Optimizing the primary particle size distributions of pressurized metered dose inhalers by using inkjet spray drying for targeting desired regions of the lungs

Conventional suspension pressurized metered dose inhalers (pMDIs) suffer not only from delivering small amounts of a drug to the lungs, but also the inhaled dose scatters all over the lung regions. This results in much less of the desired dose being delivered to regions of the lungs. This study aimed to improve the aerosol performance of suspension pMDIs by producing primary particles with narrow size distributions. Inkjet spray drying was used to produce respirable particles of salbutamol sulfate. The Next Generation Impactor (NGI) was used to determine the aerosol particle size distribution and fine particle fraction (FPF). Furthermore, oropharyngeal models were used with the NGI to compare the aerosol performances of a pMDI with monodisperse primary particles and a conventional pMDI. Monodisperse primary particles in pMDIs showed significantly narrower aerosol particle size distributions than pMDIs containing polydisperse primary particles. Monodisperse pMDIs showed aerosol deposition on a single stage of the NGI as high as 41.75?±?5.76%, while this was 29.37?±?6.79% for a polydisperse pMDI. Narrow size distribution was crucial to achieve a high FPF (49.31?±?8.16%) for primary particles greater than 2?µm. Only small polydisperse primary particles with sizes such as 0.65?±?0.28?µm achieved a high FPF with (68.94?±?6.22%) or without (53.95?±?4.59%) a spacer. Oropharyngeal models also indicated a narrower aerosol particle size distribution for a pMDI containing monodisperse primary particles compared to a conventional pMDI. It is concluded that, pMDIs formulated with monodisperse primary particles show higher FPFs that may target desired regions of the lungs more effectively than polydisperse pMDIs.     

The thermophoretic capture of large volatile aerosol particles by growing or evaporating droplets in multicomponent gas mixtures

The motion of large two-component volatile aerosol particles in a three-component gas mixture containing droplets is considered, which is caused by optical radiation. An expression is derived for the rate of deposition of aerosol particles onto the droplet surface. Analysis is made of the conditions in which the aerosol particles either deposit on the droplet surface or scatter. Numerical estimates are given for antimony-bismuth aerosol particles.     

PENETRATION OF POLYDISPERSE AEROSOLS THROUGH SCREEN DIFFUSION BATTERY

As an alternative data reduction scheme for diffusion battery measurements, penetration of polydisperse aerosol particles in a screen type diffusion battery has been calculated employing Brownian diffusion and interception as the applicable deposition mechanisms. The influences of the mean particle size and the geometric standard deviation of the aerosol on penetrations of the total particle number, radius, surface area, and the total particle volume have been examined. It is quantitatively shown that depending upon the type of aerosol instrument in use as a particle counting means and depending upon the size distribution of the measured aerosols, penetration characteristics can become markedly different. For a highly dispersed aerosol having a small mean particle size, the total radius, the surface area and the total volume of aerosol particles are shown to penetrate a diffusion battery more slowly in that order than the total number of particles. However, when the mean size of the aerosol increases, such a monotomic increase in penetration becomes no longer valid due to increasing importance of the interceptional deposition. Experimental measurements have been performed to demonstrate applications of the calculated results.     

Aerosol particle deposition and distribution in bifurcating ventilation ducts

The quantitative information gained from detailed studies of particle deposition in ducts is important, for example, to evaluate human exposure to particles within buildings, implement cleaning strategies for ventilation ducts and also understand particulate deposition in the respiratory tree. For this purpose, an experimental study for aerosol particles of diameters ranging from 8.1 to 23.2 microm was conducted in a curved bifurcating ventilation duct. At the bend segment of the duct, the particle size, bend angle, curvature ratio and Reynolds number affect aerosol deposition significantly. On the other hand, tests conducted on the bifurcating segments show that deposition increases with particle size and Reynolds number. Accumulation of particles occurs mainly around the bend segment and the ridge of carina of the bifurcation. In all segments of the duct models, particle deposition is found to be enhanced with increasing humidity which increases from 66 to 95% (i.e., close the saturation). A physical interpretation of the results obtained is also presented.     

