Process analytical technology (PAT; Raman spectroscopy and FBRM) was used to monitor the salt formation step of a development compound in real time. The data obtained were used to understand the crystallization kinetics and behavior. A mechanistic model was proposed on the basis of the sequence of events, and the mechanism was verified by the Raman profiles. Several operational parameters were studied in a matrix setting in order to identify the factors that affect the quality attributes of the final product such as particle size and morphology. The kinetic characterization through PAT revealed that the process is primarily influenced by temperature and solvent composition and that the acid addition rate and agitation speed were found to have a marginal effect. A regression model on API particle size was extracted from the data set, and its accuracy was verified at various set points of the parameter range covered in the investigation. The workflow adopted by this study illustrates how process knowledge generated by a combination of PAT and modeling, as well as a multistaged experimental plan executed on the basis of learning from technical insight, can efficiently lead to the process control as required under the current regulatory frameworks.

中文翻译：

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通过机理理解，PAT促进了药物结晶的发展

使用过程分析技术（PAT；拉曼光谱和FBRM）实时监测开发化合物的成盐步骤。获得的数据用于了解结晶动力学和行为。根据事件的顺序，提出了一种力学模型，并通过拉曼曲线验证了该机理。为了确定影响最终产品质量属性的因素（例如粒度和形态），在矩阵设置中研究了几个操作参数。通过PAT进行的动力学表征表明，该过程主要受温度和溶剂组成的影响，并且发现酸的添加速度和搅拌速度具有边际效应。从数据集中提取了API粒径的回归模型，并在研究涵盖的参数范围的各个设定点上验证了其准确性。这项研究采用的工作流程说明了由PAT和建模相结合产生的过程知识以及基于从技术洞察中学习而执行的多阶段实验计划如何能够有效地导致当前监管框架要求的过程控制。