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26 August 2020 Inhalation mannitol particles, although they produce differently shaped particles, which combined with any differ- ences in density directly impact the aerodynamic size. Comparison of the crystallinity between the two par- ticles may help to elucidate whether either material contains significant amorphous material or whether the crystal structure may be susceptible to change with heat and humidity over time. Summary ere are many different technologies that drug devel- opers can use to advance innovative inhaled drug products. ese include bottom-up techniques that form droplets and dried particles from bulk solution, top-down approaches that reduce API particle size to manufacture aerosolizable powders and a combina- tion of the two. Selecting the best approach for a given problem statement depends on the API characteristics and the target product profile, including the inhaled BCS, of the drug in development. While multiple particle engineering approaches are available for pulmonary formulation development, spray drying and jet milling are proven, scalable approaches and drug developers may benefit from considering them as a first pass. By evaluating these approaches initially, developers can determine whether a more complicated approach is required and which path is best suited for the API and treatment. In the event that multiple particle engineering technolo- gies are suitable, developers can optimize for speed to patient and take into consideration the process throughput, yield and equipment availability. References 1. Forum of International Respiratory Societies. e Global Impact of Respiratory Disease—Second Edi- tion. Sheffield, European Respiratory Society, 2017. https://www.who.int/gard/publications/e_Global_ Impact_of_Respiratory_Disease.pdf. 2. Hastedt JE, Bäckman P, Clark AR, et al. Scope and relevance of a pulmonary biopharmaceutical classifica- tion system. AAPS/FDA/USP Workshop March 16-17, 2015 in Baltimore, MD. AAPS Open. 2016. 2:1. 3. Hastedt JE, Bäckman P, Cabal A, et al. Classifica- tion of inhaled medicines: Development of an inha- lation-based biopharmaceutical classification system. Drug Delivery to the Lungs. 2019. 30: 29-32. 4. Overhoff KA, Johnston KP, Tam J, et al. Use of thin film freezing to enable drug delivery: A review. Jour- nal of Drug Delivery Science and Technology. 2009. 19(2): 89-98. 5. Vishali DA, Monisha J, Sivakamasundari SK, et al. Spray freeze drying: Emerging applications in drug delivery. Journal of Controlled Release. 2019. 300: 93-101. In order to understand how effectively these engi- neered powders would perform in respiratory delivery, the TSI Aerodynamic Particle Sizer (St. Paul, MN, US), using a time-of-flight principle, was used to determine the aerodynamic particle size distribution of these powders. e mass-weighted cumulative dis- tribution (assuming a density of 1.6 g/cc) is plotted in Figure 3, which shows that the aerodynamic size dis- tribution is narrower for the spray-dried material than for the jet-milled material. Table 2 provides several aerodynamic diameter summary values for the two dis- tributions, showing that the mass median aerodynamic diameter (MMAD) is similar between the two materi- als. However, the broader distribution of large particles in the jet-milled material results in a smaller fraction of the jet-milled powder that is effective for inhalation (most commonly defined as particles with an aerody- namic diameter less than 5 µm). In this case, both jet milling and spray drying appear to be viable approaches for engineering respirable Table 2 Aerodynamic size summary as measured by time-of-flight, including the mass median aerodynamic diameter (MMAD), mean diameter and geometric standard deviation (GSD), a measure of log-normal distribution breadth. Material MMAD (µm) Mean Diameter (µm) Cumulative Mass < 5 µm Diameter (%) GSD (um) Spray-Dried Mannitol 3.2 3.8 84 1.7 Jet-Milled Mannitol 3.4 4.9 66 2.1 Figure 3 Cumulative mass under the specified aerodynamic particle size as measured by time-of-flight, based on an assumed density of 1.6 g/cc for crystalline mannitol. Cumulative Mass < Stated Size (%) Spray-Dried Mannitol Jet-Milled Mannitol Aerodynamic Diameter (µm) 100 75 50 25 0 0.5 5 50