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 ( t ind ) increases with temperature. In addition, correlations were observed with R 2 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 simplified classical nucleation theory model was derived to reveal the relationship between ln( t ind V ) and (ln S ) −2 ( S is the supersaturation ratio). Regions of very strong and very weak dependence on (ln S ) −2 were identified. Final product characterization and in-process observations of particle morphology at t = t ind collectively support that heterogeneous- and homogeneous-nucleation mechanisms are responsible for low S and high S regions, respectively. Therefore, the utility of an integrated-PAT approach for understanding a dynamic multicomponent antisolvent crystallization process and elucidating the nucleation mechanism was demonstrated.