(410b) Combining Reaction with Crystallization and a Size-Based Biocatalyst Separation for the Continuous Manufacturing of Amoxicillin
- Conference: AIChE Annual Meeting
- Year: 2022
- Proceeding: 2022 Annual Meeting
- Group: Pharmaceutical Discovery, Development and Manufacturing Forum
- Time: Tuesday, November 15, 2022 - 3:51pm-4:12pm
In this work, we combine the reaction and crystallization in the same mixed suspension mixed product removal (MSMPR) vessel to improve the selectivity and productivity of the system as well as intensify the overall process. Additionally, we operate the process in a continuous fashion, leading to increased productivity, decreased process footprint, and easier operation in comparison to a batch process. Biocatalyst retention within the reactor was achieved by immobilizing PGA on a solid support of a defined size range (300-425 Î¼m), and withdrawal of the product slurry through a stainless-steel mesh filter of 300 Î¼m, thereby achieving a size-based separation between product crystals and biocatalyst. As amoxicillin trihydrate crystals will grow much larger than 300 Î¼m normally without intervention, an external wet-mill loop was employed to decrease their size below the mesh filter threshold. Additionally, crystallization of amoxicillin was observed to be rate limiting, so we investigated the use of a second MSMPR, operated in the absence of biocatalyst, to allow for its complete desupersaturation from solution. It was determined that a residence time of 1 hour was sufficient to desupersaturate amoxicillin and improve product yield by 10%. Lastly, while these process improvements led to a high productivity of 500 g/L/d, the conversion of the beta-lactam donating moiety, 6-aminopenicillinoic acid (6-APA), and the side-chain donor, 4-HPGME, were low at only 53% and 40%, respectively. To address this limitation, we were able to isolate both substrates separately via pH-swing crystallization at pH values of 4.0 and 8.0 for 6-APA and 4-HPGME, respectively, exploiting their solubilityâs opposite sensitivity to changes in pH. With the recovery and reuse of substrates, the overall conversion, defined as the fraction of the compound fed into the system which does not leave the system as waste, was improved to greater than 90% for both substrates.
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