(697d) Impurity Control in the Continuous Reactive Crystallization of Beta-Lactam Antibiotics

Beta-lactam antibiotics such as cephalexin and ampicillin can be synthesized and crystallized simultaneously with the use of penicillin G acylase (PGA) as a catalyst. However, PGA also catalyzes the degradation of the antibiotic to form a slightly soluble by-product—phenylglycine in the case of cephalexin or ampicillin—that can contaminate the solid product [1]. It is important that by-product concentration remain below the solubility limit so that pure antibiotic can be filtered immediately without the need for recrystallization or other further purification. In a continuous process, online detection of phenylglycine crystals is necessary to ensure product quality. Focused beam reflectance measurement (FBRM) has been used to observe the nucleation of the byproduct in real time. However, it is desirable to take preemptive action to avoid nucleation of the by-product at all. The combination of several process analytical technologies such as ATR-FTIR and inline polarimetry enable the detection of phenylglycine before the solubility limit is reached. Purity can then be enforced by changing the crystallizer conditions to increase enzyme selectivity or decrease enzyme activity, both at a cost to productivity and conversion, but without the need to stop the continuous process due to solid phase impurity. A model of the reactive crystallization system is used to inform controller actions. Experiments conducted in a fed-batch crystallizer, where phenylglycine accumulation is easier to control, are used to evaluate phenylglycine crystal detection by FBRM as well as model accuracy. A mixed-suspension mixed-product removal (MSMPR) crystallizer is used to evaluate different control actions, such as decreasing pH (which simultaneously decreases antibiotic solubility and increases PGA selectivity), changing temperature (increasing temperature decreases solubility of phenylglycine but increases PGA activity while decreasing temperature has the opposite effect), and changing feed reactant concentrations (changing the reactant ratio affects both selectivity and activity).

References:

[1] McDonald, M.A., Bommarius, A.S., and Rousseau, R.W. (2017) Chem. Eng. Sci. 165, 81-88.