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

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Division of Product Quality Research (DPQR, HFD-940), Office of Testing and Research (OTR), Office of Pharmaceutical Sciences (OPS), Center for Drug Evaluation and Research (CDER), US Food and Drug Administration (FDA), Life Science Building 64, FDA White Oak Campus, 10903 New Hampshire Avenue, Silver Spring, Maryland 20993, United States
*Tel.: 001-301-796-0095. Fax: 001-301-796-9816. E-mail: [email protected]
Cite this: Ind. Eng. Chem. Res. 2014, 53, 4, 1688–1701
Publication Date (Web):January 7, 2014
Copyright © 2014 American Chemical Society

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    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 simplified classical nucleation theory model was derived to reveal the relationship between ln(tindV) 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 = tind 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.

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    Table 1: Some important first-principles for homogeneous (HON) and heterogeneous (HEN) nucleation phenomena, as well as nucleation-induction phenomena. S1: Measures to ensure the experimental consistency and repeatability. Table 3: The linear regression results for (1) tind vs Q; (2) tind-PVM vs tind-PFBRM; (3) tind-NIR-PCA vs tind-PFBRM; and (4) ln(tindV) and (ln S)−2 for FBRM-based method and NIR–PCA-based method at the different temperatures.

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