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Inhalation February 2023 29 lations. A crystallization event was identified above 40% RH for both the sodium chloride and manni- tol formulations. A form change from amorphous to crystalline can have adverse effects on desirable aerodynamic properties. Considering this data, along with the hygroscopic nature of the formulation, the handling and packaging of these powders was criti- cal. To further understand the formulation space and performance, all formulations were staged onto sta- bility with approximately 0.5 g in a glass amber vial overpackaged in a mylar bag with desiccant. Sam- ples were placed in environmental chambers held at 25 °C/60% RH and 40 °C/75% RH. Performance and stability feasibility were large drivers for the suc- cess of this formulation platform. e one-month stability results were critical in for- mulation selection. e sodium chloride formula- tions showed minimal change after one month at both conditions. e mannitol formulation exhib- ited some increase in particle size growth at the accelerated condition, most notable under the Dv90 measurement by Malvern Mastersizer. Interestingly, the mannitol formulation had the lowest water con- tent after one month on stability. is would sug- gest the mechanism for particle growth was likely not driven by the hygroscopic formulation design. Leveraging the initial formulation characterization, the particle morphology of the mannitol formula- tion did appear slightly smoother than its sodium chloride counterpart at equivalent leucine loadings. in mylar bags with desiccant. Geometric particle size, water content, crystallinity and thermal properties showed minimal change from the initial timepoint for both conditions, demonstrating stability of both spray-dried intermediates. Considering the formu- lation design, both water content and particle size changes on stability are of high concern. Ultimately, the leading formulation contained 8 wt% budesonide, 30 wt% leucine and the remain- der sodium chloride based on water uptake during dynamic vapor sorption testing and favorable short- term stability performance. Successful one-month stability allowed the program to move forward with scale-up feasibility work on a clinical-scale dryer. Processing conditions were opti- mized for spraying 8/62/30% budesonide/sodium chloride/leucine (Bud/NaCl/Leu) and targeting par- ticles with a Dv50 of approximately 1.3 microns. Overall, analytical characterization of four different processing conditions showed relatively little differ- ence between each spray lot except for geometric particle size. As expected, sprays with lower parti- cle size distributions were more difficult to collect, resulting in a lower yield. Further optimization was made, including tradeoffs between geometric particle size and yield, which ultimately led to successfully manufacturing the leading formulation at a clinically relevant scale for both toxicological supplies and long-term stability assessment. Gemcitabine formulation selection Building upon the foundation from the budesonide EEG formulation feasibility, a gemcitabine formu- lation study was initiated. In this case, IV dosing indicated a high API loading was necessary, along with the hygroscopic excipient and surface modi- fier. Active pharmaceutical ingredient loading was probed from 40% to 60% and leucine content was varied from 20% to 30%. e remaining formula- tion space was filled with sodium chloride. A single formulation containing mannitol was formulated as a comparator to sodium chloride performance (Fig- ure 2). e optimized spray-drying process from the previous studies was leveraged for this work on the feasibility-scale dryer. Initial characterization of these formulations con- sisted of the following tests: water content by Karl Fischer titration, assay/related substances by high performance liquid chromatography (HPLC), par- ticle morphology by scanning electron microscopy (SEM), thermal characterization by modulated dif- ferential scanning calorimetry, appearance, physical state by X-ray powder diffraction, particle size dis- tribution by Malvern Mastersizer (Malvern Panalyt- ical, Malvern, UK) and water sorption by dynamic vapor sorption. e water sorption profile was of particular interest for understanding the operating space and thresholds for these hygroscopic formu-