Search

The utilization of hydrogen is gaining increasing attention due to its high heating value and environmentally friendly combustion product. The supercritical water circulating fluidized bed reactor is a promising and potentially clean technology that can generate hydrogen from coal gasification. Cyclone is a vital part of the reactor which can separate incomplete decomposition of pulverized coal particles from mixed working fluid. This paper aims to gain in-depth understanding of the cyclone separation mechanisms under supercritical fluid by computational fluid dynamics (CFD). Although the amount of supercritical carbon dioxide in mixed working fluid is minor, it obviously influences the flow fields and separation efficiency of a cyclone. The simulation results suggest that both the decreasing content of supercritical carbon dioxide and adding the extra dipleg cause the promoting performance of cyclones. Research findings could refine the design of supercritical fluid–solid cyclones.

To analyze the effect of different endoscopic endonasal approaches (EEAs) on nasal airflow and heating and humidification in patients with pituitary adenoma (PA) by computational fluid dynamics (CFD).A three-dimensional pre-surgical model (Pre) of the nasal cavity and 6 that were post-EEA surgery were created from computed tomography scans as follows: small posterior septectomy (0.5 cm, sPS), middle posterior septectomy (1.5 cm, mPS), large posterior septectomy (2.5 cm, lPS), and sPS with middle turbinate resection (sPS-MTR), mPS-MTR, and lPS-MTR. Simulations were performed by CFD to compare the changes in different models.The temperature in the nasal vestibule rose more rapidly than in other parts of the nasal cavities in all models. There were no apparent differences in temperature and humidity among the models in sections anterior to the middle turbinate head (C6 section). MTR significantly influenced airflow distribution between the bilateral nasal cavities and the different parts of the nasal cavity, while changes in temperature and humidity in each section were mainly affected by MTR. The temperature and humidity of the choana and nasopharynx of each postoperative model were significantly different from those of the preoperative model and the change in values significantly correlated with the surface-to-volume ratio (SVR) of the airway.Changes due to the different nasal structures caused different effects on nasal function following the use of EEA surgery for the treatment of PA. CFD provided a new approach to assess nasal function, promising to provide patients with individualized preoperative functional assessment and surgical planning.

Effective evaluation and prediction of aerosol transport deposition in the human respiratory tracts are critical to aerosol drug delivery and evaluation of inhalation products. Establishment of an in vitro-in vivo correlation (IVIVC) requires the understanding of flow and aerosol behaviour and underlying mechanisms at the microscopic scale. The achievement of the aim can be facilitated via computational fluid dynamics (CFD) based in silico modelling which treats the aerosol delivery as a two-phase flow. CFD modelling research, in particular coupling with discrete phase model (DPM) and discrete element method (DEM) approaches, has been rapidly developed in the past two decades. This paper reviews the recent development in this area. The paper covers the following aspects: geometric models of the respiratory tract, CFD turbulence models for gas phase and its coupling with DPM/DEM for aerosols, and CFD investigation of the effects of key factors associated with geometric variations, flow and powder characteristics. The review showed that in silico study based on CFD models can effectively evaluate and predict aerosol deposition pattern in human respiratory tracts. The review concludes with recommendations on future research to improve in silico prediction to achieve better IVIVC.

Microparticulate formulations of intranasal drug administration, i.e. nasal powder, have aroused widespread interest in academia and industry. However, low drug bioavailability due to poor hydrophilicity and rapid clearance of nasal mucosa remains an important challenge. Herein, with resveratrol as poorly water-soluble model drug, hydroxypropyl-β-cyclodextrin as complexation agent and excipient, chitosan as mucoadhesive enhancer, a series of uniform microparticles were fabricated using a self-designed microfluidic spray granulation platform. The effects of feed solution composition and process technique on particle size, morphology, density and flowability were investigated. The obtained powder presented the significantly enhanced resveratrol dissolubility over 1800 times pure resveratrol and the excellent antioxidant activity with Net AUC value exceeding 60. Chitosan played an important role in adjusting resveratrol release behavior and improving particle mucoadhesive property. This study shows promise for facile and scalable production of high-quality nasal powder using combined complexation method with spray drying and spray freeze drying technique.

