(646b) Crystallization Kinetics and Solubility of Amoxicillin Trihydrate in the Presence of Synthesis Substrates
- Conference: AIChE Annual Meeting
- Year: 2022
- Proceeding: 2022 Annual Meeting
- Group: Separations Division
- Time: Thursday, November 17, 2022 - 12:33pm-1:02pm
In this work, we investigated the solubility and crystallization of amoxicillin trihydrate with and without the presence of various reaction components, such as 4-hydroxyphenylglycine (4-HPG), 6-aminopenicillinoic acid (6-APA), and 4-hydroxyphenylglycine methyl ester (4-HPGME). The effects of pH, temperature, ionic strength, and presence of each component on the solubility of amoxicillin were determined. The solubility was found to increase with pH value, temperature, and ionic strength, and the three reaction components increased amoxicillin solubility, with 6-APA having the largest impact. However, ionic strength alone could not explain the increase in solubility in presence of the other reaction components, and there were possibly interactions occurring between the molecules of each reaction component and amoxicillin in the liquid phase. To confirm such interactions, single components and mixtures were analyzed via Raman and ATR-FTIR spectroscopy to explore possible interactions between the functional groups present in each compound and amoxicillin. The knowledge of amoxicillin solubility was important in determining its supersaturation under various conditions, which is the main driving force for crystallization.
We also conducted several seeded and unseeded batch amoxicillin crystallizations with and without the presence of 6-APA or 4-HPGME. We used offline microscopy and focused-beam reflectance measurement (FBRM) to monitor the solid phase, with high performance liquid chromatography (HPLC) to monitor the liquid phase. Solid and liquid phase data were fit to classical nucleation and growth models. Differences in nucleation and growth parameters with pure amoxicillin and in the presence of 6-APA or 4-HPGME were examined. A model considering the effects of 6-APA and 4-HPGME on the crystallization of amoxicillin hydrate was developed and may be incorporated into a reactive crystallization model to inform future manufacturing processes for the more efficient production of amoxicillin.
- EncarnaciÃ³n-GÃ³mez, L.G., A.S. Bommarius, and R.W. Rousseau, Reactive crystallization of Î²-lactam antibiotics: strategies to enhance productivity and purity of ampicillin. Reaction Chemistry & Engineering, 2016. 1(3): p. 321-329.
- McDonald, M.A., et al., Continuous reactive crystallization of Î²-lactam antibiotics catalyzed by penicillin G acylase. Part I: Model development. Computers & Chemical Engineering, 2019.
- Fan, Y., Y. Li, and Q. Liu, Enhanced Dissolution of 7-ADCA in the Presence of PGME for Enzymatic Synthesis of Cephalexin. Applied Biochemistry and Biotechnology, 2021.