Integrated Process Analytical Technology Approach for Nucleation Induction Time Measurement and Nucleation Mechanism Assessment for a Dynamic Multicomponent Pharmaceutical Antisolvent Crystallization System

A comprehensive, real-time PAT process monitoring scheme of using near-infrared (NIR) spectroscopy, focused beam reflectance measurement (FBRM), and particle vision microscopy (PVM) was established for process characterization and process understanding of a model dynamic multicomponent pharmaceutical antisolvent crystallization system. The NIR spectra were subjected to principal component analysis (PCA) to construct the process trajectory; and the final products were characterized by X-ray powder diffraction (XRPD), raman spectrometry, and microscopy. Regardless of the PAT technique (i.e., the NIR–PCA method, the FBRM method, and the PVM method) used, this study shows that the nucleation induction time (tind) increases with temperature. In addition, correlations were observed with R2 of 0.70–0.98 between PVM method and FBRM method and of 0.58–0.84 between NIR–PCA method and FBRM method. Accounting for the dynamic nature of the experiments and changes in the liquid volume (V) as a function of time, a simpl...

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