Crystallization is an important unit operation in pharmaceutical drug substance manufacturing for the isolation of organic products. Impurity control is a recurring critical quality attribute in most commercial pharmaceutical crystallization processes. A systematic workflow that can reveal the incorporation mechanism of various impurities during crystallization and guide us to understand impurity rejection is useful for crystallization process design. Such a workflow was recently published by Urwin et al. Herein, we present three case studies implementing this workflow, covering surface deposition, conglomerate formation, and agglomeration as principal routes for impurity incorporation during crystallization of a drug substance’s active pharmaceutical ingredient and its intermediates. We demonstrate the experimental steps to identify various impurity incorporation mechanisms and discuss the strategy for impurity rejection in each case. We built upon the previous approach to demonstrate a material sparing approach through our case studies. We highlight the value of stepwise dissolution and show the importance of doing it early in the impurity incorporation identification stage. At this stage, we introduce a missing incorporation mechanism in prior work, namely, conglomerate systems. We show how to identify and resolve this mode of incorporation mechanism through stepwise dissolution and solubility-limited rejection maps.

中文翻译：

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在药物开发中应用基于工作流程的结晶设计优化杂质抑制的案例研究

结晶是药物原料药生产中用于分离有机产品的重要单元操作。杂质控制是大多数商业药物结晶过程中反复出现的关键质量属性。一个系统的工作流程可以揭示结晶过程中各种杂质的掺入机制，并指导我们理解杂质排斥，这对结晶工艺设计很有用。Urwin 等人最近发布了这样的工作流程。在此，我们介绍了实施此工作流程的三个案例研究，涵盖了表面沉积、聚结物形成和附聚作为原料药活性药物成分及其中间体结晶过程中掺入杂质的主要途径。我们演示了识别各种杂质掺入机制的实验步骤，并讨论了每种情况下的杂质排斥策略。我们建立在以前的方法之上，通过我们的案例研究来展示材料节约方法。我们强调了逐步溶解的价值，并展示了在杂质掺入识别阶段尽早进行的重要性。在此阶段，我们引入了先前工作中缺失的合并机制，即集团系统。我们展示了如何通过逐步溶解和溶解度限制排斥图来识别和解决这种掺入机制模式。我们强调了逐步溶解的价值，并展示了在杂质掺入识别阶段尽早进行的重要性。在此阶段，我们引入了先前工作中缺失的合并机制，即集团系统。我们展示了如何通过逐步溶解和溶解度限制排斥图来识别和解决这种掺入机制模式。我们强调了逐步溶解的价值，并展示了在杂质掺入识别阶段尽早进行的重要性。在此阶段，我们引入了先前工作中缺失的合并机制，即集团系统。我们展示了如何通过逐步溶解和溶解度限制排斥图来识别和解决这种掺入机制模式。