Acid-base extraction is efficient at separating compounds with a large difference in solubility between their charged and their uncharged form. Therefore, this procedure will not work for:
* Zwitterions with acidic and basic functional groups in the same molecule.
** For instance, glycine is soluble in water at most pH values and is therefore difficult to be extracted into organic media.
* Lipophilic compounds.
** Compounds such as tetrabutylammonium salts or fatty acids do not easily dissolve in the aqueous phase in their charged form.
* Basic amines.
** Amines like ammonia, methylamine, or triethanolamine are miscible or significantly soluble in water at most pH and cannot be extracted into organic media.
* Hydrophilic inorganic acids.
** Acids like acetic acid are indefinitely miscible in water and have limited solubility in organic solvents.