Remdesivir is one of the effective drugs proposed for the treatment of coronavirus disease 2019 (COVID-19). However, the study on inhalable regimen is currently limited though COVID-19 is respiratory diseases and infects lung area. This work aims to prepare inhalable remdesivir formulations and verify their effectiveness through

This work aimed to evaluate the relative inhalation parameters that affect the deposition of inhaled aerosols, including mouth-throat morphology, airflow rate, and initial condition of emitted particles. In vitro experiments were conducted using the US Pharmacopeia (USP) throat and a realistic mouth-throat (RMT) with Handihaler®. Then, in silico study of the gas-solid flow was performed by computational fluid dynamics and discrete phase method. Results indicated that aerosol deposition in RMT was higher compared to that in USP throat at an airflow rate of 30 L/min, with 33.16 ± 7.84% and 21.11 ± 7.1% lung deposition in USP throat and RMT models, respectively, which showed a better correlation with in vivo data from the literature. Increasing airflow rate resulted in better drug aerosolization, while the fine particle dose trend ascended before declining, with the peak value obtained at a flow rate of 40 L/min. Overall, the effect of geometrical variation was more significant. Additionally, in silico results demonstrated clearly that the initial conditions of the emitted particles from inhalers affected the subsequent deposition. Larger momentum possessed by the central aerosol jet entering the mouth directly led to stronger impaction, which resulted in the deposition in the front region of mouth-throat models. This study is beneficial to develop an in silico method to understand the underlying mechanisms of in vivo mouth-throat deposition.

Understanding the deposition mechanisms of pharmaceutical aerosol in the mouth-throat (MT) is crucial to developing an in vitro method which aims to better predict in vivo lung deposition. This paper investigated the effect of geometrical variation, particle size and airflow rate on the fine particle deposition in the US pharmacopeia throat (USP), idealized mouth-throat (IMT) and realistic mouth-throat (RMT) models. The flow-field equations were solved with the SST model by computational fluid dynamics (CFD) and monodispersed particles in the size range of 1–30 μm were tracked with discrete phase method (DPM). The results indicated that the deposition fraction and spatial distribution were highly sensitive to the geometrical variation and respiratory conditions such as the inhalation airflow rate and particle size. Moreover, the effect of geometrical variation on the particle escape pattern was more dominant. Comparing to the IMT model, more uniformly distribution of escape particles was observed at the outlet of RMT. While the total deposition fractions in IMT and RMT were similar, the spatial distributions of deposited particles were significantly different. In the RMT model, fewer particles were deposited in mouth and trachea, but the depositions in the pharyngeal and laryngeal regions were more uniform. These conclusions could help study the in vitro-in vivo correlation of dry powder inhaler systems.

The application of mRNA as a novel kind of vaccine has been proved recently, due to the emergence use authorization (EUA) by FDA for the two COVID-19 mRNA vaccines developed by Moderna and BioNTech. Both of the two vaccines are based on canonical linear mRNA, and encapsulated by lipid nanoparticle (LNP). Circular mRNA, which is found to mediate potent and durable protein expression, is an emerging technology recently. Owing to its simplicity of manufacturing and superior performance of protein expression, circular mRNA is believed to be a disruptor for mRNA area. However, the application of circular mRNA is still at an initiation stage, proof of concept for its usage as future medicine or vaccine is necessary. In the current study, we established a novel kind of circular mRNA, termed C-RNA, based on Echovirus 29 (E29)-derived internal ribosome entry sites (IRES) and newly designed homology arms and RNA spacers. Our results demonstrated that this kind of circular mRNA is able to mediate strong and durable protein expression, compared to typical linear mRNA. Moreover, for the first time, our study demonstrated that direct intratumoral administration of C-RNA encoding a mixture of cytokines achieved successful modulation of intratumoral and systematic anti-tumor immune responses and finally leading to an enhancement of anti-PD-1 antibody-induced tumor repression in syngeneic mouse model. Additionally, after an optimization of the circular mRNA formulation, a significant improvement of C-RNA mediated protein expression was observed. With this optimized formulation, C-RNA induced enhanced anti-tumor effect via intratumoral administration and elicited significant activation of tumor-infiltrated total T cells and CD8+ T cells. Collectively, we established C-RNA, a novel circular mRNA platform, and demonstrated that it can be applied for direct intratumoral administration for cancer therapy.

Effective pulmonary drug delivery plays an essential role in the treatment of diseases. Drug aerosolization and inhalers play an essential role in the therapeutic effect of pulmonary diseases. The main objective of this paper is to evaluate the effect of inhalers, inhalation flow rates, and particle properties on the transport and deposition of 1-19 μm particles in a realistic airway model. Computational fluid dynamics coupled with the discrete phrase model (CFD-DPM) was performed to predict the transport and deposition of inhaled particles. Good agreement in deposition mechanisms was observed with the in vivo published data, which proved the effectiveness of the numerical method in pulmonary drug delivery. Airflow structure as well as deposition pattern showed that differences in turbulence, reverse flow, and vortex formulation between the two different models are determined by the existence of inhaler geometry. Enhancing the air flow rate and particle diameter increases the particle inertial as well as the turbulence level, resulting in an uptrend in deposition fraction (DF) of the mouth-throat (MT) region. In conclusion, this in silico method is valuable to help understand the in vitro - in vivo correlation (IVIVC) of pulmonary drug delivery.

