Journal article
Crystallization Kinetics of Cephalexin Monohydrate in the Presence of Cephalexin Precursors
Crystal growth & design, v 19(9), pp 5065-5074
04 Sep 2019
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Abstract
The solubility and crystallization kinetics of cephalexin monohydrate, an important beta-lactam antibiotic, are reported for the first time for an aqueous solution. The nucleation and growth kinetics are determined with online process analytical technologies (PAT) and offline image analysis to support implementation of a continuous process. Effects of two cosolutes, 7-aminodesacetoxycephalosporanic acid (7-ADCA) and phenylglycine methyl ester (PGME), on nucleation and growth are examined. These cosolutes are precursors in the enzymatic synthesis of cephalexin. Primary nucleation of cephalexin was unaffected by the cosolutes, but 7-ADCA, even in small quantities (<10 mM), significantly decreased the cephalexin monohydrate growth rate; PGME had a less significant impact on growth rate. Possible mechanisms of growth inhibition are discussed; a model wherein cosolutes slow growth by pinning advancing growth steps and halting step advancement below a critical supersaturation best explains the data. Impact on crystal purity is also discussed. The needle-like shape of cephalexin monohydrate caused two mixing issues: (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 mixing issues limited determination of secondary nucleation kinetics to a modest range of conditions. 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. These kinetic data, PAT tools, and process insights are discussed in the context of a continuous manufacturing scenario.
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Details
- Title
- Crystallization Kinetics of Cephalexin Monohydrate in the Presence of Cephalexin Precursors
- Creators
- Matthew A. McDonald - Georgia Institute of TechnologyGrant D. Marshall - Georgia Institute of TechnologyAndreas S. Bommarius - Georgia Institute of TechnologyMartha A. Grover - Georgia Institute of TechnologyRonald W. Rousseau - Georgia Institute of Technology
- Publication Details
- Crystal growth & design, v 19(9), pp 5065-5074
- Publisher
- Amer Chemical Soc
- Number of pages
- 10
- Grant note
- U01FD006484-01 / U.S. FDA; United States Department of Health & Human Services Specialty Separations Center at Georgia Institute of Technology 1540017 / NSF I/UCRC Center for Pharmaceutical Development (CPD)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Chemical and Biological Engineering
- Web of Science ID
- WOS:000484830800020
- Scopus ID
- 2-s2.0-85069960356
- Other Identifier
- 991021958008404721
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InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Web of Science research areas
- Chemistry, Multidisciplinary
- Crystallography
- Materials Science, Multidisciplinary