Abstract
Integration of racemization and a resolution process is an attractive way to overcome yield limitations in the production of pure chiral molecules. Preferential crystallization and other crystallization‐based techniques usually produce low enantiomeric excess in solution, which is a constraint for coupling with racemization. We developed an enzymatic fixed bed reactor that can potentially overcome these unfavorable conditions and improve the overall yield of preferential crystallization. Enzyme immobilization strategies were investigated on covalent‐binding supports. The amino acid racemase immobilized in Purolite ECR 8309F with a load of 35 mg‐enzyme/g‐support showed highest specific activity (approx. 500 U/g‐support) and no loss in activity in reusability tests. Effects of substrate inhibition observed for the free enzyme were overcome after immobilization. A packed bed reactor with the immobilized racemase showed good performance in steady state operation processing low enantiomeric excess inlet. Kinetic parameters from batch reactor experiments can be successfully used for prediction of packed bed reactor performance. Full conversions could be achieved for residence times above 1.1 min. The results suggest the potential of the prepared racemase reactor to be combined with preferential crystallization to improve resolution of asparagine enantiomers.
Highlights
Manufacturing optically pure compounds is important for the pharmaceutical and fine chemical industries
Preferential crystallization and other crystallization-based techniques usually produce low enantiomeric excess in solution, which is a constraint for coupling with racemization
In this work we focus on the combination of batch Preferential crystallization (PC) and racemization (Figure 1A)
Summary
Manufacturing optically pure compounds is important for the pharmaceutical and fine chemical industries. Pure chiral molecules can be obtained by resolution of racemic mixtures, but these separation methods suffer from a maximum yield of 50% with respect to the desired enantiomer. We propose the combination of preferential crystallization, a cost-effective resolution process, with a packed bed reactor containing the immobilized racemase. This process design has the potential to maximize yield to 100% with high product purity, while providing convenient enzyme-product separation and catalyst reuse. Racemization kinetics of pure free racemase was determined at different temperatures and the AAR behavior was evaluated for various reaction conditions such as dosage (relative amount of enzyme) and initial enantiomeric excess. We reported results on the racemase performance in a packed bed reactor at steady state conditions
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