Scaling up of chromatographic separations

Lode EG, Rosenfeld A, Yuan QS, Root TW, Lightfoot EN. Refining the scale-up of chromatographic separations. J Chromatogr 1998 796 3-14. 

Scale-up of chromatographic separations usually is done by testing at several sizes following a sequence such as analytical column. I in. (245 mm) diameter preparative column, 6 in. (15 cm) diameter eolumn. 3 ft (1 m) diameter column, with optimum injection-eJution policy determined at each step. Each scale of operation has its own distribation and packing method problems associated with it, which can ba solved only partially by resting at a smaller scale. 

The approach taken is loosely based on the input-process-output meta-model utilized to transform a problem statement into a functional process. The section Scope definition discusses the intended purpose and potential constraints of the isolation effort, followed by an overview of the Toolbox available to the practitioner (input). The section Method development scouting and scale-up reviews platform-based, highly automated approaches to selectivity scouting, development of the isolation as well as options for scaling up the chromatographic separation depending on purpose and constraints (process). The final section. Performing the task, explores a work breakdown structure approach to the preparative isolation of impurities as a unit operation in the development process (output). 

The reader will find here a complete mathematical development of the models of chromatography and other physical laws which direct the chemical engineer in the design and scale-up of chromatographic processes. For preparative chromatographic separations, our ultimate purpose is the optimization of the experimental conditions for maximum production rate, minimum solvent consumption, or minimum production cost, with or without constraints on the recovery yield. The considerable amormt of work done on this critical topic is presented in the... 

The concept of theoretical plates in chromatography is described elsewhere, and is not repeated here (18,19). Pieri et al. have described the application of the theoretical plate concept to column scale-up and demonstrated its utility in scale-up of pheromone separation over silica gel (15). We have found this same approach to be useful in separations over ion exchange resins used as chromatographic supports. In essence, this approach gives an estimate of column length for a given separation if the particle size is changed. This is based on empirical correlation of the number of theoretical plates, JV, ... 

M. Seko, H. Takeachi, and T. lnada. Scale-up for Chromatographic Separation of p-Xylene and... 

Another important simpliflcation, which makes the scale-up of chromatographic plants easier, is to always use the same feed concentration. Since higher feed concentration also results in higher productivity, feed concentration is fixed at the maximum allowed concentration, which depends on the chromatographic system and the solubility of the feed components. However, in SMB processes, feed concentration affects the size of the operating parameter region for a total separation and. 

Dingenen, J. (2005) Scaling-up of preparative chromatographic enantiomer separations, in Preparative... 

From a medicinal chemist s perspective, nuclear magnetic resonance (NMR) was still the analytical tool of choice, whereas mass spectrometry, infrared (IR), and elemental analyses completed the necessary ensemble of analytical structure confirmation. Synthesis routines were capable of generating several milligrams of product, which is more than adequate for proton and carbon NMR experiments. For analyses that involved natural products, metabolites, or synthetic impurities, time-consuming and often painstaking isolation methods were necessary, followed by expensive scale-up procedures, to obtain the necessary amount of material for an NMR experiment. In situations that involved trace-mixture analysis, radiolabeling approaches were often used in conjunction with various formats of chromatographic separation. 

Lor a particular analytical separation, each biosolute will have an optimal k] value for maximum resolution with a designated column, flow rate, and mobile phase composition. Similar criteria apply in preparative (overload) chromatography with multicomponent mixtures, where resolution is similarly enhanced following optimization of chromatographic selectivity and zone bandwidth. The conventional approach to process purification with low molecular weight solutes has frequently been based on linear scale-up of the performance of an analytical column system. In these cases, high-resolution separations can be achieved often without the burden of conformational or... 

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