Active pharmaceutical ingredient (API)-embedded dry powder for inhalation (AeDPI) is highly desirable for pulmonary delivery of high-dose drug. Herein, a series of spray freeze-dried (SFD) ciprofloxacin hydrochloride (CH)-embedded dry powders were fabricated via a self-designed micro-fluidic spray freeze tower (MFSFT) capable of tuning freezing temperature of cooling air as the refrigerant medium. The effects of total solid content (TSC), mass ratio of CH to L-leucine (Leu) as the aerosol dispersion enhancer, and the freezing temperature on particle morphology, size, density, moisture content, crystal properties, flowability, and aerodynamic performance were investigated. It was found that the Leu content and freezing temperature had considerable influence on the fine particle fraction (FPF) of the SFD microparticles. The optimal formulation (CH/Leu = 7:3, TSC = 2%w/w) prepared at - 40°C exhibited remarkable effective drug deposition (~ 33.38%), good aerodynamic performance (~ 47.69% FPF), and excellent storage stability with ultralow hygroscopicity (~ 1.93%). This work demonstrated the promising feasibility of using the MFSFT instead of conventional liquid nitrogen assisted method in the research and development of high-dose AeDPI.