Inhaled administration of polymyxin B is increasingly used to treat multi-drug resistant bacterial lung infections. However, the lack of clinical data on the pharmacokinetics of inhaled administration makes drug dose design, efficacy assessment and drug safety assessment a challenge. In this study, clinical data from intravenous injections were deconvoluted by an equal-step numerical deconvolution algorithm to derive the drug absorption rate of polymyxin B in vivo. The absorption rate was substituted into a published pulmonary absorption compartment model to predict the systemic pharmacokinetics of polymyxin B. It was demonstrated that the intravenous PK dataset with the pulmonary compartment model provided reliable estimates of the accuracy and bias of inhaled systemic pharmacokinetics.

Since complex structure of the human respiratory system leads to the profound effect of the air flow and particle deposition, a realistic and flexible airway model is crucial for predicting in vivo lung deposition of pharmaceutical aerosol. This work presented a CFD study of air and particle flows in a realistic parametrically controlled airway model developed by Kitaoka under different inspiratory conditions. The results were analysed with simulation data obtained in the classic Weibel airway (WA) model and compared with previous experimental and simulation studies. The comparison showed both difference and similarity between two models. The inspiratory airflow was symmetric in the WA model, whereas in the Kitaoka model non-symmetrical airflow was dominated throughout airways. The Kitaoka model, in comparison to the WA model, also showed more complicated particle deposition pattern with larger particle deposition efficiency. The flow rate, however, showed a similar effect to both models; i.e. generally particle deposition efficiency was higher as flowrate was higher. The Kitaoka model was then extended from 7 generations (KG7) to 11 generations (KG11) to study the effect of airway generation. The simulations showed little difference between two structures in terms of inspiratory air velocity and particle deposition efficiency. This suggests that the KG7 model is sufficiently structured to obtain realistic particle deposition pattern. The study demonstrates the Kitaoka model has a great potential in modelling lung deposition of particles under different conditions.

Active dry powder inhalers (DPIs) actuated by low air volume provide distinct advantages for delivering aerosols to patients with poor respiratory capacity. This work aims to investigate the effects of piercing aperture location and inlet flow rate on device-emptying, and to identify the mechanism of particle deposition in a realistic mouth-throat (MT) region. Computational fluid dynamics (CFD) is employed to predict dispersion parameters that measure turbulence intensity, and mono-sized particles are tracked by the discrete phase model (DPM). Results show that the piercing aperture location and the inlet flow rate both have significant impacts on device emptying. Strong correlations have been established between the emitted dose and flow field parameters. The pattern and distribution of the deposited particles in the realistic MT region are highly sensitive to particle size, flow rate and reservoir length. This work provides profound insights into the performance of the active DPIs and an additional perspective on device design.

Understanding the aerosolisation mechanism of carrier-based formulation with high drug loadings is crucial to developing high-dose dry powder inhalers. This paper investigated the effect of carrier-drug mass ratio in different conditions based on the combined computational fluid dynamics (CFD) and discrete element method (DEM) approach, aiming to develop better understanding of the aerosolisation mechanism of carrier-based formulation with high drug loadings. The carrier-based formulations composed of drug (salbutamol sulphate) and carrier (polystyrene bead) were formed with varied carrier-drug mass ratios ranging from 5:1 to 25:1. The aerosolisation process after impaction with a target wall was simulated and focuses mainly on the effects of four variables: carrier size, air flow velocities, impact velocities and impact angles. Dynamics of impact process and post-impact analysis were discussed. The fine particle fractions (FPFs), the amount of fine particles below 5 μm in the aerosol, were measured to characterise the aerosolisation performance. The results showed that increasing the carrier-drug mass ratio will improved the aerosolisation performance. The influencing degree of carrier-drug mass ratio on aerosol performance was dependent on the carrier size. For a larger carrier with a high carrier-drug ratio corresponding to high surface coverage, the airflow velocity, impact velocity and angle have only a minor effect on the aerosolisation performance. The best solution was to use the smaller carriers to replace the larger ones if the requirements of drug loading and FPFs need to be satisfied at the same time. These conclusions could be used to help design the optimal carrier-drug mass ratio formulations for different carrier-based dry powder inhaler systems.

