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method but typically will require comparison against cascade impaction to prove its validity. Still, laser diffraction, in its present state, is not suit- able for the more complex aerosols for which cascade impaction was originally adapted. While consider- able effort is being made in the design of "engi- neered" particles for inhalation, there is a gap between the pace of product development and the development and regulatory acceptance of alterna- tive methods for aerodynamic sizing or other tech- niques that can reliably predict particle deposition distribution following inhalation. De ve l o p i n g a n d va l i d a t i n g m e t h o d s f o r f a s t , detailed analyses of complex inhaled systems that could provide information related to their respira- tory tract deposition and disposition 15 to under- stand the critical attributes affecting local and sys- temic effects of inhaled products would be a very significant advance. Oropharyngeal deposition: Understanding it or avoiding it? e human oropharyngeal cavity is a complicated and dynamic structure, with inter- and intra-subject variability in its anatomy and airflow patterns, mak- ing particle deposition within it a very complex phe- nomenon. Oropharyngeal deposition can be also highly dependent on the way a patient uses an inhaler. I am impressed by the increasing sophistica- tion of both the physical/anatomical and computa- tional models for this problem. Nevertheless, are there still opportunities to make the science of oro- pharyngeal deposition more predictive, more pre- cise, more patient-oriented? Of course, there is always room for improvement! But let me offer some different perspectives, with which I believe we can all agree: Deposition of orally inhaled products in the oropharynx is invariably wasteful; it can contribute to adverse events and is the biggest source of intra- and inter-subject variabil- ity in pulmonary deposition. 16, 17 Variable loss of medication to the oropharynx is a limiting factor for drugs with a narrow therapeutic index. erefore, my suggestion to the new generation of inhalation scientists, who may be interested in fluid dynamics, devices and formulations, is to find practi- cal ways of minimizing oropharyngeal deposition, rather than devoting their talents to further refine- ments of oropharyngeal deposition modeling. I believe existing tools to measure oropharyngeal deposition in humans, including gamma scintigra- phy and laboratory and computational methods, which have been, or can be, validated against human data, are now adequate for this task. 18 Luckily, we know that controlling particle size, shape and velocity, as well as time of delivery during the inspiration portion of a patient's breathing, can min- ment. 7 Nevertheless, it still lacks the ability to deter- mine the aerodynamic size distribution. e introduction of inertial impaction methods in the 1980s for the then-new type of products—sus- pension metered dose inhalers and carrier-based dry powder products—was a big step in the right direc- tion. Cascade impaction is still the only general method, accepted to date, which can provide aerody- namic size distribution for the components of phar- maceutical inhalation aerosols that relates to their regional deposition in the respiratory tract. at is the great strength of this method; it is uniquely suit- able for complex aerosol systems in which the drug and excipient concentrations—in particles or drop- lets of different sizes—are not the same, or where the structure and shape of the particles are such that their optical properties cannot be readily transformed into aerodynamic size. Yet anyone who has done cascade impaction will appreciate it is a very laborious method that requires considerable knowledge and experience, as well as a fair amount of maintenance and control, if the equipment is to be used correctly. 8 It also can be chal- lenging to use it in certain circumstances. For exam- ple, it was shown years ago 9-12 that cascade impaction could be an unreliable method to determine drug aerodynamic size distribution for nebulized aqueous solutions because their propensity for rapid evapora- tion and condensation is very difficult to control. Aqueous droplet size is highly sensitive to relatively small fluctuations in temperature, especially if the aerosol is relatively dilute. 9,10 Indeed, the cascade impaction method for nebulized aqueous systems originally introduced by Mercer, et al. 13 was based on deliberate, complete evaporation of water (and other volatile components) prior to entry into the impac- tor. But that approach has other challenges, as den- sity of the solid residues needs to be determined and will likely be different from that of water. Further- more, the particle dynamic shape factor may not be unity, as is the case for spherical particles. Both parameters need to be established in order to ascer- tain particle aerodynamic size. Laser diffraction as a sizing method So are there alternatives that may be easier to use and more appropriate for such volatile systems with drugs in solution? Laser diffraction as a sizing method for solution aerosols was elegantly validated against cascade impaction by Clark. 14 Laser diffrac- tion is an ideal method for these types of aerosols, where the concentration of the drug in each droplet is the same and the optical size distribution can be readily converted into aerodynamic size distribution. It also has the advantage of measuring the size distri- bution at the exit from the mouthpiece, mimicking the entry into the oral cavity. Laser diffraction is also simple and quick to use. Regulators will consider this Inhalation February 2019 19