Deposition of aerosol particles in vertical channels from an isotropic turbulent flow

Equations for the rate of turbulent deposition of aerosol particles in vertical tubes are suggested. It is noted that the rate of deposition of particles is determined by the gravitation component and turbulent diffusion. The thickness of the layer of depositions and its influence on the basic characteristics of a turbulent flow are determined. The results obtained are compared with available experimental values of the rate of deposition of particles in vertical tubes.     

Deposition of aerosol particles in a model vitreous chamber

The purpose of this study was to assess quantitatively the aerosol deposition in a model eye chamber to identify the mechanism(s) of deposition and delivery efficiency for application in retinal disease treated with vitrectomy. Dry aerosol particles were produced with mixtures of fluorescein and a variable concentration of cesium chloride, which ranged in aerodynamic size from 0.6 to 1.3 μm. The aerosol was injected through a small inlet tube into Teflon chambers that had a vented, spherical cavity (diameter ?"). Two filling times of 60 s and 90 s were used. Although significant loss occurred in the syringe, the mass deposited within the chambers increased with aerosol concentration and ranged from 0.5 to nearly 15 μg. Between 60 and 90% of the mass was deposited on the lower surface of the chamber. The mechanism of deposition was consistent with diffusion through a boundary layer during filling followed by sedimentation of the remaining suspended aerosol particles. Based on these results, an aerosol with a median particle size of 1.3 μm was shown to provide a therapeutically effective dose of 5-fluorouracil. The approach is general and can be applied to the aerosol delivery of other drugs to the vitreous chamber.     

A NEW APPROACH TO HYDRODYNAMIC INTERACTIONS IN POLYDISPERSE SUSPENSIONS

A general approach is presented for the computation of hydro dynamic interactions between spheres of disparate sizes in a polydisperse suspension of rigid spheres in a Newtonian solvent. The theory applies when the particle-based Reynolds number is small ( usually valid for colloidal suspensions ). The cornerstone of the method consists of a new class of image solutions for singularities near a rigid sphere. The new approach facilitates analytical [ see equations (12) and (13)] and numerical computations as well as physical interpretation of the velocity fields induced by the particles. The applications in particle aggregation and aerosol deposition are discussed. In addition, the solution methodology can be extended to more general situations, such as interactions between viscous drops.     

Chemical Deposition on Aerosol Particles

Problems on the growth of aerosol particles in chemical deposition with allowance for the influence of a buffer (impurity) gas have been investigated theoretically.     

Cathodic electrophoretic deposition of barium titanate films from aqueous solution

Cathodic electrophoretic deposition (EPD) of barium titanate from aqueous suspensions was performed on nickel substrate. Cathodic deposition allows preparation of thin layers from aqueous solution on base metal electrodes, such as Ni or Cu, without creating an intermediate oxide layer during the deposition. This opens the opportunity to prepare complex shapes of dielectric layers onto base metals for co-firing, using relatively cheap and environmentally benign aqueous EPD. Stable barium titanate colloidal suspension with a concentration of 10 g/100 mL at pH of 9.2 has been prepared for the deposition. The characteristics of electrophoretic deposition of those positively charged particles onto cathode were investigated. A uniform and dense layer was obtained for films deposited at 3 V for 2 min. The calculated film thickness for the sintered layer at these conditions was ∼1 μm. The morphology can be controlled, and in particular the pore size and distribution can be controlled via the applied voltage. At low voltage a uniform layer can be obtained whereas at high voltage a large number of macropores appears in the deposit and their size increase with the increasing of the voltage due to gas bubble formation.     

The electrical and optical properties of thin layers of nano-sized antimony doped tinoxide particles

For the use in anti-static films on glass or polymeric substrates, transparent conductive layers can be prepared by spinning an aqueous suspension of nano-sized antimony-doped tinoxide (ATO) particles. These layers have a resistivity which is substantially higher than that of homogeneous ATO layers which are deposited by physical vapour deposition techniques. By curing the films to temperatures up to 700 °C, the resistivity of the particle layer can be decreased by two or three decades. Because the nano-sized particles are prepared by a low-temperature process a different mechanism can contribute to this decrease in resistivity. Possible effects which may influence the conductivity are sintering of the particles, change of the bulk material and the presence of an insulating layer at the outside of the particles. This decrease can be explained by the presence of an insulating antimony-rich layer on the outside of the particles, the thickness of which is reduced when the layer is cured. At temperatures above 350 °C, sintering of the particles also highly influences the decrease in resistivity. At temperatures above 700 °C, the resistivity is increased due to segregation of the antimony to the surface of the particle.     

