The purpose of this study is to investigate the suitability of the crystallization process to produce microcrystals of progesterone for respiratory drug delivery. Crystallization of progesterone was carried out from water-isopropanol (IPA) mixture. The antisolvent (water) was added at two different addition rates (10 and 100 mL/min). The mass percentage of antisolvent was varied between (50% and 75%), and the initial drug concentration was adjusted at (0.5 and 1 g/L). The effect of crystallization method (antisolvent precipitation or combined cooling and antisolvent) was also examined. These operating conditions were investigated in a 2(4) factorial design in an effort to optimize the process. Different solid-state and surface characterization techniques were applied in conjunction with measurements of powder flow properties using aerodynamic particle sizer (APS). Powder dispersibility and aerosol performance were analyzed using Anderson Cascade Impactor (ACI). Antisolvent addition rate, initial drug concentration and dynamic solvent composition are shown to have a significant effect on the aerosol characteristics of progesterone microcrystals. An increase of 38.73% in the fine particle fraction (FPF) was demonstrated for some powders produced by combined cooling and antisolvent crystallization. In conclusion, it was possible to control particle size and hence, pulmonary deposition using process parameters alone, and produce particles with a narrow particle size distribution and a mean particle size of 5 microm with nearly no particles larger than 10 microm by direct crystallization. The suitability of deep pulmonary deposition was proved by the platelet-like morphology of processed microcrystals and greater surface-to-volume ratio than spherical particles.