Constant size, variable density aerosol particles by ultrasonic spray freeze drying

This work provides a new understanding of critical process parameters involved in the production of inhalation aerosol particles by ultrasonic spray freeze drying to enable precise control over particle size and aerodynamic properties. A series of highly porous mannitol, lysozyme, and bovine serum albumin (BSA) particles were produced, varying only the solute concentration in the liquid feed, c _s, from 1 to 5 wt%. The particle sizes of mannitol, BSA, and lysozyme powders were independent of solute concentration, and depend only on the drop size produced by atomization. Both mannitol and lysozyme formulations showed a linear relationship between the computed Fine Particle Fraction (FPF) and the square root of c _s, which is proportional to the particle density, ρ, given a constant particle size d _g. The FPF decreased with increasing c _s from 57.0% to 16.6% for mannitol and 44.5% to 17.2% for lysozyme. Due to cohesion, the BSA powder FPF measured by cascade impaction was less than 10% and independent of c _s. Ultrasonic spray freeze drying enables separate control over particle size, d _g, and aerodynamic size, d _a which has allowed us to make the first experimental demonstration of the widely accepted rule d _a = d _g(ρ/ρ _o) ^1/2 with particles of constant d _g, but variable density, ρ (ρ _o is unit density).