Particle MMAD

The vapor pressure and the design of the canister nozzle determine the aerosol jet and eventually impaction. Low vapor pressure increases drng delivery from a particular spacer due to a reduced jet and therefore rednced impaction. Airomir salbutamol pMDl containing HFA propellant delivered less drug as fine particles (MMAD < 5 pm) compared with the Ventolin salbutamol pMDI containing chloroflnorocarbon (CFC) propellant but a higher output from a spacer, probably due to a lower jet velocity (29). 

Panicles entrained in the airstream deposit along the airway as a function of size, density, airstream velocity, and breathing frequency. Sizes of rougjily spherical or irregularly shaped particles arc commonly characterized by relating the settling velociiy of the particle to that of an idealized spherical particle. For example, an irregular particle which settles at the same rate as a 5 pm spherical particle has a mean mass aerodynamic diameter (MMAD) of. 5 pm. Since spherical particle mass, is a function of particle diameter, J... 

Finer particles ( < 3 pm), termed respirable particles, pass beyond the ex-trathoracic airways and enter the tracheobronchial tree. Impaction plays a significant role near the tracheal jet, but sedimentation predominates as the effects of rapid conduit expansion dampen in the distal trachea and beyond. Sedimentation occurs when gravitational forces exerted on a particle equal drag forces, i.e., when particle velocity falls to u . As mean inspiratory air-stream velocity gradually declines along the tracheobronchial tree, particle momentum diminishes and 0.5-3 pm MMAD particles settle out of the airflow and onto mucosal surfaces. 

Mean airflow velocities approach zero as the inspired airstream enters the lung parenchyma, so particle momentum also approaches zero. Most of the particles reaching the parenchyma, however, are extremely fine (< 0.5 pm MMAD), and particle buoyancy counteracts gravitational forces. Temperature gradients do not exist between the airstream and airway wall because the inspired airstream has been warmed to body temperature and fully saturated before reaching the parenchyma. Consequently, diffusion driven by Brownian motion is the only deposition mechanism remaining for airborne particles. Diffusivity, can be described under these conditions by... 

FIGURE 5.28 Estimated overall airway deposition as a function of initial particle size and particle hygroscopicity for particles with mass median aerodynamic diameters (MMAD) between 0.1 and 10 p.m. ° Geometric dispersion, a measure of particle size distribution, principally affects only smaller MMAD,... 

Hygroscopic Particle Deposition Determined by Initial MMAD... 

Published results on the concentration and size distribution of small particles in mainstream smoke vary widely, with concentrations ranging from 107 to 1011 cm-3 and with NMAD (number median aerodynamic diameter) ranging from 0.2 to 0.7 fim (Ishizu et a/., 1978). The MMAD (mass median aerodynamic diameter) of undiluted mainstream smoke particles ranges between 0.93 and 1.00 finl (Langer and Fisher, 1956 Holmes et a/., 1959). Lower values of the MMAD for diluted mainstream smoke, which decreased with degree of dilution, are reported by Hinds (1978). However, the particle size distributions for mainstream smoke appear to have little relevance to its retention and distribution in the lung, for reasons discussed below. Note that the concentration of tars in mainstream smoke is about 1,000 times that of air in smoke-filled rooms. 

None of the pharmacopeias state any requirements for particle size. However, the particle size specifications set should be appropriate for the intended use of the product. For example, if the particles are intended to reach the deep lung, the MMAD of particles exiting the device should be less than 5 xm. In general, the smaller the aerosol MMAD, the greater the deposition in the lung. 

Both from deposition studies and force balances it can be derived that the optimum (aerodynamic) particle size lies between 0.5 and 7.5 pm. Within this approximate range many different subranges have been presented as most favourable, e.g. 0.1 to 5 pm [24], 0.5 to 8.0 pm [25], 2 to 7 pm [26] and 1-5 pm [27-29]. Particles of 7.5 pm and larger mainly deposit in the oropharynx [30] whereas most particles smaller than 0.5 pm are exhaled again [31]. All inhalation systems for drug delivery to the respiratory tract produce polydisperse aerosols which can be characterized by their mass median aerodynamic diameter (MMAD) and geometric standard deviation (oq). The MMAD is the particle diameter at 50% of the cumulative mass curve. 

The model has been used to predict the sampling efficiency of the VE for a wide range of MMAD and GSD values typical of what might be encountered in cotton textile processing. These parameter values are for the actual size distribution of particles in the sampled air, and not for those collected on the membrane filter. These results are summarized in Table II. A remarkable feature of this model is that it predicts that the VE will collect significant amounts of particles with aerodynamic diameters greater than 30 pm. 