A major problem of utilizing co-firing technique is controllably distributing fuel mixtures of pulverized coal and granular biomass in a common pipeline. This research related into particle velocity distribution in the vertical pipe after a right angle elbow was undertaken using the Laser Doppler Anemometry (LDA) technique and a coupled computational fluid dynamics (CFD)-discrete element method (DEM) simulation. According to the similarity criterion of Stokes Number, three types of glass beads were used to model the dilute gas-solid flow of pulverized coal or biomass pellets. In the vertical pipe after an elbow (R/D = 1.3, R is the bend radius as 100 mm and D is pipe diameter as 75 mm), a horseshoe shape feature has been found on cross-sectional distributions of the axial particle velocity for all three types of glass beads on the first section which is 15 mm away from the blend exit. At the further downstream sections, the horseshoe-shaped feature is gradually distorted until it completely disappears. The distance for total disintegration is about 300 mm away from the first section for the first type of glass beads, 150 mm away for the second type and 75 mm away for the third one. As for particle number rate, its cross-sectional distribution on the first section shows that a rope is formed at the pipe outer wall where the maximum particle number rate occurs. On the whole, the rope formed by the first type of glass beads can be still observed at the section which is 450 mm away from the first section. For the second type of glass beads, the rope will disintegrate from the section (300 mm away) according to the cross-sectional distributions of the dimensional value of particle axial velocity divided by air conveying velocity. Overall, the roping characteristic is not obviously shown in the gas-solid flow of the third type of glass beads after the first section. All of these indicate that ropes formed from larger particles disperse more easily, for reasons perhaps related to their higher inertia. In addition, CFD-DEM analysis was employed to determine the particle characteristics to confirm this assumption. The numerical results indicated that the flow pattern has the highest axial velocity near the elbow to form the ‘horseshoe’ pattern. As the particles with lower Stokes Number were easier to follow the air flow, this is the reason why the horseshoe pattern of smaller particles was more obvious than larger particles.

Aim: Inhaled allergens from house dust mite (HDM) are a major source of allergic disease such as allergic rhinitis and asthma. It has been a challenge to properly evaluate health risks caused by HDM related allergens including mite bodies, eggs and fecal pellets. This paper presents a numerical study on particle deposition of dust mite allergens in a human nasal cavity. Materials and methods: A realistic nasal cavity model was reconstructed from CT scans and a Computational Fluid Dynamics analysis of steady airflow was simulated. The discrete phase model was used to trace particle trajectories of three dust mite related particles. Results: The flow and particle model were validated by comparing with nasal resistance measurement and previous literature respectively. Aerodynamic characteristics and deposition of dust mite allergens in the nasal cavity were analyzed under different breathing conditions including rest and exercising conditions. Conclusions: The numerical results revealed the roles of different nasal cavity regions in filtering various types of dust mite allergens with consideration of breathing conditions.

Particles encountered in nature and engineering practice are normally not spherical but of irregular shapes. Particle shape plays a key role in determining the behaviour of bulk solids, which poses a number of challenges in modelling and simulation of particulate systems. Discrete element method (DEM) has been recognized as a promising method to meet the challenges. This paper presents a review of the recent efforts in developing DEM approaches to model non-spherical particulate systems (NSPS) and strategies of coupling such a non-spherical DEM model with computational fluid dynamics (CFD) for particle-fluid flows. It mainly covers four important aspects: the techniques for representation of non-spherical particles and their contact detection, the models describing inter-particle collision dynamics and fluid-particle forces, CFD-DEM coupling methodologies including averaged volume method and immersed family methods and the applications of the developed theories to the modelling of different NSPS. The main findings are discussed and summarized as a part of the review. Finally, the needs for future development are highlighted.

This paper investigated the behaviour of agglomerate–agglomerate collision based on a combined computational fluid dynamics (CFD) and discrete element method (DEM) approach, aiming to develop better understanding of the underlying the mechanisms of loose drug agglomerates aerosolisation in DPIs. The collision between two mannitol agglomerates in a T-shape pipe was simulated. The effects of key variables such as agglomerate strength, air flow rate and collision angle were investigated. The aerosolisation performance was characterised with the size distribution of fragments and fine particle fraction (FPF) which was the mass fraction of the fragments with size less than 5 μm. The results showed that the collision between agglomerates has a significant effect on aerosolisation process. For a given agglomerate, there was a threshold velocity, above which would increase aerosolisation and otherwise would decrease. The analyses of airflow field and the agglomerate properties indicated that the aerosolisation performance was determined by two competitive factors, i.e. interparticle cohesion and total collision energy. An index to character of aerosolisation efficiency was provided based on the ratio of total collision energy and agglomerate strength. This index could be used to help design the high-dose DPI for the different drug agglomerates varied in strength.

