Real-Time Monitoring of Solid–Liquid Slurries: Optimized Synthesis of Tetrabenazine
Yusuke Sato, Junliang Liu, Andrew J. Kukor, Jeffrey C. Culhane, John L. Tucker, David J. Kucera, Brian M. Cochran, Jason E. Hein
Abstract
Solid-liquid slurries are vital and increasingly prevalent in the pharmaceutical and chemical industries. Despite the importance of these heterogeneous systems, process control and optimization are fundamentally hindered by a lack of compatible real-time analytical techniques. We present herein an online HPLC monitoring platform enabling access to real-time compositional information on slurries. We demonstrate the system by investigating the heterogeneous synthesis reaction of tetrabenazine. Furthermore, we integrated our online HPLC platform with the orthogonal monitoring techniques of a pH probe and a microscopic imaging probe to provide additional mechanistic insight. These combined insights enable the optimization of tetrabenazine synthesis in terms of reaction time, byproduct formation, and diastereomeric purity of the final product.