Electrophoretic deposition of ZnO nanoparticles, from micropatterns to substrate coverage

We report on an electrophoretic deposition (EPD) method that is suited for the preparation of both ZnO thin films and micropatterns. By applying small DC voltages between a Cu electrode and a conductive Si substrate, submersed in a suspension of ZnO quantum dots, we can cover entire substrates with ZnO layers of a tuneable thickness ranging from a few monolayers to 200?nm. The deposition occurs selectively at the cathode, which indicates that the ZnO particles have a positive charge. Atomic force microscopy was used to study the influence of the deposition voltage, time, and the quantum dot concentration on the final layer thickness. By using lithographically patterned Si substrates, the same technique enables the formation of ZnO micropatterns of variable thickness with dimensions down to 5?μm. This is done by depositing a ZnO layer on a Si substrate that is covered with a patterned, developed photoresist. After EPD, the resist is removed by submersing the substrate in the appropriate solvent without damaging the ZnO deposit. This illustrates the robustness of the layers obtained by EPD.     

Numerical simulation of multilayer deposition in an obstructed channel flow

Simulation of multilayer deposition of dry aerosol particles in turbulent flows has gained a growing interest in various industrial and research applications. The multilayer deposition of carbonaceous aerosol particles in a turbulent channel flow obstructed by a succession of square ribs is here numerically investigated. The multilayer particle bed growth on the various wall surfaces affects the air flow, which in turn affects the overall deposition rate. An iterative numerical procedure is therefore suggested to simulate the evolution of the graphite layer. The iterative process used to reproduce the layer build-up is decomposed as follows: Reynolds-Avergared Navier Stokes is employed to generate the flow field. The turbulent dispersion of the particles is reproduced through the use of a continuous random walk model. After statistically sufficient deposition of particulate matter, the layer build-up is computed using mechanics of dry granular material. The layer build-up model shows good agreement with data obtained from experimental tests carried out on-site.     

Electrophoretic deposition of alumina on stainless steel from non-aqueous suspension

Electrophoretic deposition of alumina on stainless steel has been investigated. The influence of different organic media and deposition parameters such as solid concentration, applied voltage and time of deposition on deposit yield has been evaluated. Maximum deposit yield was obtained for solvent media that imparts highest magnitude of surface charge on alumina in suspension. The deposit yield increased linearly with concentration of alumina powder in suspension, and applied voltage following Hamakers law. A similar linearity in yield was observed at short deposition times, but a deviation in linearity was observed at higher time of deposition, which is attributed to the shielding effect of the deposited layers and accumulation of ions at the electrode, and depletion of powder in the suspension with progress in deposition.     

Methodology for selection of charging agents for electrophoretic deposition of ceramic particles

The zeta potential of particles is a key factor in the electrophoretic deposition process. It plays a role in the stabilization of the suspension by determining the intensity of repulsive interactions as well as in determining the direction and velocity of particle migration.The zeta potential can be controlled by addition of charging agents such as acids, bases, and specifically adsorbed ions or polyelectrolytes, to the suspension. Thus there exist a variety of additives that affect the charge magnitude and its polarity. These additives act by different mechanisms.The main criteria for the selection of a charging agent are the preferred polarity and deposition rate of the particles. While the deposition rate is directly dependent on the zeta potential, which is determined by the charging additive, the influence of such an additive is exerted also by its effect on the ionic conductivity of the suspension. The latter determines the potential drop in the bulk of the suspension, which constitutes the driving force for the transfer of the particles to the electrodes.The present work will describe the methodology developed at Cerel for the selection of a charging agent based on its effect on the zeta potential/pH curve, on the isoelectric point and on the ionic conductivity of the suspension.     

