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A general methodology for the determination of pK a values by CE was proposed in 1992, and further refined by the addition of terms concerning the rate of electroosmotic flow and a method of handling potential discontinuities between buffer electrolytes.62,63 An important step was made by Ishihama64 when he studied multivalent compounds and derived relationships between pK a and zone mobility that were more easily applicable than the earlier equation proposed by Kiso.58 Developments over the next decade would include further examinations of the pK a equations, comparing different regression techniques, and better experimental methods.65 Improvements included using charged polymer coatings of the capillary wall to influence the rate, influencing the electroosmotic flow to enable measurements at a lower pH,66 and the use of pressure applied over the capillary to shorten measurement times for screening purposes.67 Recent work includes efforts undertaken by Fuguet et al68–70 to improve the internal standard method first proposed by Gluck and Cleveland.65 High performance liquid chromatography The first observation that the time of elution can be changed by adjusting the pH level was made by Singhal.71 By changing the pH, the performance of the HPLC was optimized, in this case ion-exchange chromatography
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