Quality-by-Design (QbD): Examining the Impact of Process Variables On Particle Size Distribution for a Pharmaceutical Co-Precipitation Process Using Real-Time Lasentec FBRM and PVM Process Monitoring and Design of Experiments (DoE) Approach

Particle size distribution (PSD) is a critical quality attribute for many pharmaceutical unit operations, such as crystallization, granulation, mixing, and tabletting. Various formulation and process factors could impact PSD to different extents of a particular unit operation. Therefore, it is important to know how those variables impact the PSD and how to optimize various variables to achieve a desired PSD. These two aspects constitute an essential element of pharmaceutical process Quality-by-Design (QbD). In this work, a pharmaceutical (naproxen) and a polymer (eudragit) co-precipitation process was monitored in real-time by using Lasentec FBRM and PVM technologies. The impact of various process variables such as co-precipitation slurry temperature, non solvent addition rate, and stirring rate on the PSD of the co-precipiate were examined systematically, using a design of experiments (DoE) approach. The results were interpreted and discussed in the context of particulate process engineering principles. The practical implication of the process knowledge gained for the establishment of operational process space will be discussed under the framework of ICH Q8(R1).