Swishing and Swish TLC: The Most Important Analytical Paper Ever for Chemical Process Development

In Kilomentor’s assessment, the most important analytical paper in the literature in terms of usefulness to process development chemists is almost unknown.  George B. Smith and George V. Downing wrote a note called Phase Solubility Analysis as the Basis of a Separation Method [Anal. Chem. 51(13) 2290-2293 (1979).]

In this article, the authors describe a polishing purification technique for essentially pure chemical solids used at Merck Sharpe & Dohme laboratories informally called “swishing.” 

The technique is not readily applicable to small samples. Swishing is actually an exhaustive equilibrium trituration.

Swish purification of several grams or several hundred grams of material is accomplished by overnight equilibration in a suitable liquid (an anti-solvent or very poor solvent), with magnetic stirring on a small scale or with mechanical agitation in a Morton flask for large quantities. This is followed by filtering, separating, and retaining the filtrate. 

Separating the trituration liquid from the residual solid results in a highly purified solid phase on the one hand and a solution in which many minor impurities are dramatically concentrated on the other.  It is the enriched impurities in the filtrate that are of particular interest here. When thin-layer chromatography (TLC) is used to see the pattern and intensities of the impurities, the combined method is called Swish TLC. 

If the solid mixture of impurities and main compound from one swishing is now subjected to a second swish purification, the impurities may be even further concentrated, often sufficient to provide samples of one or more impurities, which are often of previously undetermined structure. The technique is a powerful resource to identify and characterize minor impurities, for a Drug Master File, for example. Very often swish TLC can reveal impurities that are otherwise below the limit of detection of the standard analytical method. 

Swish TLC is also a forensic method by which patterns of impurities 'fingerprint' a particular process used to manufacture a substance.

Swish purification and swish TLC could usefully be studied using constant boiling azeotropic mixtures which are predominantly either water or hydrocarbons but contain small amounts of other solvents which would provide a useful boost to the overall solvency.

It strikes me, although I can find no experimental implementations, that using a blender to macerate the solid in the antisolvent might make the technique more efficient.