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.

中文翻译：

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过程分析技术（PAT）通过协同冷却和溶液介导的相变辅助识别导致阿奇霉素结晶的晶体尺寸分布定制的操作空间

在线成像和ATR-FTIR应用于丙酮和水的混合物中的阿奇霉素结晶，以识别始终导致尺寸范围小于180μm（D ₅₀ = 78.3μm）的定制晶体尺寸分布（CSD）的操作空间， 180–425μm（D ₅₀ = 155μm）和425–850μm（D ₅₀在不改变溶剂或添加晶体生长改性剂的条件下，其最大粒径为433μm），同时满足所有其他要求，包括药物稳定性，纯度，杂质含量以及避免在二水合物晶体中出现一水合物。在丙酮和水的混合物中阿奇霉素的结晶既有趣又具有挑战性，因为它通过两个变量的协调操纵来实现结晶：引入水作为抗溶剂，并通过冷却降低温度。尽管目标产物晶体是阿奇霉素二水合物，但它只能首先产生一水合物，然后通过溶液介导的相变（SMPT）转化为二水合物。使用在线成像探头实时观察到从一水合物到二水合物的SMPT现象，并使用ATR-FTIR识别并量化了影响过渡的因素。此外，发现引入水的方式可能影响水合物的转变和产物的晶体尺寸分布。基于对多个变量与晶体生长行为之间因果关系的理解，定义了导致三个所需CSD的操作空间。首先在1 L结晶器中获得结果，然后在25 L结晶器中验证结果。定义了导致三个所需的CSD的操作空间。首先在1 L结晶器中获得结果，然后在25 L结晶器中验证结果。定义了导致三个所需的CSD的操作空间。首先在1 L结晶器中获得结果，然后在25 L结晶器中验证结果。