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 in Merck Sharpe & Dohme laboratories informally called “swishing.” Swish purification of several grams or several hundred grams of material is accomplished by overnight equilibration in a suitable solvent (an anti-solvent or very poor solvent actually), with magnetic stirring on a small-scale or with mechanical agitation in a Morton (creased) flask for large quantities. This is followed by filtering and retaining the filtrate separately. The technique is not readily applicable to small samples. Swishing is actually exhaustive equilibrium trituration.
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.
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.
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