The importance of particle size to spray hazard analysis that can help developers of spray products with this task and actively support registration applications. However, these models all rely on, and are driven by, one key spray characteristic: droplet size distribution. Droplet size is crucial to determining the internal point of deposition, or how deeply a droplet/particle will penetrate the respiratory system following inhalation. Orally inhaled and nasal drug product (OINDPs) developers make use of this feature to direct active pharmaceutical ingredients (APIs) to the required deposition site within the body. For instance, cold and flu drugs targeting the nasopharyngeal region will be expected to be delivered above 30μm in size. Those targeting the tracheobronchial region in the throat will tend to have a particle size of around 10-30μm. Finally, particles intended to deposit in the pulmonary region require a smaller particle size of typically below 5μm in order to ensure successful deposition within the deep lung. These same size data can also be used to avoid in vivo deposition and prevent entry into the body via these routes.1 Measuring droplet size is complicated by the fact that the size of droplets within a spray is influenced by a range of variables, including viscosity of the formulation, the concentration of individual ingredients, propellant composition, the physical attributes of the delivery device/packaging and the method of operation of the product. Any change to these parameters will affect the spray pattern and/or particle/droplet size distribution. Particle size will also change considerably throughout the spray event. Three analytical techniques are currently in regular use amongst spray developers to determine particle size at a variety of points following actuation: time of flight spectroscopy, cascade impaction and laser diffraction. Finding the right technique for the product depends on the concentration of particles, the particle size range, the speed of measurement required, the measurement conditions that must be applied and—most importantly—the overall needs of the experiment. Time of Flight Time of flight spectroscopy makes use of the relationship between particle size and acceleration rate to determine the aerodynamic radius of particles within a spray. Particles are accelerated through an orifice and passed between two sequential laser beams. Small particles accelerate quickly while larger particles accelerate more slowly. The time it takes for a particle to pass through both beams is used to give an indication of size. Time of flight spectroscopy offers the benefit of aerodynamic measurement and also provides particle counting with good resolution, even at low volume. However, the technique has a restricted size and sampling range, and spray concentration is limited to avoid the influence of particle coincidence. Furthermore, the shear force applied during acceleration can affect droplet size and lead to inaccuracies. Consequently, it is inappropriate for high shear actuation procedures. These characteristics make time of flight measurements best suited to measuring particle size at low aerosol concentrations such as in the breathing zone of a consumer during spraying or when monitoring the particles remaining in the air following a spray event. Time of flight measurements are therefore valued for monitoring the risk of accidental exposure; in high spray concentration environments, such as OINDP administration, they are less effective. Within aerosol testing, they are commonly used to simulate consumer exposure within intended and foreseeable use scenarios. Aerodynamic impaction Aerodynamic impaction is a physical separation technique that makes similar use of the relationship between particle velocity and aerodynamic radius. It separates particles on the basis of inertia, a function of velocity and aerodynamic particle size. Particles are entrained within an air stream, which passes through a series of stages, each with a defined number of nozzles. Beneath each stage is a collection plate. At any given stage, particles with sufficient inertia break free of the prevailing air currents and impact on the collection plate (Figure 1). Particles with insufficient velocity (inertia), in contrast, remain entrained within the air flow and move to the subsequent stages where the process is repeated until the spray components have been separated on the basis of size. Andersen cascade impactors are a commonly used tool to perform this analysis and have a vertical plate set up. Cascade impactors were originally designed for the ambient sampling of air quality. Today, they are used for mandatory tests for OINDP development because of the defining influence of particle size distribution on in vivo drug deposition for these products; they are not stipulated for noninhaled spray products. For these products, the technique is best used to sample in an intermediate situation, such as from a chamber, in order to more closely mimic inhalation of the spray plume. 2 By physically collecting particles, cascade impactors have the added advantage of allowing chemical identification of the components present within the spray through the use of a secondary measurement technique. Cascade impaction can therefore be used to generate component specific particle size distribution data. However, the technique has the disadvantage of being more time consuming than comparable spray analysis Figure 1: Schematic of a nozzle in an Andersen Cascade Impactor. Cascade impaction separates particles on the basis of their inertia, which is a function of aerodynamic particle size. 42 Spray May 2014
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