Design and operation of enzymatic reactive crystallization: Applications in chiral purity and kinetically controlled synthesis

Encarnacion-Gomez, Luis G.

Title:

Design and operation of enzymatic reactive crystallization: Applications in chiral purity and kinetically controlled synthesis

dc.contributor.advisor	Rousseau, Ronald W.
dc.contributor.author	Encarnacion-Gomez, Luis G.
dc.contributor.committeeMember	Bommarius, Andreas S.
dc.contributor.committeeMember	Kawajiri, Yoshiaki
dc.contributor.committeeMember	Realff, Matthew J.
dc.contributor.committeeMember	Liotta, Charles
dc.contributor.department	Chemical and Biomolecular Engineering
dc.date.accessioned	2016-01-07T17:22:32Z
dc.date.available	2016-01-07T17:22:32Z
dc.date.created	2015-12
dc.date.issued	2015-08-18
dc.date.submitted	December 2015
dc.date.updated	2016-01-07T17:22:32Z
dc.description.abstract	The work presented in this thesis is aimed to design efficient reactive crystallization operations that could potentially be implemented in the manufacture of enantiomerically pure compounds and β-lactam antibiotics. Multiple aspects of solution thermodynamics, reaction engineering and crystallization from complex solutions are involved and will be discussed in detail through the following chapters. The first piece of this work utilizes reactive crystallization for the manufacture of enantiomerically pure amino acids. Chemo-enzymatic stereoiversion reactions are used to enrich saturated or supersaturated solutions to favor the selection of a desired enantiomer. L-Methionine and L-Phenylalanine were resolve successfully from racemic mixtures by cyclic stereoinversion. r D-amino acids were oxidized by D-amino acid oxidase (D-AAO) and the resulting ketoacid was subsequently reduced by ammonia borane producing a racemic-mixture After the necessary enantiomeric enrichment was reached, system conditions were changed to induce supersaturation and promote crystal formation. In each case crystals with chemical and enantiomeric purities greater than 99% wt. were recovered. experimental information about reaction and crystallization kinetics was used to developed models. Such models were used to design model-based optimizations in which the productivity of the operation was enhanced by selecting an optimal temperature profile. The second example is a reactive crystallization towards the manufacture of β-lactam antibiotics. One of the major drawbacks of the utilization of enzymes towards the manufacture of β-lactam antibiotics is the fact that the same enzyme that catalyzes the synthesis of the antibiotic also catalyzes its hydrolysis and thus, its degradation. The reaction scheme is a kinetically controlled synthesis in which the desired product is an intermediate within the network. Hence, the focus of this work is to design an efficient reactive crystallization in which the product is crystallized before it is consumed by hydrolysis. In order to accomplish this goal we have study solution equilibria, reaction kinetics, and crystallization kinetics. Even though crystallization kinetics of ampicillin has been previously reported; the reported models are not applicable to a reactive crystallization scheme for a variety of reasons. In this work, we have developed a robust model that can be applied to multiple crystallization protocols that are consistent with the conditions at which the enzymatic reaction can be performed. Finally, a reactive-crystallization scheme in which ampicillin was successfully recovered from solution was developed. In this work, crystal seeds were used to promote crystallization of the desired product from the complex media. The results indicated that is possible to perform the reaction and crystallization in parallel, and still recover crystals with high purity. This work is the first example in which ampicillin was produced and recovered with high purity in a single stage. Previous work on reaction crystallization of antibiotics reported ampicillin crystallization; however, this was accompanied by precipitation of by-products which greatly reduces the applicability of the operation as product purification is required after the reaction.
dc.description.degree	Ph.D.
dc.format.mimetype	application/pdf
dc.identifier.uri	http://hdl.handle.net/1853/54322
dc.language.iso	en_US
dc.publisher	Georgia Institute of Technology
dc.subject	Crystallization
dc.subject	Reactive-crystallization
dc.subject	Enantiomers
dc.subject	Antibiotics
dc.title	Design and operation of enzymatic reactive crystallization: Applications in chiral purity and kinetically controlled synthesis
dc.type	Text
dc.type.genre	Dissertation
dspace.entity.type	Publication
local.contributor.advisor	Rousseau, Ronald W.
local.contributor.corporatename	School of Chemical and Biomolecular Engineering
local.contributor.corporatename	College of Engineering
relation.isAdvisorOfPublication	54a1d094-6cef-41c7-8168-e36b41eaf4f7
relation.isOrgUnitOfPublication	6cfa2dc6-c5bf-4f6b-99a2-57105d8f7a6f
relation.isOrgUnitOfPublication	7c022d60-21d5-497c-b552-95e489a06569
thesis.degree.level	Doctoral