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Inhalation April 2023 13 as trehalose and mannitol [13]. Selection of bulking sugar depends on API properties and target product attributes and is a complex topic beyond the scope of this article. Leucine is a common excipient for pul- monary particles and is used to achieve product attri- butes such as modified surface morphology, enhanced aerosolization and flowability, and improved physical stability through reduction in hygroscopicty [14]. Product collection Separating the spray-dried powder from the exhaust gas stream is a critical step in recovery of the newly engineered drug particles. Two primary technologies are used for this: cyclones and filter baghouses. Cyclones operate on inertia to remove solids from gas streams, using a basic operating principle similar to that of a centrifuge. Gas enters the cyclone and is forced into a spiraling motion. Inertia carries the particles to the outer edge of the cyclone, where they impact with the chamber wall then drop to the bot- tom of the cyclone and into the collection container. Cyclones are simple to operate and low cost to main- tain, as they contain no moving parts. However, the collection of respirable-sized particles using a cyclone is difficult, due to their small geometric size and cor- responding aerodynamic properties. Typical cyclone collection efficiency decreases rapidly as particle size falls below 5 µm. Specialized high efficiency cyclones can be used to increase batch yields, but often result in considerably higher pressure drops compared to Formulation options available for pulmonary delivery are more limited than for oral delivery. e number of precedented excipients is relatively small and the total amount of each excipient acceptable for lung exposure is often low. As of July 2022, the United States Food and Drug Administration (FDA) Inactive Ingredient Database listed 62 materials precedented for delivery to the lungs, compared to more than 1,300 materials listed for oral delivery [11]. Of these 62, only a few have been used in a spray-dried products for inhala- tion. With occasional exceptions for materials that are Generally Recognized as Safe (GRAS), most devel- opment programs aim to only use materials already precedented for use in inhaled formulations, due to the additional safety and tolerability data required to justify using novel materials [12]. Table 2 illustrates the limited number of precedented materials. Alter- native materials can be evaluated, but development teams should weigh regulatory requirements for demonstrating the respiratory safety of novel excipi- ents prior to formulating [13]. Excipient selection is a key aspect of respiratory prod- uct development because while the options for excip- ients are limited, they can provide essential product improvements. ese may be increased solid- state stability, enhanced aerosolization properties or dis- solution performance, or other product-specific changes [14]. Lactose has been used in carrier-based DPI formulations and as a bulking agent in engi- neered particle formulations, as can other sugars such Level of Precedence Spray-Drying Excipient Purpose Approved DPPC Microcarrier, dispersibility, bulking DSPC Microcarrier, dispersibility, bulking Mannitol Osmolality Glycine Buffer, stabilizer Buffer salts (e.g., citrate, sulfate) Buffer, glass stabilizer Clinical Development Leucine Dispersibility Trileucine Dispersibility Trehalose Glass stabilizer, bulking agent Fumaryl diketopiperazine (FDKP) Carrier Literature PLA, PLGA Controlled-release Polysaccharides Dispersibility, bulking Cyclodextrins Dispersibility, bulking Lactose Bulking Sucrose Bulking Adapted from reference 30. Table 2 Excipients used in the manufacture of inhalable dry powders by spray drying