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Amikacin, an aminoglycoside antibiotic lacking a UV chromophore, was developed into a drug product for delivery by inhalation. A robust method for amikacin assay analysis and aerosol particle size distribution (aPSD) determination, with comparable performance to the conventional UV detector was developed using a charged aerosol detector (CAD). The CAD approach involved more parameters for optimization than UV detection due to its sensitivity to trace impurities, non-linear response and narrow dynamic range of signal versus concentration. Through careful selection of the power transformation function value and evaporation temperature, a wider linear dynamic range, improved signal-to-noise ratio and high repeatability were obtained. The influences of mobile phase grade and glassware binding of amikacin during sample preparation were addressed. A weighed (1/X2) least square regression was used for the calibration curve. The limit of quantitation (LOQ) and limit of detection (LOD) for this method were determined to be 5 μg/mL and 2 μg/mL, respectively. The method was validated over a concentration range of 0.05–2 mg/mL. The correlation coefficient for the peak area versus concentration was 1.00 and the y-intercept was 0.2%. The recovery accuracies of triplicate preparations at 0.05, 1.0, and 2.0 mg/mL were in the range of 100–101%. The relative standard deviation (Srel) of six replicates at 1.0 mg/mL was 1%, and Srel of five injections at the limit of quantitation was 4%. A robust HPLC-CAD method was developed and validated for the determination of the aPSD for amikacin. The CAD method development produced a simplified procedure with minimal variability in results during: routine operation, transfer from one instrument to another, and between different analysts.Charged Aerosol Detection (CAD) was successfully used for a Non-chromophoric aminoglycoside (Amikacin).Details for optimization of Power function value and evaporative temperature are shown for CAD.The HPLC-CAD method passed the stringent requirements for phase II validation.The CAD method is much easier to operate and transfer from one instrument to another.CAD performance is nearly on par with that of the conventional UV absorbance detector.