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28 FEBRUARY 2023 Inhalation Processing conditions were altered to increase yields, decrease particle sizes and decrease outlet humidity conditions. An 8/72/20% budesonide/mannitol/leu- cine model formulation was chosen for this work, and would later be the basis around which the for- mulation composition is explored. With improved processing conditions, ve EEG for- mulations were carried into the study and manufac- tured using the same equipment setup (Figure 3). e formulation space included both hygroscopic components, sodium chloride and mannitol, as well as an assessment of leucine loading. Literature data suggests that 10-20% leucine is all that is needed for su cient dispersion enhancement [5]. However, both mannitol and sodium chloride could compete for the surface so higher amounts of leucine were deemed interesting for this study. Higher amounts of leucine also allow the critical concentration thresh- old to be reached earlier in the drying process, which improves stability performance. An initial round of characterization was performed to assess the chemical and physical properties of each formulation. Assay, geometric particle size, water content, residual solvent, morphology, crystallinity and thermal properties were performed on all for- mulations. Water sorption and desorption were per- formed on both the mannitol and sodium chloride formulations with 72% of each hygroscopic EEG component for comparison (Figure 4). Sodium chlo- ride demonstrated a slightly higher amount of water uptake than mannitol, making it a potentially pre- ferred excipient over its mannitol counterpart. Considerations for moving forward with two formu- lations included: manufacturability (speci cally yield and di culty/time/cost) and desired physical and chemical properties. e 8/62/30% mannitol and sodium chloride formulations were further progressed, testing their stability after one month at 25 °C/60% relative humidity (RH) and 40 °C/75% RH stored Budesonide formulation selection For the budesonide/lung in ammation program, the formulation selection journey began with two- fold technical assessments. e rst was the assess- ment of solubility in blended water/ethanol systems as the active ingredient has low aqueous solubility and the excipients of choice such as sodium chlo- ride, mannitol, and leucine have good solubility in water. e solubility data informed the operating space and enabled a total solids loading of 1% in a 50/50 ethanol/water solvent blend. e second assessment included process space prob- ing to generate and collect the correct particle sizes from the spray dryer. As mentioned above, these formulations necessitate a smaller particle size com- pared to those normally considered for inhalation. In spray drying, the particle size is determined by the droplet size formed during atomization and the sol- ids content of the solution being sprayed. e drop- let size is a function of the ratio of liquid to gas ow rates at the nozzle. In the budesonide case, the target particle size dis- tribution would have a Dv50 of 1.5 µm or less compared with more standard inhalation delivery formulations which target a Dv50 of around 2.5 µm. For reference, the Dv50 is a common particle size distribution metric by which 50% of the distribution on a volume basis is less than the metric and 50% is larger than the metric. Initial spray conditions were re ned on the feasibil- ity scale dryer through three sprays of 3 grams each. Figure 3 EEG formulation design space showing concentration of active pharmaceutical ingredient and leucine in test formulations for both programs. B indicates budesonide formulations and G indicates gemcitabine formulations. 10 20 30 40 50 60 10 20 30 40 50 60 Leucine (wt%) 40 35 30 25 20 • Leucine (wt%) Leucine (wt%) vs. API (wt%) API (wt%) Figure 4 Water sorption/desorption curves for leading formulations. Comparisons between formulations with mannitol and sodium chloride are shown. Mannitol formulation sorption Mannitol formulation desorption NaCl formulation sorption NaCl formulation desorption 0 10 20 30 40 50 60 70 80 Target %RH 1 0 Change in Mass (%)