Operação ótima de reator para síntese enzimática de ampicilina com cristalização simultânea dos produtos
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2007-03-05Autor
Ribeiro, Marcelo Perencin de Arruda
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Nowadays, industrial production of semi-synthetic penicillins requires low
temperatures, organochloride solvents and yields a great amount of non-recyclable wastes.
During the last decades, concerns about environmental impacts have increased, as well as the
environmental legislation restrictions. Thus, the pursuit of cleaner routes has been
encouraged. Enzymatic synthesis of these antibiotics, using penicillin G acylase (PGA) as
biocatalyst, may be carried out at mild temperatures and pH, and is an environmentalfriendly
route, alternative to the chemical synthesis. However, the low yields of the
enzymatic process are still a drawback for their industrial implementation. An enzymatic
semi-batch reactor using aqueous-precipitated medium is a promising approach to improve
process efficiency. Yet, finding the optimal operation condition of the reactor is still a
challenge, in order to make the enzymatic route economically competitive.
This thesis addresses this issue, focusing on several aspects of the enzymatic
synthesis of ampicillin. The comprehension of the reaction mechanism, still not a consensus
in the literature, was improved especially with respect to the role of the beta-lactam nucleus
during the formation of the acyl-enzyme intermediate, which has important consequences on
the reactor operation.
Diffusion in the biocatalyst pores and its influence on the pH profile within this
micro-environment were assessed through computer simulations. Results indicate
considerable diffusion resistances within the biocatalyst, yielding important pH profiles. The
process complexity leaded to the use of simplified mechanistic or empirical kinetic models.
Applying dynamic optimization (optimal control) techniques, feed profiles for
the reactants were obtained. A simplified model for the integrated semi-batch reactor for enzymatic synthesis of ampicillin with product crystallization was used for this purpose.
Different techniques of dynamic optimization provided qualitatively the same optimum
heuristics for the process operation.
Since simplified models were used in optimal open-loop control algorithms,
theoretical feed policies may diverge from those that would be needed to maintain the track of
the concentration profiles of the optimized reactor. Moreover, disturbances in the input
variables might lead the system to a different course. Thus, on-line monitoring is essential in
pilot plants or industrial reactors. Multivariate calibration using UV spectra was the basis for
the development of a system of analysis via flow injection (FIA), with good results.
Ampicillin synthesis assays using an industrial biocatalyst (Recordatti, Italy)
were run in order to improve some simplified kinetic models.
The re-estimated models were inserted in optimization algorithms, providing
trajectories in accordance with the same heuristics previously obtained. Experimental results
obtained after two runs in the integrated semi-continuous reactor put into evidence a
mismatch between model responses and the real process. This difference may be explained by
the extrapolation of the kinetic model with respect to the enzymatic reactor load. On the other
side, using a biocatalyst wrapped with a secondary inert matrix might alter the microenvironment
of the enzyme, especially with respect to pH.
Using a model that takes into account the effect of pH on the kinetics seems to
be important to allow the fine-tuning of the industrial reactor selectivity and productivity.