(477b) Direct Measurement of Growth Rate Dispersion in the Reactive Crystallization of Ampicillin Trihydrate

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

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

Keywords: Growth rate dispersion, β-lactam antibiotics, penicillin G acylase

In this study, the growth rates of individual ampicillin trihydrate crystals in isothermal and quiescent conditions were measured by optical microscopy. Supersaturation was generated by the penicillin G acylase (PGA) catalyzed reaction to synthesize ampicillin from 6-aminopenicillanic acid (6-APA) and phenylglycine methyl ester (PGME) [1]. The growth rate of ampicillin trihydrate crystals under the same conditions showed considerable variation, an example of growth rate dispersion (GRD). Quiescent conditions and isothermal generation of supersaturation allowed nucleation, breakage, and heat transfer to be eliminated as sources of GRD. Curiously, the crystals showed zero growth at low supersaturation; growth was activated only beyond a threshold supersaturation, possibly due to the presence of other species such as the reactants 6-APA and PGME. The growth rate and threshold supersaturation are correlated, and both also correlate with seed crystal size. Changes in solubility of ampicillin due to 6-APA or PGME were also ruled out, leading to the conclusion that each crystal has an intrinsic growth rate dependence on the supersaturation. [2]

[1] McDonald, M. A., Bommarius, A. S., and Rousseau, R. W. (2017) Enzymatic reactive crystallization for improving ampicillin synthesis, Chemical Engineering Science 165, 81-88.

[2] McDonald, M. A., Bommarius, A. S., and Rousseau, R. W. (2019) Direct measurement of growth rate dispersion during reactive crystallization of ampicillin trihydrate, Processes IN PREPARATION