Aerodynamic diameter, inhaled particles

The fate of an orally inhaled particle is strongly dependent on its aerodynamic diameter. Generally, particles larger than ca. 5 pm will inertially impact the mouth or throat, and be swallowed. Particles in the range of ca. 3-5 pm in diameter will reach the upper or conducting airways of the lung and can deposit on the smooth muscle of these structures. Particles of approximately 1-3pm may follow the airstream all the way to the alveoli and be deposited, and particles less than about 1 pm may be exhaled. Thus, careful control of the particle size distribution of medical aerosols is essential for effective drug delivery. 

Figure 1 Particle retention in the lungs after a bolus inhalation of iron oxide particles of 3.5-pm-aerodynamic diameter Inhalation started from functional residual capacity, tidal volume 600 cm, volumetric lung depth of the aerosol bolus, VL = 50 mL.

Inhalable fraction Particles with aerodynamic diameters up to 10 xm, which can enter the lungs. 

Fig. 1. Deposition of inhaled particles of different sizes (mass median aerodynamic diameters) in the three regions of the respiratory tract. Each shaded area indicates the variability of deposition when the aerosol distribution parameter, o, (geometric standard deviation) was varied from 1.2 to 4.5. The assumed tidal volume was 1450 cm3. (Reproduced from Health Physics, vol. 12, pp. 173-207,1966 by permission of the Health Physics Society).

A role for iron has been suggested in pathological effects derived from reactive oxygen following the inhalation of other particulate matter in the atmosphere. As with asbestos, the size of the particles is especially important, and particles with an aerodynamic diameter of less than 10 pm have been associated with increased mortality and morbidity. 

Studies have shown that in order to clear the oropharyngeal impaction barrier (comprising the mouth, throat, and pharynx), particles with aerodynamic diameters smaller than 5 pm are required [3,4]. Only particles with aerodynamic diameters less than 3 pm reach the terminal bronchi and the alveoli in significant numbers [5]. Therefore, the particle diameter required to be produced by the delivery system depends to a great extent on the intended target lung tissue. Lung deposition is also affected substantially by the specific inhalation dynamics of the patient, which in turn are influenced by the delivery device. This article addresses various attributes of the dry powder inhalation product, from intrinsic material properties to final product performance. 

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. 

As described in Section 3.3 in more detah, particles in the aerosol cloud should preferably have an aerodynamic diameter between 0.5 and 7.5 pm. Currently three different types of devices are used to generate aerosol clouds for inhalation nebulizers (jet or ultrasonic), (pressurized) metered dose inhalers (pMDIs) and dry powder inhalers (DPIs). The basic function of these three completely different devices is to generate a drug-containing aerosol cloud that contains the highest possible fraction of particles in the desired size range. 

Indicates the presence of inhalable and respirable particles. As a rough guide, particles with aerodynamic diameters below 100 p,m have the potential to be inhaled. Particles with aerodynamic diameters of above 1—5 p,m have the greatest probability of settling in the nasopharyngeal region whereas particles with aerodynamic diameters below 1-5 p,m are most likely to settle in the tracheobronchial or pulmonary regions, i.e., are respirable. 

In an attempt to increase the amount of particles retained in the lungs, large porous particles with low density (p < 0.1 g/cm2) have been designed (Edwards et al. 1997). The particles were composed of 50% lactide and 50% glycolide. Porous and nonporous particles loaded with testosterone were aerosolized into a cascade impactor system from a dry powder inhaler (DPI) and the respirable fraction was measured. Nonporous particles (d = 3.5 pm, p = 0.8 g/cm3) exhibited a respirable fraction of 20.5 3.5%, whereas 50 + 10% of porous particles (d = 8.5 pm, p = 0.1 g/cm3) were respirable, even though the aerodynamic diameter of the two particle types were nearly identical. Porous particles as a consequence of their large size and low mass density can... 

A study in dogs indicates that absorption of inhaled metallic silver particles with a median aerodynamic diameter of approximately 0.5 pm is extensive, and is not dependent upon particle size (Phalen and Morrow 1973). Absorption was measured in one dog that remained anesthetized during the entire period between exposure and sacrifice. In this dog, 3.1% (0.8 pg) of the deposited material was dissolved, transported out of the lungs, and was found mostly in liver and blood 6 hours after exposure a 1 pg/cm /day absorption rate for metallic silver was estimated by the authors. Up to 90% of the deposited silver was estimated to be absorbed into the systemic circulation based on all experimental data. Clearance from the lung to the blood was triphasic, with half-lives of 1.7, 8.4, and 40 days. 

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. 

A recent application of particle formation by solvent evaporation and spray-drying techniques is based on the concept of the aerodynamic diameter. According to Eq. (8.5), the aerodynamic diameter dAer is correlated with the true particle diameter dP and the particle density pp° 5. It is evident that particles formed in a particle-formation process can be much bigger, provided that their density is very small. Increased bioavailability of such large porous insulin particles (Fig. 8.14) has been demonstrated on inhalation by rats and has been correlated with a... 

An additional form of air-conditioning is concerned with the removal of particulates, such as dust, microorganisms and allergens, from the inspired air. The large cross-sectional area of the nasal cavity and relatively low air velocities are ideal for particle deposition, as is the turbulence caused beyond constrictions where changes in air flow direction occur. The efficiency of particle removal from the air-stream is dependent on a number of factors including the aerodynamic diameter of the inhaled particles ... 

Typically, uranium is present in limited eoneentrations in the air, and uranium partiele inhalation is minimal (ATSDR, 1999 Harley et al, 1999). Uranium particle deposition in the respiratory traet is governed by the physical forces that effeet partiele behavior in the air, as well as the anatomy of the respiratory traet (ATSDR, 1999 Bleise et al, 2003 Phalen and Oldham, 2006). The anatomy of the lungs is important as this affects the clearance mechanisms available to deal with deposited particles, and the degree of actual uranium absorption that will occur. In addition to the aerodynamic diameter (AD) of the particle, the solubility of the inhaled uranium is an important determinant as to how much uranium will be absorbed (Eidson, 1994 Lang et al, 1994). 

The penetration of inhaled particles in human airways depends on their size. As defined by new standards (European EN 481 and International ISO 7708), the cut-off aerodynamic diameter of the total thoracic fraction is 10 pm it is related to the smallest particles penetrating beyond the larynx. Because these particles are strongly responsible for the inhalation risk, their on-line measurement must be representative. The variations in intensities of deposited fractions as a function of particle diameter is shown in Fig. 9.11. 

Another motivation for particle size reduction of APIs is to facilitate getting the compound to a desired area of the body. For example, pulmonary drug delivery by dry powder inhalation is an administration route where particle size reduction is required to achieve drug delivery to the target region of the lung. The aerodynamic diameter of a particle should be in... 

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