Ion association titration for the determination of local anesthetics in pharmaceuticals with tetrabromophenolphthalein ethyl ester as an indicator.

Solvent extraction–spectrophotometries based on ion association formation have been established for the improvement of the sensitivity for the determination of ionic compounds such as anionic and cationic surfactants using hydrophobic dye ions. For example, anionic surfactants were determined using Methylene Blue,1 Ethyl Violet,2 Co(III)-5-Cl-PADAP3 and Malachite Green.4 Bromocresol Green,5 2,6dichlorophenolindophenol6 and tetrabromophenolphthalein ethyl ester (TBPE)7,8 have been used for the determination of cationic surfactants and disinfectants. These methods were developed for enhancing their extractability and removing interfering substances. Though the sensitivities of these methods were very good, the procedures were tedious and timeconsuming. As a simple method, two phase titration utilizing ion associate extraction has been developed.9–11 However, it was very difficult to determine an end point in two phase titration methods reported so far, because the color change at the end point was attributed to the phase transfer of the ion associate formed with an indicator; the difference of hues between an aqueous and an organic phase was not clear, and color reflection gives a serious error. Tsubouchi et al. reported12,13 that, when TBPE was used as an indicator, it was possible to detect a color change only in the organic phase because of the direct formation and extraction of ion associate with the indicator existing in the organic phase. The method has been applied to the determination of quaternary ammonium salts.12,13 Later, the author (T. S.) found that ion associates formed between aromatic amines and TBPE were red or redviolet.14 The present paper deals with ion association titration of local anesthetic pharmaceuticals such as procaine, dibucaine and tetracaine (Scheme 1), providing sharp end point detection and high precision as well as the possibility of differential titration of mixtures including quaternary ammonium salts and aromatic amines. Experimental