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

摘要

Process Analytical Technology (PAT) has become an essential part forpharmaceutical process and product understanding, real-time process monitoring andcontrol during the last several years. Previously, we reported the development of a novelreal-time PAT-based approach to measure the nucleation induction time and elucidate thenucleation and growth mechanisms of a dynamic pharmaceutical co-precipitation processat 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-precipitationprocess (naproxen-Eudragit L100-alcohol-water) at various ratios of drug/polymer. Realtimeinline process monitoring and nucleation induction time (t_(ind)) measurement havebeen accomplished using FBRM and PVM simultaneously. It was shown that: (1) theplots of t_(ind) vs. the ratio of naproxen to polymer (Q) display two distinct linear segments;(2) the plots of ln(t_(ind)) 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 thenucleation 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 demonstratedthe utility of real time process PAT monitoring on process understanding and processkinetic mechanism elucidating, thus could enhance the science-based pharmaceuticalregulation in the Quality-by-Design (QbD) domain.