Respimat&reg, Soft MistTM is a newly developed spray inhaler. Different from traditional nebulizers, metered-dose inhalers, and dry powder inhalers, this new type of inhaler can produce aerosols with long duration, relatively slow speed, and a high content of fine particles. Investigating the effect of the key geometric parameters of the device on the atomization is of great significance for generic product development and inhaler optimization. In this paper, a laser high-speed camera experimental platform is built, and important parameters such as the geometric pattern and particle size distribution of the Respimat&reg, Soft MistTM are measured. Computational fluid dynamics (CFD) and the volume of fluid method coupled with the Shear Stress Transport (SST) k-&omega, turbulence model are applied to simulate the key geometric parameters of the device. The effects of geometric parameters on the spray velocity distribution and geometric pattern are obtained. The angle of flow collision, the sphere size of the central divider and the length and width of the flow channel show significant impacts on the spray atomization.

Purpose. To use computational fluid dynamics (CFD) technology to fundamentally understand (1) the effect of surgical treatments on nasal physiology for secondary atrophic rhinitis and (2) the priority of operations. Subjects and Methods: With the aid of medical imaging and CFD modeling, three virtual operations (nasoseptal perforation repair, cavity narrowing, and a combination of both) were performed to analyze airflow, nasal resistance, and wall shear stress. Results. Compared with the cavity-narrowing virtual operation, nasal resistance was not significantly altered by septal perforation repair virtual operation. Airflow allocation changed with more air flowing through the olfactory area and less though the nasal floor after all operations, especially the cavity-narrowing operation. Wall shear stress at the original epistaxis area and the nasal floor was reduced after the cavity-narrowing operation. Conclusions. Simulation results suggest that the cavity-narrowing operation takes priority over septal perforation repair if a staged surgery approach is adopted. If only one operation can be chosen, the cavity-narrowing operation is better than the septal perforation repair. This work shows that CFD-based modeling may aid precision medicine.

The consequent lack of basic understanding of the cohesiveness of ash particles at high temperature is a major hindrance to advancing biomass combustion technology. This paper presents an investigation of the effect of temperature on tensile strength by a combined experimental and numerical method. Experimentally, tensile strength and fracture distance of palm residues combusted at 820 °C were measured as a function of temperature (25–800 °C). The results showed that the tensile strength is strongly dependent on temperature and the liquid bridge between particles may transform into partially solid bonds with increasing temperature. In numerical simulation by means of discrete element method (DEM), the cohesive force between particles was modelled using the so called Bonded Particle Model (BPM) and Capillary Force Model (CFM). The parameters of BMP and CFM models at different temperatures were determined by an empirical equation. Comparison with the existing test results showed that the model can reasonably describe the behaviour of biomass combustion ash under various temperatures. It was therefore confirmed that the proposed cohesive force model can be used in the DEM-based simulation of biomass ash deposition in the combustion devices, leading to better understand the phenomena of shedding and erosion in the future.

The Andersen cascade impactor (ACI) is a device designed to fractionate aerosols by their aerodynamic diameters. This work developed a computational fluid dynamics (CFD) model to investigate flow characteristics and particle deposition behaviour in an ACI. A novel Iterative Simulation (IS) modelling technique was adopted to map the flow information between the source and target zones of individual models, hence enabling the establishment of flow fields across the whole device as a single domain. Particle trajectories and deposition were evaluated using the Lagrangian tracking approach in conjunction with the application of a kinetic energy criterion ( KE c ). The model was validated by comparing the simulation results with literature and manufacturer's data. The effect of flow rate was evaluated by using the standard and high flow rates of 28.3 and 60 L min −1 . The results showed that operating the ACI at high flow rates reduced the impactor performance by magnifying the cross-flow interactions and recirculation vortices. The heavy wall losses observed at Stages 2 and 3 of the impactor were attributed to more pronounced recirculation vortices at these stages. Increasing particle deposits underneath Stages 0 and 1 around the central ring of jet outlets can be attributed to counter-current flows arising from the central holes in the plates. These conclusions have significant implications for the design and operation of the ACI.

Carrier-based dry powder inhalers (DPIs) are widely used for rapid and convenient delivery of drug to the site of action. This work aimed to predict powder aerosolisation in DPIs through numerical modelling. A multi-scale modelling technique based on the combined computational fluid dynamics (CFD) and discrete element method (DEM) approach was developed. The simulation results of the detachments of the drug particles from single carrier under different impact velocities and angles were comparable with those measured in the experiments in terms of fine particle fraction FPF loaded . Empirical equations were developed to link the detachment performance with impact velocity and impact angle. Then the dynamics of the carrier particles in Aerolizer® was simulated. The results indicated that the carrier-wall impaction was the dominant mechanism for drug aerosolisation performance. By linking the empirical equations with the carrier-wall impact energy, the predictions showed that for a given formulation mass with a fixed carrier/drug ratio, the inhaler performance decreased with carrier size and increased with air flow rate. Device empty efficiency, however, was independent with carrier size and flow rate. The multi-scale model was able to provide quantitative information to better understand the aerosolisation mechanisms of carrier-based formulation.

