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ISBN 9783843920438

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978-3-8439-2043-8, Reihe Ingenieurwissenschaften

Christian Wolfrum
Zur verfahrenstechnischen Beschreibung der chemischen Synthese von Oligonukleotiden

152 Seiten, Dissertation Technische Universität Berlin (2015), Softcover, A4

Zusammenfassung / Abstract

New applications in pharmaceutical drug development, molecular diagnostic as well as totally new approaches outside the well-known applications create an increasing demand for chemically synthesized short DNA molecules, so called oligonucleotides. To perform a systematic analysis of the determining process parameters a computational fluid dynamics (CFD) model was developed. The model is designed for synthesis in packed bed reactors and includes an experimentally obtained reaction kinetic model. The results of simulations using the CFD model were validated with further experimental data in terms of flow conditions and reaction kinetics which showed a good match between the simulations and the experiments. Simulations were carried out to analyse the influence of process parameters like residence time and reactor geometry. Furthermore the negative impact of inhomogenities in the packed bed was shown. The CFD model was used to analyse the scale-up from gram to kilogram synthesis scales. It was shown that columns with length-to-diameter ratio of about 1 are best suited for kilogram scales in terms of pressure loss and synthesis efficiency. Although optimizing strategies for non-ideal setups could be shown. Besides the computational simulations of the state-of-the-art packed-bed based process a new synthesis approach was developed. The new synthesis process uses the differences in solubility of two polymers to utilize the advantages of performing the chemical reaction in homogenous liquid phase as well as easy and fast purification steps between the single reaction steps. All substances needed for the new synthesis have been successfully synthesized. The basic feasibility of the overall synthesis process has been proven through the synthesis of a dT dimer oligonucleotide.