The main purpose of this investigation was to investigate the agglomeration mechanism of azithromycin dihydrate in mixed water and acetone systems and improve the powder properties of azithromycin dihydrate. The solubilities and crystallization processes of azithromycin monohydrate and dihydrate in mixed water + acetone systems were measured and investigated. The solubilities of the two hydrates were very close, and the products obtained from water + acetone mixtures were strongly agglomerated. It was found that surface nucleation and growth of dihydrate on monohydrate crystals during the hydrate transformation process were the reasons which caused agglomeration. There was no hydrate transformation during the crystallization process of azithromycin in ethyl acetate, and the products were single crystals. By comparison of the powder properties of agglomerated and nonagglomerated solids, the agglomeration has a serious impact on the crystal size distribution, bulk density, and flowability.