Online imaging and ATR-FTIR were applied to azithromycin crystallization in a mixture of acetone and water to identify the operational spaces that consistently led to tailored crystal size distribution (CSD) in the size ranges of <180 μm (D50= 78.3 μm), 180–425 μm (D50= 155 μm), and 425–850 μm (D50= 433 μm), under the constraints of no change of solvent or addition of crystal growth modifiers, in the meantime satisfying all other specifications including drug stability, purity, impurity content, and avoidance of monohydrates in the dihydrate crystals. Azithromycin crystallization in an acetone and water mixture is both interesting and challenging, as it achieves crystallization via coordinated manipulation of two variables: introduction of water as an antisolvent and temperature reduction via cooling. While the target product crystals are azithromycin dihydrates, it can only first produce monohydrates which are then transformed to dihydrates through solution mediated phase transition (SMPT). The phenomenon of SMPT from monohydrates to dihydrates was visually observed in real-time using an online imaging probe, and the factors affecting the transition were identified and quantified using the ATR-FTIR. Furthermore, it was found that the way water was introduced could affect the hydrate transition and the crystal size distribution of the product. Based on the understanding of the causal relationships between the multiple variables and crystal growth behavior, the operational spaces leading to the three desired CSDs were defined. The results were first obtained in a 1 L crystallizer and then validated in a 25 L crystallizer.