An Integrated Process Analytical Technology (PAT) Approach to Examine the Effect of Temperature on Nucleation Kinetics of a Dynamic Pharmaceutical Co- precipitation Process

摘要

Process Analytical Technology (PAT) has become an essential part for pharmaceutical process and product understanding, real-time process monitoring and control during the last several years. Previously, we reported the development of a novel real-time PAT-based approach to measure the nucleation induction time and elucidate the nucleation and growth mechanisms of a dynamic pharmaceutical co-precipitation process at 25°C. The goal of this work is to understand the effect of temperature (15°C, 25°C, 35°C) on nucleation induction time for a dynamic pharmaceutical co-precipitation process (naproxen-Eudragit L100-alcohol-water) at various ratios of drug/polymer. Real- time inline process monitoring and nucleation induction time (tind) measurement have been accomplished using FBRM and PVM simultaneously. It was shown that: (1) the plots of tind vs. the ratio of naproxen to polymer (Q) display two distinct linear segments; (2) the plots of ln(tind) vs. (lnS)~(-2) (S is the maximum allowable super-saturation level) display two distinct linear segments which agree well with the classic nucleation theory (CNT); (3) Quantitative relationships based on CNT among the kinetic parameter A, dimensionless thermodynamic parameter B, and temperature (T) suggest that the nucleation and growth process is followed by the interface transfer mechanism. Therefore, at low S level, the nucleation is governed by primary heterogonous nucleation; while at high S level it is governed by primary homogeneous nucleation; after nucleation, the growth is controlled by the interface transfer mechanism. This work demonstrated the utility of real time process PAT monitoring on process understanding and process kinetic mechanism elucidating, thus could enhance the science-based pharmaceutical regulation in the Quality-by-Design (QbD) domain.