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Inhalation August 2020 23 Supercritical fluid technologies 7 use high pressure to change physical properties of a gas (as defined at standard room temperature and pressure). Carbon dioxide is typically used since, under supercritical conditions, it mimics solvent properties of a liq- uid and diffusivity of a gas. is carrier is typically selected based on inertness, cost and nontoxicity. Oftentimes, the process is limited by drug solubil- ity in carbon dioxide, which is typically low. Car- bon dioxide's low critical temperature can also help protect sensitive compounds from thermal decom- position. The process can be beneficial in terms of eliminating organic solvents and harsher processing conditions, but its effectiveness tends to be limited for more hydrophilic compounds. Addition of water or ethanol can aid in dissolution of polar compounds. Controlled solidification to achieve appropriate par- ticle sizes is a technique based on generating an envi- ronment where the API (with or without excipients) is forced from solution into a solid by adjusting the solu- bility into a highly mixed zone, either by changing the solution 8 or reacting an intermediate to the final prod- uct, which is insoluble in the liquid phase. 9 Depending on the kinetics and the API properties, the particles may be amorphous. Additionally, as the API or formu- lation is precipitated into a suspension, another step is required to remove the liquid and yield the dry powder. Top-down approaches: Milling to reduce particle size Top-down engineering approaches to manufacture aerosolizable powders entail milling a crystalline mate- rial to the desired size. Prior to milling, the starting material may be produced from the API manufactur- ing process, including crystallization, bulk drying or lyophilization. e starting material sizes are typically larger than what is respirable. Depending on the mate- rial, an initial milling step may be required before it is further processed into respirable particles. Milling approaches can be divided between wet mill- ing and dry milling. In the case of wet milling, stabiliz- ers can be added to mitigate the higher surface energy associated with smaller particles. However, wet milling requires a subsequent process step to create a dry pow- der suitable for inhalation, so dry milling tends to be a more direct approach for creating respirable powders. e most common type of dry milling for the cre- ation of respirable particles is the jet mill, which relies on a gas stream to add energy to the milling cham- ber and carry the particles out of the chamber once a critical size is reached. e gas flow within the jet mill causes particles to collide with each other and fracture. Large particles remain in the jet mill for fur- ther size reduction, while smaller particles are able to change direction and are carried out of the mill via a classification port. Spray drying is one of the more common techniques used throughout the pharmaceutical industry in terms of bottom-up approaches. Part of the popularity of spray drying is due to flexibility in solvent selection, which can be tailored to varying API and excipient solubilities. Processing parameters (nozzle selection, feed rate, temperature, etc.) also have a large operating range, which can make it seem daunting to identify optimal operating conditions. e advantages to this broad processing space include flexibility in engi- neering the particle shape, size and the physical state (amorphous or crystalline) depending on material properties, all of which can be extremely beneficial for pulmonary delivery. Excipients can be added to aid in stability, aerosol dispersibility or bioavailabil- ity. Spray drying can produce reliable powder from batch to batch, and scalability is relatively easy com- pared to other approaches, making it a front runner for commercial consideration. While there have been concerns about potential denaturing of proteins with respect to elevated temperatures and shear from a spray dryer, 4 drug developers can evaluate this concern on a case-by-case basis. Spray freeze drying (SFD) combines spray drying and freeze drying techniques into one process. Typ- ically, the process breaks down into atomization of liquid into droplets, solidification of droplets as they contact cold fluid (typically, liquid nitrogen) and sublimation of droplets using low temperature and pressure. e extremely fast cooling rates can reduce phase separation between the drug and excipients, yielding improved molecular distribution. This approach can be very beneficial for compounds sen- sitive to temperature, pH and salt concentration, and may eliminate organic solvent use as well. is tech- nique demands low pressure and low temperature, which can involve high capital and operational costs. Compared to spray drying, spray freeze drying costs may run 30-50 times higher and most developed SFD units are not appropriate for commercial use, often making scale-up extremely challenging. 4, 5 in film freezing 4, 6 is related to SFD, but involves droplets of solution applied to a steel drum filled with a cryogen such as liquid nitrogen. e droplets freeze on the drum as it rotates and are then scraped off by a blade. e frozen material falls into a collection con- tainer cooled by liquid nitrogen or dry ice. e collec- tion container then gets lyophilized to remove solvent through sublimation. While this technique can be used to improve bioavailability of poorly water-soluble compounds, solvent selection can greatly affect this process. Not only does the solvent need to be spread to a thin layer, it also needs high thermal diffusivities for this process to be effective. e overall cost of opera- tions must be considered, given the use of cryogen and optimally low humidity environmental controls to minimize water vapor condensation on the steel drum.