(322a) Continuous Synthesis, Crystallization, and Isolation of Amoxicillin

Authors: 
McDonald, M. A., Georgia Institute of Technology
Rousseau, R. W., Georgia Institute of Technology
Grover, M. A., Georgia Institute of Technology
Bommarius, A. S., Georgia Institute of Technology
Continuous synthesis, crystallization, and isolation of amoxicillin

Matthew A. McDonald*, Ronald W. Rousseau*, Martha A. Grover*, and Andreas S. Bommarius*

*School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, USA

Keywords: Continuous manufacturing, β-lactam antibiotics, reactive crystallization, penicillin G acylase

Amoxicillin is the highest-volume antibiotic in the world; production is in excess of 10,000 tons per annum. State-of-the-art production facilities use penicillin G acylase (PGA) immobilized on beads to first produce crude amoxicillin from the precursors 6-aminopenicillanic acid (6-APA) and 4-hydroxy phenylglycine methyl ester (4-HPGME), then purify the amoxicillin by crystallization(s), before finally readying it for formulation. Some of these steps have recently been made continuous, but the process is still characterized by a series of distinct batch operations. In this study, amoxicillin trihydrate, ready for formulation, is produced continuously in a single reactive crystallization[1]. The combination of reaction and crystallization has been shown to increase the yield of the PGA-catalyzed reaction and improve productivity of the entire process [2]. Process analytical technology is used to monitor the process and operate a segregation line, allowing aberrant material to be segregated from the product line without significant loss of material. The potential for model based feedback and feed-forward control is also discussed.

[1] McDonald, M. A., Bommarius, A. S., Rousseau, R. W., and Grover, M. A. (2019) Continuous reactive crystallization of β-lactam antibiotics catalyzed by penicillin G acylase. Part I: Model development, Computers & Chemical Engineering, 123, 331-343

[2] McDonald, M. A., Bommarius, A. S., Grover, M. A., and Rousseau, R. W. (2019) Continuous reactive crystallization of β-lactam antibiotics catalyzed by penicillin G acylase. Part II: Case study on ampicillin and product purity, Computers & Chemical Engineering, ACCEPTED