(401c) An Integrated Process Analytical Technology (PAT) Approach to Examine the Effect of Temperature On Nucleation Kinetics of a Dynamic Pharmaceutical Co-Precipitation Process

Authors: 
White, M., FDA
Foringer, R., FDA CDER


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 250C.  The goal of this work is to understand the effect of temperature (150C, 250C, 350C) on nucleation induction time for a dynamic pharmaceutical co-precipitation process (naproxen-Eudragit L100-alcohol-water) at various ratios of drug/polymer. It shows that at various temperatures studied, the plots of nucleation induction time vs. the ratio of naproxen over Eudragit L100 display two distinct linear segments: at low drug/polymer ratio, the induction time decreases quickly with the ratio in a linear fashion (R2 value of 0.92~0.97); at high drug/polymer ratio, the induction time decreases slowly with the ratio in a linear fashion (R2 value of 0.50-0.69). Furthermore, the plots of ln(tind) vs. (lnS)-2 display two distinct linear segments at various temperatures studied: at low apparent super-saturation S level, the R2 value of 0.65~0.93 and slope values of 15.4~53.3 were found; at high S level, the R2 value of 0.88~0.95 and slope values of 67.4~160.5 were found. These distinguished features agree well with the classical nucleation theory (CNT): at low S level, the process is controlled by heterogonous nucleation mechanism; at high S level, the process is controlled by homogeneous nucleation mechanism. Direct in situ observation of the nucleation process by PVM provides additional evidence for this mechanism illustration. This work demonstrated the utility of real time process PAT monitoring on process understanding and process kinetic mechanism illustrating, thus could enhance the science-based pharmaceutical regulation in the Quality-by-Design (QbD) domain.