(322a) 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