Enhancing blending efficiency and in vitro aerosol performance of low-dose inhalable dry powders with spray freeze dried microparticles

Carrier-based dry powder inhaler (DPI) products deliver low-dose drugs to the lungs by blending micronized drug particles with carriers. Traditional methods for obtaining fine particles, such as milling or spray drying, are not suitable for high-value, heat-sensitive drugs. Hence, we propose a novel strategy for preparing carrier-based DPI products based on spray freeze dried (SFD) particles. Due to their spherical, porous, and brittle structure, they can be easily fragmented and uniformly attached to carriers under mild blending conditions. Additionally, these low-density fragments can detach from the carrier during inhalation, potentially achieving better pulmonary delivery performance. In this work, previously developed SFD ciprofloxacin/leucine particles were chosen as model particles, and commonly used lactose as carriers, then blended via TURBULA® T2F. The effects of model particle mass content, mechanical strength, carrier size distribution, blending time, and blending speed on both blending uniformity and in vitro aerosol performance were investigated. An image analysis method based on energy dispersive spectroscopy mapping images was proposed to rapidly determine blending uniformity, showing good correlation with concentration quantification methods. Optimized formulation (SFD-C₁, 3.6 % mass content) and process parameters (blending speed of 25 rpm for 10 min) render excellent blending uniformity and fine particle fraction (∼ 50.40 %). This strategy potentially expands the application field of carrier-based DPI products.