Quality-by-Design: An Integrated Process Analytical Technology Approach to Determine the Nucleation and Growth Mechanisms During a Dynamic Pharmaceutical Coprecipitation Process

Abstract

The objective of this study was to demonstrate the feasibility of using an integrated process analytical technology (PAT) approach to determine nucleation and growth mechanisms of a dynamic naproxen (drug)-Eudragit L100 (polymer) coprecipitation process. The influence of several thermodynamically important formulation and process variables (drug/polymer ratio, alcohol, and water usages) on coprecipitation process characteristics was investigated via real-time in situ focused beam reflectance measurement (FBRM) monitoring and near real-time particle vision microscopy measurement. The final products were characterized by near-infrared (NIR) spectroscopy and NIR chemical imaging microscopy. The coprecipitation nucleation induction time (t(ind) ) was measured by both FBRM trend statistics and process trajectory method, respectively. Furthermore, nucleation kinetics was evaluated based on t(ind) measurement and corresponding supersaturation ratio (S) estimated. It was found that plots of ln(t(ind) ) versus (ln(2) S)(-1) consist of two linear segments and are consistent with classical primary nucleation mechanisms. Apparently, the coprecipitation process is governed by heterogeneous primary nucleation mechanism at low S (14 ≤ S ≤ 503) and by homogeneous primary nucleation mechanism at high S (1216 ≤ S ≤ 3649). Off-line characterizations collectively supported this statement. Therefore, it demonstrated that integration real-time PAT process monitoring with first-principles modeling and off-line product characterization could enhance understanding to coprecipitation process dynamics and nucleation/growth mechanisms, which is impossible via off-line techniques alone.