(284a) Crystallization Kinetics of Cephalexin in the Presence of Cephalexin Precursors

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: impurity incorporation, β-lactam antibiotics, process analytical technology

Cephalexin is an important antibiotic that has seen growth across all markets over the past decade as use of other β-lactam antibiotics, such as amoxicillin, has decreased or plateaued. The nucleation and growth kinetics are determined with online process analytical technologies (PAT). Effects of two precursors to cephalexin, 7-aminodesacetoxycephalosporanic acid (7-ADCA) and phenylglycine methyl ester (PGME), on nucleation and growth are examined. Primary nucleation of cephalexin was unaffected by both precursors. Growth of cephalexin, however, was hindered by 7-ADCA, even in small quantities (<10 mM), and to a lesser extent by PGME. Possible mechanisms of growth inhibition are discussed; a model wherein the precursors slow growth by adsorbing to the crystal surface and pinning advancing growth steps best explains the data. Impact on crystal purity is also discussed. Secondary nucleation also appeared to be affected by the precursors but not to the same extent as growth. Offline image analysis indicated that secondary nucleation is dominant over primary nucleation and that breakage of high-aspect ratio crystals may play a role in crystal breeding. The needle-like shape of cephalexin monohydrate also resulted in two interesting phenomena: (1) at low stir rates dead zones formed when heterogeneous nuclei on baffles grew into a sherbet-like unmixed slurry and (2) at high stir rates the incorporation of air into the slurry resulted in the accumulation of a stable foam that did not interact with the liquid slurry. These kinetic data, PAT tools, and process insights are discussed in the context of a continuous manufacturing scenario [1].

[1] McDonald, M. A., Marshall, G. D., Bommarius, A. S., Grover, M. A., and Rousseau, R. W. (2019) Crystallization kinetics of cephalexin monohydrate in the presence of cephalexin precursors, Crystal Growth & Design, SUBMITTED