonstrated for small-volume determination of temperature-induced solid-state dehydration events, which may enable spatially or temporally mapping for future studies of dehydration mechanisms and kinetics, as a function of commercially relevant nanoscale heterogeneities.

Dustiness quantifies the propensity of a finely divided solid to be aerosolized by a prescribed mechanical stimulus. Dustiness is relevant wherever powders are mixed, transferred or handled, and is important in the control of hazardous exposures and the prevention of dust explosions and product loss. Limited quantities of active pharmaceutical powders available for testing led to the development (at University of North Carolina) of a Venturi-driven dustiness tester. The powder is turbulently injected at high speed ( ~ 2 × 10) into a glass chamber; the aerosol is then gently sampled ( ~ 2 × 10) through two filters located at the top of the chamber; the dustiness index is the ratio of sampled to injected mass of powder. Injection is activated by suction at an Extraction Port at the top of the chamber; loss of powder during injection compromises the sampled dustiness. The present work analyzes the flow inside the Venturi Dustiness Tester, using an Unsteady Reynolds-Averaged Navier-Stokes formulation with the Shear Stress Transport turbulence model. The simulation considers single-phase flow, valid for small particles (Stokes number <1). Results show that ~ 24% of fluid-tracers escape the tester before the Sampling Phase begins. Dispersion of the powder during the Injection Phase results in a uniform aerosol inside the tester, even for inhomogeneous injections, satisfying a necessary condition for the accurate evaluation of dustiness. Simulations are also performed under the conditions of reduced Extraction-Port flow; results confirm the importance of high Extraction-Port flow rate (standard operation) for uniform distribution of fluid tracers. Simulations are also performed under the conditions of delayed powder injection; results show that a uniform aerosol is still achieved provided 0.5 s elapses between powder injection and sampling.

Resistance parameters are essential for the prediction of pressure drop in bag filters. The reported values for limestone dust differ in magnitude and also depend on operating parameters. In this work, experimental data is provided from a pilot scale pulse-jet regenerated bag filter test facility for three types of needle felts using air and limestone dust at ambient conditions. Results reveal that specific resistance of filter media is independent of velocity while the specific resistance of filter cake increases linearly with filtration velocity. Residual pressure drop is almost constant, independent of upper pressure drop limit. The cake resistance at constant velocity fits to a second degree polynomial whereas it increases linearly with the velocity. A linear relation is reported here for all the cases. The resistance of filter cake decreases at higher upper pressure drop limit.

Bag filters are commonly used for fine particles removal in off-gas purification. There dust laden gas pervades through permeable filter media starting at a lower pressure drop limit leaving dust (called filter cake) on the filter media. The filter cakeformation is influenced by many factors including filtration velocity, dust concentration, pressure drop limits, and filter media resistance. Effect of the stated parameters is investigated experimentally in a pilot scale pulse-jet bag filter test facility where lime stone dust is separated from air at ambient conditions. Results reveal that filtration velocity significantly affects filter pressure drop as well as cake properties; cake density and specific cake resistance. Cake density is slightly affected by dust concentration. Specific resistance of filter cake increases with velocity, slightly affected by dust concentration, changes inversely with the upper pressure drop limit and decreases over a prolonged use (aging). Specific resistance of filter media is independent of upper pressure drop limit and increases linearly over a prolonged use.

It is possible to assess viscoelastic properties of materials by means of the stress relaxation test. This method records the decrease in pressing power in a tablet at its constant height. The cited method was used to evaluate the time-dependent deformation for six various materials: microcrystalline cellulose, cellulose powder, hydroxypropyl methylcellulose, mannitol, lactose monohydrate, and hydrogen phosphate monohydrate. The decrease in pressing powering of a tablet during a 180 s period was described mathematically by the parameters of three exponential equations, where the whole course of the stress relaxation is divided into three individual processes (instant elastic deformation, retarded elastic deformation and permanent plastic deformation). Three values of the moduli of plasticity and elasticity were calculated for each compound. The values of elastic parameters A have a strong relationship with bulk density. The plastic parameters P represent particle tendency to form bonds. The values of plasticity in the third process P ranged from 400 to 600 MPas. Mannitol had higher plasticity and lactose monohydrate on the contrary reduced plasticity. A linear relation exists between A and P for the third process. No similar interpretation of moduli calculated on the basis of three exponential equations has been realized yet.

Pulse-jet bag filters are frequently employed for particle removal from off gases. Separated solids form a layer on the permeable filter media called filter cake. The cake is responsible for increasing pressure drop. Therefore, the cake has to be detached at a predefined upper pressure drop limit or at predefined time intervals. Thus the process is intrinsically semi-continuous. The cake formation and cake detachment are interdependent and may influence the performance of the filter. Therefore, understanding formation and detachment of filter cake is important. In this regard, the filter media is the key component in the system. Needle felts are the most commonly used media in bag filters. Cake formation studies with heat treated and membrane coated needle felts in pilot scale pulse jet bag filter were carried out. The data is processed according to the procedures that were published already [Powder Technology, Volume 173, Issue 2, 19 April 2007, Pages 93-106]. Pressure drop evolution, cake height distribution evolution, cake patches area distribution and their characterization using fractal analysis on different needle felts are presented here. It is observed that concavity of pressure drop curve for membrane coated needle felt is principally caused by presence of inhomogeneous cake area load whereas it is inherent for heat treated media. Presence of residual cake enhances the concavity of pressure drop at the start of filtration cycle. Patchy cleaning is observed only when jet pulse pressure is too low and unable to provide the necessary force to detach the cake. The border line is very sharp. Based on experiments with limestone dust and three types of needle felts, for the jet pulse pressure above 4 bar and filtration velocity below 50 mm/s, cake is detached completely except a thin residual layer (100-200 μm). Uniformity and smoothness of residual cake depends on the surface characteristics of the filter media. Cake height distribution of residual cake and newly formed cake during filtration prevails. The patch size analysis and fractal analysis reveal that residual cake grow in size (latterly) following regeneration initially on the base with edges smearing out, however, the cake heights are not leveled off. Fractal dimension of cake patches boundary falls in the range of 1-1.4 and depends on vertical position as well as time of filtration. Cake height measurements with Polyimide (PI) needle felts were hampered on account of its photosensitive nature.