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J Pharm Sci. 2014 Sep;103(9):2937-2949. doi: 10.1002/jps.23955. Epub 2014 Apr 16.

Design, characterization, and aerosol dispersion performance modeling of advanced co-spray dried antibiotics with mannitol as respirable microparticles/nanoparticles for targeted pulmonary delivery as dry powder inhalers.

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University of Kentucky College of Pharmacy, Department of Pharmaceutical Sciences-Drug Development Division, Lexington, Kentucky 40536-0596.
GlaxoSmithKline, Analytical Sciences, Product Development, King of Prussia, Pennsylvania 19406.
The Ohio State University College of Medicine, Departments of Pediatrics and Internal Medicine, Lung and Heart-Lung Transplant Programs, Columbus, Ohio 43205; The Ohio State University College of Medicine, The Davis Heart and Lung Research Institute, Columbus, Ohio 43205.
The University of Arizona-Tucson, College of Pharmacy, Skaggs Pharmaceutical Sciences Center, Tucson, Arizona 85721-0202. Electronic address:


Dry powder inhalation aerosols of antibiotic drugs (a first-line aminoglycoside, tobramycin, and a first-line macrolide, azithromycin) and a sugar alcohol mucolytic agent (mannitol) as co-spray dried (co-SD) particles at various molar ratios of drug:mannitol were successfully produced by organic solution advanced co-spray drying from dilute solute concentration. These microparticulate/nanoparticulate aerosols consisting of various antibiotic drug:mannitol molar ratios were rationally designed with a narrow and unimodal primary particle size distribution, spherical particle shape, relatively smooth particle surface, and very low residual water content to minimize the interparticulate interactions and enhance in vitro aerosolization. These microparticulate/nanoparticulate inhalation powders were high-performing aerosols as reflected in the aerosol dispersion performance parameters of emitted dose, fine particle fraction (FPF), respirable fraction (RF), and mass median aerodynamic diameter (MMAD). The glass transition temperature (Tg) values were significantly above room temperature, which indicated that the co-SD powders were all in the amorphous glassy state. The Tg values for co-SD tobramycin:mannitol powders were significantly lower than those for co-SD azithromycin:mannitol powders. The interplay between aerosol dispersion performance parameters and Tg was modeled where higher Tg values (i.e., more ordered glass) were correlated with higher values in FPF and RF and lower values in MMAD.


aerosols; anti-infectives; confocal Raman microscopy; glass transition; lung; particle size respiratory delivery; pulmonary drug delivery; solid state particle engineering design; spray drying

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