Mathematical Modeling of Emulsion Solvent Diffusion for Spherical Crystallization: How To Deconvolute Primary Crystal Size Distribution from Agglomerate Size Distribution?

• Published in: Industrial & engineering chemistry research 2020-04, Vol.59 (13), p.6288-6300
• Main Authors: Pal, Kanjakha, Ramkrishna, Doraiswami, Nagy, Zoltan K
• Format: Article
• Language: English
• ISSN: 0888-5885; 1520-5045
• DOI: 10.1021/acs.iecr.9b05583

Spherical crystallization (SC) is a novel process intensification strategy, which can substantially reduce the manufacturing cost for solid oral dosage forms. However, although the manufacturability of the product agglomerates could be controlled, control over the product bioavailability has remained elusive. The major bottleneck over the simultaneous control over product manufacturability and bioavailability is the lack of in situ Process Analytical Technology (PAT) tools, which allow for multiscale monitoring of particulate processes. In this work, mechanistic population balance models (PBMs) have been used to obtain a multiscale understanding of the droplet population, as well as the crystal population within the droplets. The use of mechanistic models enables multiscale process understanding, which is very difficult with in situ PAT tools. The evolution of the crystal population within the droplets is found to be widely different for two different droplet sizes. The time scales of fundamental rate processes, viz. crystal nucleation and growth, have also been elucidated for different droplet sizes. The mathematical modeling framework developed here enhances process understanding and can set the foundation for implementation of a quality-by-design (QbD) framework for SC, which is strongly encouraged by the U.S. Food and Drug Administration (FDA).