In-Line Raman Spectroscopy for Polymorph Monitoring During Continuous Crystallization.

In-line monitoring of continuous crystallization processes can provide real-time information about the polymorph composition, potentially providing a superior understanding and control of the crystallization kinetics throughout the process. Here, we present a case study using in-line Raman spectroscopy as a process analytical technology (PAT) tool to enable fast, in-situ, non-destructive, and quantitative measurement of complex polymorphic transitions during flow-induced continuous crystallization of a model compound, which has two main polymorphs only showing subtle differences in the fingerprint regions of their Raman spectra. Second derivative Raman spectra were used for qualitative monitoring of polymorph changes, and a Gaussian curve fitting method was developed and utilized for quantitative determinations of polymorph compositions in continuous crystallizations under an array of process conditions. This study illustrates the complex and dynamic nature of polymorph transitions during continuous crystallization under various process conditions as well as the ability of in-line Raman spectroscopy to monitor the process qualitatively and quantitatively in order to have greater understanding of the process design space and to avoid conditions that lead to undesired polymorphs in the crystallization process.