This paper elucidates the important role of numerical technique in investigating powder dispersion mechanisms in pharmaceutical dry powder inhalers, using the commercial Aerolizer® as a model inhaler device. A coupled computational fluid dynamics (CFD) and discrete element method (DEM) technique was adopted to simulate fluid flow and particles, respectively. The shear stress of turbulent flow had no visible effect on powder dispersion while the agglomerate–agglomerate interactions occurred only when the agglomerates were ejected from the capsule. Multiple major impactions occurred between the agglomerates and the chamber wall, which fragmented the agglomerates into large pieces without generating many fine particles. The subsequent impactions between the fragments with the grid were identified as the key factor for the dramatic increase in FPF (i.e. amount of fine particles below 5 μm in the aerosol). The inhaler was more efficient with increasing air flow rate in terms of the FPF, but its performance decreased at a higher flow of 130 Lmin− 1 due to much larger depositions (i.e. increased device retention). This work has demonstrated the capability of CFD-DEM modeling to study various dispersion mechanisms and their relative importance, which provides a rational basis for future improvement of inhaler devices.

The effect of mechanical impaction on the aerosol performance of pharmaceutical powders comprising smooth and rough-surfaced spherical particles was investigated. Bovine serum albumin (BSA) was chosen as a model drug and powders prepared using spray drying. Surface roughness and adhesion force properties of BSA were measured by atomic force microscopy. The aerosol performance of the powders was assessed by impaction using a customised throat model built with specific mitre joints (0, 15, 45 and 90°), coupled with a liquid impinger through a laser diffractometer. Results showed enhanced aerosol performance of BSA by mechanical impaction, with the effect increasing with the impaction angle and being more pronounced with corrugated BSA. This is attributed to the lower cohesion force between the corrugated particles, enabling them to de-agglomerate more readily on impaction. In conclusion, impaction causes significantly better deagglomeration in corrugated particles than smooth particles. A combination of mechanical impaction and rough surface will help maximise the aerosol performance of powders for inhalation drug delivery.

Previous studies have reported that carrier-drug mass ratio has a significant influence on the aerosol performance of dry powder inhalation systems. This paper investigated the effect of carrier-drug mass ratio in different inhaler designs based on a multi-scale modelling technique combined computational fluid dynamics (CFD) and discrete element method (DEM) approach, aiming to develop better understanding of the aerosolisation mechanism of carrier-based formulation . Different formulations containing drug (salbutamol sulphate) and carrier (lactose) were used in experimental and numerical works with varied carrier-drug mass ratios ranging from 1:10 to 1:200. The fine particle fractions (FPFs) in the original and cross grid inhaler-throat model were measured to characterize the aerosolisation performance. The dynamics of the carrier particles in the original and cross grid inhaler-throat model were simulated. The experimental results showed that the significant difference between the original and cross-grid design for the pure drug but not for the carrier system. The numerical results showed that there was no much different in FPFs until a critical threshold was exceeded when the drug loading increased.

The design of a dry powder inhaler device has significant influence on aerosol performance; however, such influence may be different between the drug-only and carrier-based formulations. The present study aims to examine the potential difference on the dispersion between these distinct types of formulations, using Aerolizer(®) as a model inhaler with the original or modified (cross-grid) designs. A coupled CFD-discrete element method analysis was employed to determine the flow characteristics and particle impaction. Micronized salbutamol sulphate as a drug-only formulation and three lactose carrier-based formulations with various drug-to-carrier weight ratios 1:5, 1:10 and 1:100 were used. The in vitro aerosolization performance was assessed by a next-generation impactor operating at 100 L/min. Using the original device, FPFloaded was reduced from 47.5 ± 3.8% for the drug-only formulation to 31.8 ± 0.7%, 32.1 ± 0.7% and 12.9 ± 1.0% for the 1:5, 1:10 and 1:100 formulations, respectively. With the cross-grid design, powder-mouthpiece impaction was increased, which caused not only powder deagglomeration but also significant drug retention (doubling or more) in the mouthpiece, and the net result is a significant decrease in FPFloaded to 36.8 ± 1.2%, 20.9 ± 2.6% and 21.9 ± 1.5% for the drug-only, 1:5 and 1:10 formulations, respectively. In contrast, the FPFloaded of the 1:100 formulation remained the same at 12.1 ± 1.3%, indicating the increased mouthpiece drug retention was compensated by increased drug detachment from carriers caused by increased powder-mouthpiece impaction. In conclusion, this study has elucidated different effects and the mechanism on the aerosolization of varied dry powder inhaler formulations due to the grid design.

