Respirable amikacin dry powders for inhalation by a Quality by Design procedure

Background: Amikacin as a liposomal solution for nebulization is an antibiotic under study for the treatment of Pseudomonas aeruginosa infections in cystic fibrosis patients. In a previous study, the respirability of amikacin dry powders obtained by spray drying was maximized using a Design of Experiment (DoE) approach. This study intended to explore the most influential process and formulation DoE parameters in the production by spray drying of amikacin inhalation powders. The aim was to discover using a Central Composite Design (CCD) the factor combination for the best product respirability. Methods: Three DoE parameters at three levels were explored: drying temperature, ethanol percentage in amikacin feed solution and feed rate. The spray dried powders were characterized such as morphology by scanning electron microscopy, water content (%) and volume diameter. The in vitro aerodynamic assessment was performed using Fast Screening Impactor. Results: The yield of the spray drying process was always higher than 80% and the residual water content (%) was always lower than 10%. The D(v,50), was between 2.37 and 3.68 μm. The most influent factors on the mentioned Critical Quality Attributes were the feed rate and the ethanol percentage in the feed solution. Increasing feed rate or the percentage of ethanol in the feed solution allowed obtaining particles with a smaller size. The powders obtained from feed solutions without ethanol showed a very low emitted dose. Moreover, a solution without ethanol showed the lowest fine particle dose (3.45 mg ± 1.14). Conclusions: The presence of ethanol in the feed solution promoted the amikacin spray dried powder respirability. The CCD let to identify the process factors combination to optimize the production of respirable amikacin spray dried powders for inhalation.