This study aimed to investigate the surface energy factors behind improved aerosolization performance of spray-dried colistin powder formulations compared to those produced by jet-milling. Inhalable colistin powder formulations were produced by jet-milling or spray-drying (with or without L-leucine). Scanning electron micrographs showed the jet-milled particles had irregularly angular shapes, while the spray-dried particles were more spherical. Significantly higher fine particle fractions (FPFs) were measured for the spray-dried (43.8-49.6%) vs. the jet-milled formulation (28.4 %) from a Rotahaler at 60L/min; albeit the size distribution of the jet-milled powder was smaller. Surprisingly, addition of L-leucine in the spray drying feed-solution gave no significant improvement in FPF. As measured by inverse gas chromatography, spray-dried formulations had significantly (p<0.001) lower dispersive, specific and total surface energy values and more uniform surface energy distributions than the jet-milled powder. Interestingly, no significant difference was measured in the specific and total surface energy values between the spray-dried formulation with or without L-leucine. Based upon our previous findings in the self-assembling behavior of colistin in aqueous solution and the surface energy data obtained here, we propose the self-assembly of colistin molecules during spray-drying, contributed significantly to the reduction of surface free energy and the superior aerosolization performance.

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