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Purpose-This study aims to understand the impact of spray drying nozzles on particle surface composition and aerosol stability.Methods-The combination formulations of colistin and azithromycin were formulated by 2fluid nozzle (2N) or 3-fluid (3N) spray drying in a molar ratio of 1:1. A 3-factor, 2-level (2 3 ) factorial design was selected to investigate effects of flow rate, inlet temperature and feed concentration on yield of spray drying and the performance of the spray dried formulations for the 3N.Results-FPF values for the 2N formulation (72.9 ± 1.9% for azithromycin & 73.4 ± 0.8% for colistin) were higher than those for the 3N formulation (56.5 ± 3.8% for azithromycin & 55.1 ± 1.6% for colistin) when stored at 20% RH for 1 day, which could be attributed to smaller physical size for the 2N. There was no change in FPF for both drugs in the 2N formulation after storage at 75% RH for 90 days; however, there was a slight increase in FPF for colistin in the 3N formulation at the same storage conditions. Surface enrichment of hydrophobic azithromycin was measured by X-ray photoelectron spectroscopy for both 2N and 3N formulations and interactions were studied using FTIR.Conclusions-The 3-fluid nozzle provides flexibility in choosing different solvents and has the capability to spray dry at higher feed solid concentrations. This study highlights the impact of hydrophobic azithromycin enrichment on particle surface irrespective of the nozzle type, on the prevention of moisture-induced deterioration of FPF for hygroscopic colistin.