Alkalimetry in alcohol–water mixtures with potentiometric end-point detection: Critical remarks on a newer method of European Pharmacopoeia Original Research Article

A new method of the European Pharmacopoeia (Ph. Eur.)—alkalimetry in alcohol–water mixture with potentiometric end-point detection—for the assay of halide salts of alkaloids and other organic N-bases has been investigated using 13 substances. The results were compared to those obtained by nonaqueous direct acidimetry. In general, our measurements show that the Ph. Eur. method may be regarded as an environment-friendly, precise, reproducible approach, with average S.D. ±0.33. However, in six cases out of 13, the method did not work. In these cases, the first inflexion point, which should appear due to the neutralization of a defined, small volume of HCl added to the solution of the sample before the titration, was missing on the potentiometric titration curves. This was observed for papaverine chloride, pilocarpine chloride, pyridoxine chloride, thiamine chloride, histamine dichloride and noscapine chloride; this missing inflexion point hampered the exact measurement of the alkaloid content. This study shows that the method, in the present official form, can be applied only for compounds with pKa values of seven or higher. For the salts of weaker bases, a modified approach (titration in 70% ethanol, without addition of HCl) is proposed.