Several groups have investigated the effect of surfactants on emitted droplet size. In the early work performed by Polli et al., the surfactant sorbitan trioleate decreased the MM AD of the CFC dexamethasone suspension when added to the formulation (52). A suspension of terbutaline in a CFC system containing sorbitan trioleate surfactant was shown to have little change in emitted particle size when either 2.8 or 14mg/mL of surfactant was added (53). Interestingly, the surfactant had a significant effect on the obscuration (droplet concentration) of the laser diffraction instrument used to determine particle size. Surfactants may lead to an increase in MMAD due to decreased evaporation rates from aerosol droplets. This may occur because of their tendency to associate at the air liquid interface (54). 

Minimal data are available from typical inhalation studies in laboratory animals to allow evaluation of extent or dose-dependency in inhaled arsenic absorption. Beck, Slayton and Farr (2002) reported a study in which rabbits were exposed to 0.05, 0.1, 0.22, or 1.1 mg m-3 of arsenic trioxide 8 hours/day, seven days/week for eight weeks. The particle size (mass median aerodynamic diameter, MMAD) ranged from 3.2 to 4.1pm. On the basis of minimal elevation of inorganic arsenic in plasma until exposure levels were at or above 0.22 mg m-3, the authors concluded that systemic uptake of arsenic trioxide following inhalation exposure was low and did not contribute significantly to body burden until relatively high levels of exposure were achieved. 

Can failures occur from time to time. The release of fission products from them depends on the temperature and type of fuel. If the fuel is uranium metal, as in the Windscale and Magnox reactors, and the can fails, the uranium will oxidise in air or C02. In laboratory experiments, the mass median aerodynamic equivalent diameter (MMAD) of the particles produced by oxidation of uranium increased from about 40 ptm when the temperature of oxidation was 600°C to 500 jum at 1000°C (Megaw et al., 1961). At high temperature, a coherent sintered oxide layer formed on the uranium and this hindered the formation of particles. 

Aerosol particles deposit in the lung by three principal mechanisms inertial impaction gravitational sedimentation and Brownian diffusion. Particles with a larger MMAD are deposited by the first two mechanisms, while smaller particles access the peripheral region of the lung by diffusion. 

II). When fine (MMAD <2 pm), wet particles were collected downstream of a Venturi wet scrubber, the impactor and filter data typically agreed to within 20% which was well within the uncertainty of the comparison. We concluded, therefore, that wall losses were lower for small, wet particles than for larger, dry fly-ash particles. 

The MMAD and GSD of aerosols are therefore critical factors in determining the deposition patterns within the lung. Aerosols with larger MMADs will deposit higher in the respiratory tract since the aerosol particles will have greater momentum. A polydisperse aerosol is also likely to show greater deposition in the TB region than a monodisperse aerosol of the same MMAD. 

Aqueous and ethanolic formulations have been employed with the Respimat and the in vitro aerosol performance determined. Zierenberg (1999) reported fine-particle fractions of 66% for an aqueous fenoterol formulation and 81% for an ethanolic flunisolide formulation. The respective MMADs were 2.0 0.4 pm for the aqueous formulation and 1.0 0.3 pm for the ethanolic formulation [284],... 

Aerosol properties, such as particle size distribution, aerosol velocity, and hygroscopicity, affect aerosol deposition in the human lungs. Aerosol size distribution, including mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD), is one of the most important variables in governing the site of droplet or particle deposition in the lungs. ... 

Fig. 15 shows the drug mass recovered from the various stages of the impactor and device at a nominal drug dose of 75 pg per actuation. The amount of drug deposited on each stage was used to calculate the MMAD and GSD. The calculated MMAD was 2.85 pm with a GSD of 1.6. The fine particle fraction (FPF) of the aerosol was 90% (<5.8 pm) of the emitted dose, and 95% (<5.8 pm) of the dose distal to the USP throat. 

Fig. 1 Transmission (top row) and emission images for the same subject studies with small aerosols (MMAD 3.2 0.2 pm, span 1.8-middle row) and large aerosols (MMAD 6.5 0.2 pm, span 1.7-bottom row). The first three columns are selected coronal slices from the first 2 minute frame of the SPECT study, while the last column represents the corresponding planar images generated from the same SPECT study frame. SPECT PI values were 0.40 and 0.33 for the small and large particle sizes, respectively. Planar PI values were 0.47 and 0.43, respectively, for the small and large particle sizes.

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