Method development scouting and scale-up

Detailed aspects of analytical and preparative chromatography are discussed in two fundamental monographs [11, 12]. The identification of a chromatographic system providing adequate selectivity (a), that is, sufficient separation of the compound of interest from the closest eluting peak (critical pair), often is the most challenging task given the solubility - often lack thereof - of the feed, as discussed in Section 7.4.3. 

It is worthwhile to restate that the target of the method development is to maximize the separation of the critical pair, not the separation of all components from each other, as would be the case for a stability-indicating impurity profile method. The capacity factor k ) should be in the range of 1 to 5 to avoid the potential for coelution with early eluting compounds or impractical mn times. 

Coupling a screening system with an analytical fraction collector can be helpful when very small amounts (submilligrams to single-digit milligrams) are required. It often also provides the first opportunity to isolate enriched samples for further use in the method development, for example, as retention time markers. The choice of stationary phases in the method development system can be based on 

the availability of the packing material in bulk or in larger format columns  

a chemometric-based evaluation of the selectivity space using a defined or historic sample set. 

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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). 

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