Monitoring of Solvent-Mediated Polymorphic Transitions Using in Situ Analysis Tools

Abstract

In general, polymorphs have been identified by using off-line techniques such as X-ray diffraction, Raman spectroscopy, and infrared spectroscopy (IR). However, these techniques are unsuitable for process monitoring because they are slow and require sample preparation. In this study, the possibility of applying in situ techniques to the monitoring of solvent-mediated transitions was investigated. These in situ techniques include Raman spectroscopy, near-infrared spectroscopy (NIR), and focused beam reflectance measurement (FBRM), in which it is possible to perform measurements quickly and in a nondestructive manner. Raman spectroscopy is effective as a process analytical technology (PAT) tool for determining polymorphic transition because this technique is insensitive to aqueous solvents. NIR can be used for measurements on crystal polymorphs with sampling from a slurry; however, it is not effective if it is also off-line due to the interruption of the absorption band of water. Providing the particle size changes with the polymorphic transition, FBRM can be very useful as a PAT tool for monitoring not only particle distribution size but also polymorphic transition. Raman spectroscopy provides an insight into the properties of crystallization, especially the rapid quantitative analysis of polymorphic transition. This technique offers a time-saving approach for the development of the crystallization process. In situ techniques such as Raman spectroscopy can be used during scale-up to understand and monitor crystallization processes.