Purpose: The purpose of the study was to understand the role of particle size and shape changes in modifying agglomerate strength distribution and de-agglomeration of cohesive lactose powders. Methods: The relative de-agglomeration of three lactoses of different particle size distributions (Lactohale 201 or LH201, Lactohale 210 or LH210 and Lactohale 220 or LH220) was determined from laser diffraction particle sizing of the aerosol plume at different air flow rates. The agglomerate strength distributions were estimated by Monte Carlo simulation using the primary particle size, work of cohesion and tapped density distributions determined by laser diffraction, inverse gas chromatography and tapping apparatus, respectively. The morphology and particle shape parameters were determined by scanning electron microscopy and the Morphologi G3. Results: The estimated agglomerate strength correlated well with the de-agglomeration of all lactose samples at different air flow rates. While the work of cohesion of the lactose samples was not significantly different, the packing fraction was dependent on the proportion and shape of intermediate-sized, cohesive particles between 5.4 and 14 pm. For example, while the proportion of particles LH210 > LH201. Conclusion: The study reinforced the role of agglomerate strength distributions in understanding deagglomeration of cohesive materials. Modification of particle size distributions and shape characteristics contributed to the agglomerate strength changes in the lactose samples. The study enhanced the fundamental understanding of powder de-agglomeration and provided strategic approaches that could be used to improve inhalation product performance.