Quantitative application of in situ ATR-FTIR and Raman spectroscopy in crystallization processes

In this work, different process analytical technologies based on vibrational spectroscopy, i.e., attenuated total reflectance Fourier transform infrared (ATR-FTIR) and Raman spectroscopy, were applied by means of multivariate data analysis techniques. Wide applicability has been demonstrated by in situ monitoring of various crystallization processes, e.g., solubility curve measurement, cooling crystallization, and solvent-mediated polymorph transformation. A calibration strategy has been proposed to obtain accurate and robust estimations of the solute concentration by ATR-FTIR monitoring. Different calibration models and preprocessing techniques were applied and compared. It was shown that these methods allow for solute concentration monitoring of nonisothermal processes even for sparingly soluble substances such as L-glutamic acid in an aqueous environment. An extensive study has been performed to identify the underlying process parameters that influence the Raman signal, i.e., solid composition, solute concentration, suspension density, particle size and shape, and temperature. It is demonstrated that principal component analysis provides qualitative information for seeded and unseeded polymorphic transformations and enables end-point determination of a solid-state transformation process using L-glutamic acid. The multivariate calibration approach described in this work allows for quantitative application of Raman spectroscopy to a multiphase multicomponent dynamic process such as a solvent-mediated polymorphic transformation. Additionally, it was shown that multivariate analysis of Raman data allows for solute concentration estimation despite the fact that solute signals are weak and completely overlapping with signals related to the solid phase.