We hypothesize that the USP induction port may de-agglomerate carrier-free powder emitting from dry powder inhalers (DPIs).Aerosols emitting from a range of DPIs (Spinhaler®, Turbuhaler® and Osmohaler™) and induction ports (USP throat, straight tube, Alberta idealized mouth-throat geometry (AG)) were sized by laser diffraction. Total drug recovery was obtained by HPLC and fine particle fraction computed. Air flow patterns were simulated using Computational Fluid Dynamics (CFD).The straight tube did not de-agglomerate emitted powder. However, the USP throat and AG further de-agglomerated powders from the Spinhaler, but not the Turbuhaler and Osmohaler. While budesonide powder deposited similarly in all induction ports, deposition was significantly higher in the AG for both DSCG and mannitol. CFD revealed agglomerates impacting on the USP throat with higher localized velocity compared with the straight tube. CFD further showed a more complex flow pattern with high-velocity air jets in the AG, which explains the higher FPF for DSCG and the lower FPF for mannitol using the AG.The USP throat further de-agglomerated the emitted powder from the DPI when it did not sufficiently disperse the powder. Other tools such as laser diffraction may be used for cross-examining to avoid artifacts in the results.

This paper numerically investigated the mechanisms of powder de-agglomeration on mechanical impaction, aiming to explain the experimental observations in our previous study ( Adi et al., 2010). A numerical model based on a coupled computational fluid dynamics (CFD) and discrete element method (DEM) approach was developed to simulate the dispersion of drug mannitol agglomerates in the customised impaction throats containing one or two angles with different flow rates. Information in terms of particlethroat and particle-fluid interactions, number of fragments, fine particle fraction (FPF) and powder deposition was monitored over the whole process and quantitatively analysed. The results indicated that the breakage of the agglomerate was mainly attributed to the mechanical impaction and less affected by the shear effect from the flow-particle interaction. While the first impaction caused the major damage to the agglomerate, the second impaction in fact generated more fine particles with size less than 5 mm, resulting much improved dispersion performance for the throats with two angles. Powder deposition, which is dependent on impaction velocity and angle and fragment size, was another important factor affecting the dispersion. The analysis of dispersion mechanisms indicated that de-agglomeration at different conditions can be characterised by the ratio of the particle-wall impaction energy and agglomerate strength.

This paper presents an investigation of powder dispersion based on a combined computational fluid dynamics (CFD) and discrete element method (DEM) approach. Agglomerates of different particle sizes and polydispersities are dispersed in a cyclonic flow at different flow velocities. The analysis of flow field and agglomerate properties indicates that the dispersion is governed by two competitive interactions, i.e. particle–particle cohesion and particle–wall impact, with the latter related to the air flow or the particle–fluid interaction. The internal shearing induced by air flow, however, only plays a minor role in powder dispersion for the system considered. The dispersion performance is described by fragment size distribution and fine particle fraction (FPF) which is the weight percentage of fragments with size less than 4.5m. Agglomerates of finer particles are more difficult to disperse at low flow rates due to strong particle–particle cohesion, but their dispersion becomes more efficient at high flow rates. Agglomerates with narrower particle size distributions tend to have better dispersion. An index based on the ratio of particle–wall impact energy and agglomerate cohesion energy is proposed to provide a quantitative characterization of dispersion performance.

This study aims to investigate the role of impact angles on the de-agglomeration performance of powders for inhalation. Agglomerates of a model drug mannitol were impacted at customized impaction throats containing two angles (15-75 degrees and 45-45 degrees) or a single angle (15 degrees, 45 degrees and 90 degrees) using various air flow rates. The mass fraction of fine particles5microm in the aerosol (FPF(Loaded)) was measured by a liquid impinger coupled to a laser diffractometer. Results showed that for the two-angle throats, there existed an optimal angle (45 degrees) and air flow (120lmin(-1)) for the FPF(Loaded), resulting from a balance between improved de-agglomeration and enhanced throat deposition with increasing air flow. When the throat contained two equal angles of 45 degrees , most powder deposition occurred at the first angle, indicating that the first angle was likely to cause major de-agglomeration, while the second angle might act as a facilitator for further break-up, but the deposition was minimum as the fragment sizes and velocity at the second impaction were smaller. This hypothesis was supported by further studies using single-angle throats and numerical simulation (DEM-CFD). These findings imply the potential importance of using angular design features for multiple impactions to improve DPI performance.