Characterization of soft magnetic nano-material deposited with M<Superscript>3</Superscript>D technology

Direct Write Technologies are being utilized in antennas, engineered structures, sensors, and tissue engineering. One form of Direct Write Technology is Maskless Mesoscale Material Deposition (M³D). The M³D process is a process that uses aerosol formation, transport and deposition. Inks for the M³D process utilize nano-particles in suspension for deposition. Soft magnetic material was formulated as an ink suspension, deposited and characterized. This paper will report on the results obtained after depositing the soft magnetic material. The results of the permeability are calculated from magnetic structures created with the deposition. These results are compared to conventional methods of soft magnetic material formation and construction.     

Non-steady-state aerosol filtration in nanostructured fibrous media

The filtration of aerosol particles using composites of nano- and microsized fibrous structures is a promising method for the effective separation of nanoparticles from gases. A multi-scale physical system describing the flow pattern and particle deposition at a non-steady-state condition requires an advanced method of modelling. The combination of lattice Boltzmann and Brownian dynamics was used for analysis of the particle deposition pattern in a fibrous system. The dendritic structures of deposits for neutral and charged fibres and particles are present. The efficiency of deposition, deposit morphology, porosity and fractal dimension were calculated for a selected operational condition of the process.     

Influence of Surface Phenomena on the Growth of Aerosol Particles in a Buffer (Admixture) Gas

The influence of a buffer (admixture) gas on the deposition of molecules of a vapor on particles of an aerosol system is investigated.     

Solution-based aerosol deposition process for synthesis of multilayer structures

In this paper, we report the progress on 3D aerosol deposition of barium titanate (BTO) based multilayer ceramic capacitors (MLCC) using an automated process. Solution-based aerosol deposition is a promising direct-write method to produce three-dimensional (3D) structures at low temperatures. We utilize the combination of solution-based aerosol process and selective laser sintering (SLS) to develop 3D structures. The MLCC structure was synthesized on silicon substrate consisting of alternate layers of 0.5-1.0 μm thick silver electrode layer and 0.5-2 μm thick BTO ceramic. The effect of incident laser power subsequent to deposition (in the range of 105 mW and 930 mW) was systematically investigated revealing the changes in grain morphology as a function of local sintering. The results of this study are promising for development of on-substrate thin/thick film MLCCs.     

Effect of particle spatial distribution on particle deposition in ventilation rooms

We used simulations and experimental tests to investigate indoor particle deposition during four commonly used ventilation modes, including ceiling supply, side-up supply, side-down supply and bottom supply. We used a condensation monodisperse aerosol generator to generate fine diethylhexyl sebacate (DEHS) particles of different sizes along with two optical particle counters that measured particle concentration at the exhaust opening and inside a three-dimensional ventilated test room. We then simulated particle deposition using the same ventilation modes with computational fluid dynamics (CFD) method. Our simulated results indicate that mean deposition velocity/rate for particles 0.5–10 μm (aerodynamic diameter) is not affected by different ventilation modes. However, both our experimental and simulated results indicate that the deposition loss factor, a parameter defined based on mass balance principle to reflect the influence of particle distribution on deposited particle quantity, differ significantly by ventilation mode. This indicates that ventilation plays an important role in determining particle deposition due to the apparent differences in the spatial distribution of particles. The particle loss factor during ventilation modes characterized by upward air flow in the room is smaller than that of mixing ventilation; however this trend was strongly influenced by the relative location of the inlets, outlets and aerosol source.     

A computational approach to understand the breathing dynamics and pharmaceutical aerosol transport in a realistic airways

Targeted drug delivery is an advanced method discussed in the literature for optimized treatment of diseases. However, the data for a precise understanding of pharmaceutical aerosol transport to the desired positions in the airways is not sufficient in the literature. Hence, in this work the transport and deposition of particles have been studied numerically in a realistic model of the respiratory system. The model was reconstructed based on CT-scan images of a healthy 28-year-old male and the commercial code ANSYS Fluent was used for analysis. After validation, distribution and deposition patterns of particles have been presented along with analysis of flow field dynamics. It was found that majority of particles enter the right lung while deposition is higher in the left lung and that the left lower lobe, left upper lobe and right lower lobe have the highest rate of lobar deposition. It was also observed that inertial impaction plays the dominant role in deposition of larger diameter particles at higher flow rates at the upper airways. The present findings improve our insight toward regional distribution and deposition of particles and assists in more accurate prediction of particle transport for drug delivery.