Scholtzova, Angela; (2000) The scale up and modelling of high performance liquid chromatography. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis concerns the scale up and modelling of High Performance Liquid Chromatography. It aims to fulfil the need for a good empirical model which describes and predicts chromatographic performance but without recourse to a mathematical procedure which requires many assumptions and is mainly theoretical. The project therefore attempted to predict large-scale separations from small-scale analyses on the basis of fractionation diagrams. The results show that the target was met in part i.e. the model was developed but could not be verified on a large scale. The reason was the unexpectedly good separation on a large scale which equalled that achieved on the analytical scale. The project also aimed to show the sensitivity of the large scale separation to process variables, and to devise a practical protocol for running large scale chromatographic separations. The thesis contains reports of experimental optimisation of chromatography conditions which will be of interest to other chromatographic researchers. The large scale column can be packed and operated satisfactorily provided certain rules are observed. The detailed points are summarised in the conclusion to the thesis (Chapter 5). Its claims to originality and novelty are: the use of fractionation diagrams as a modelling tool for chromatographic processes. A detailed examination of 35 micron particles of polymeric origin in a large scale HPLC column (silica is widely used and majority of experiments are carried out on analytical scale). Comparisons of the behaviour of samples of different diffusion coefficient on a large scale column at various flow rates (h/v curves and the related implications). A novel method for the determination of column band broadening and extra-column band broadening. The thesis is laid out as follows: 1. The introduction section contains an overview of the history and development of HPLC, a literature survey of erythromycin analytical separation techniques, all the chromatographic theory relevant to this project including band broadening, column supports, etc., and a brief review of models used in mathematical modelling. 2. The results section describes the analytical separation of aromatic compounds where familiarisation with the HPLC system and the theory is outlined; this is followed by the analytical separation of erythromycin where the method for the separation of erythromycin is described and several aspects of the separation are investigated. The semi-preparative stage mainly describes the treatment of the packing material and the packing of the columns for the scale up studies. The natural progression to a large scale Prochrom column (180 x 60 mm) is then shown together with an explanation of the system, its operation and its results, with particular regard to efficiency and band broadening. Finally, the principles of modelling using fractionation diagrams are explained and the theory supported by results. 3. Discussion of the results obtained: a) Comparisons of the performance of large and small scale chromatography columns. b) The role of extra-column band broadening in large scale chromatography with regard to velocities and Reynolds number. c) Discussions and conclusions of findings of modelling studies based on fractionation diagrams.

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