This paper presents a numerical study of the breakage of loose agglomerates based on the discrete element method. Agglomerates of fine mannitol particles were impacted with a target wall at different velocities and angles. It was observed that the agglomerates on impact experienced large plastic deformation before disintegrating into small fragments. The velocity field of the agglomerates showed a clear shear zone during the impacts. The final breakage pattern was characterised by the damage ratio of agglomerates and the size distribution of fragments. While increasing impact velocity improves agglomerate breakage, a 45-degree impact angle provides the maximum breakage for a given velocity. The analysis of impact energy exerted from the wall indicated that impact energy in both normal and tangential directions should be considered to characterise the effects of impact velocity and angle.

The US pharmacopeia (USP) and Alberta throats were recently reported to cause further de-agglomeration of carrier-free powders emitted from some dry powder inhalers (DPIs). This study assessed if they have similar influences on commercially available carrier-based DPIs. A straight tube, a USP throat, and an Alberta throat (non-coated and coated) were used for cascade impaction testing. Aerosol fine particle fraction (FPF ≤ 5 μm) was computed to evaluate throat-induced de-agglomeration. Computational fluid dynamics are employed to simulate airflow patterns and particle trajectories inside the USP and Alberta throats. For all tested products, no significant differences in the in vitro aerosol performance were observed between the USP throat and the straight tube. Using fine lactose carriers (10 μm), Symbicort(®) and Oxis(™) showed minimal impaction inside the Alberta throat and resulted in similar FPF among all induction ports. For products using coarse lactose carriers (10 μm), impaction frequency and energy inside the Alberta throat were significant. Further de-agglomeration was noted inside the non-coated Alberta throat for Seretide(®) and Spiriva(®), but agglomerates emitted from Relenza(®), Ventolin(®), and Foradil(®) did not further break up into smaller fractions. The coated Alberta throat considerably reduced the FPF values of these products due to the high throat retention, but they generally agreed better with the in vivo data. In conclusion, depending on the powder formulation (including carrier particle size), the inhaler, and the induction port, further de-agglomeration could happen ex-inhaler and create differences in the in vitro measurements.

The performance of a dry powder inhaler (DPI) depends on powder properties as well as the air and particle flows in the device. The main principle of powder dispersion is to overcome the inter-particle cohesion using various dispersion/ de-agglomeration forces. While different dispersion mechanisms have been identified, their relative importance under different conditions is less clear. The lack of understanding of these mechanisms is a major obstacle to the advance of pharmaceutical powder aerosol technology. This paper briefly reviews our recent effort in developing a combined computational fluid dynamics (CFD) and discrete element method (DEM) approach to gain such pivotal information. Dispersions under various specifically designed conditions were simulated to exam the role of individual dispersion mechanism. The air and particle flows were analysed at the particle scale and linked to dispersion performance characterised by fine particle fraction (FPF). In addition, the dispersion mechanisms of both drug only and carrier based formulations in a commercial inhaler were studied. Our work shows that the approach has the potential to develop a theoretical framework for designing new DPIs.

This study applied computational fluid dynamics (CFD) analysis to investigate the role of device design on the aerosolization of a carrier-based dry powder inhaler (DPI). The inhaler device was modified by reducing the inlet size, decreasing the mouthpiece length and increasing the mesh grid voidage. The flow patterns in the inhaler device were examined. It was observed that there was no significant influence on the aerosol performance with the reduced mouthpiece. When the inlet size was reduced to one third of the original one, the fine particle fraction (FPF), defined as mount of inhalable fine particles below 5μm in the aerosol, was improved significantly from 17.7% to 24.3%. The CFD analysis indicated that the increase in FPF was due to increasing air velocity for the smaller inlet. No significant difference was shown in FPF when the grid voidage was increased, but more drugs deposited in the mouthpiece and throat.

The objective of this study is to investigate the effect of device design of the Aerolizer(®) on the aerosolization of a carrier-based dry powder inhaler formulation (Foradile(®)). The Aerolizer was modified by reducing the air inlet size and mouthpiece length to 1/3 of the original dimensions, or by increasing the grid voidage. Aerosolization of the powder formulation was assessed on a multi-stage liquid impinger at air flow rates of 30, 60, and 100 L/min. Coupled CFD-DEM simulations were performed to investigate the air flow pattern and particle impaction. There was no significant difference in the aerosolization behavior between the original and 1/3 mouthpiece length devices. Significant increases in FPF total and FPF emitted were demonstrated when the inlet size was reduced, and the results were explained by the increases in air velocity and turbulence from the CFD analysis. No significant differences were shown in FPF total and FPF emitted when the grid voidage was increased, but more drugs were found to deposit in induction port and to a lesser extent, the mouthpiece. This was supported by the CFD-DEM analysis which showed the particle-device collisions mainly occurred in the inhaler chamber, and the cross-grid design increased the particle-device collisions on both mouthpiece and induction port. The air inlet size and grid structure of the Aerolizer(®) were found to impact significantly on the aerosolization of the carrier-based powder.