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Evaluation of the p K a values and ionization sequence of bumetanide using 1 H and 13 C NMR and UV spectroscopy
Author(s) -
Song Benben,
Galande Amit K.,
Kodukula Krishna,
Moos Walter H.,
Miller Susan M.
Publication year - 2011
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.20443
Subject(s) - deprotonation , bumetanide , chemistry , aqueous solution , ionization , proton nmr , nuclear magnetic resonance spectroscopy , carbon 13 nmr , ion , analytical chemistry (journal) , stereochemistry , organic chemistry , ion transporter
Non‐thiazide loop diuretics such as bumetanide and furosemide are well‐established medicaments, with varying substituents that alter their chemical properties in ways that affect biological parameters, including biodistribution, efficacy, and safety. However, literature data supporting the assignment of p K a values and ionization sequence of bumetanide are limited. The present study summarizes available literature data and then characterizes nuclear magnetic resonance (NMR) and ultraviolet (UV) spectral changes over a range of pH values to delineate the apparent sequence of deprotonations. Three macroscopic p K a values, 1.44, 3.74, and 10.37, were determined in water via pH titration experiments monitored by 1 H NMR. Both 1 H and 13 C analyses support assignment of the lowest p K a value to the anilinium ion, as described for another diuretic, piretanide. However, UV data suggest that initial deprotonation of the benzoic acid competes to some extent with deprotonation of the anilinium ion, such that both pathways may operate simultaneously in an aqueous environment. Thus, the observed p K a values likely represent the macroscopic averages of the two competing deprotonation sequences. Calculated p K a values for bumetanide, piretanide, and model compounds are contrary to the deprotonation sequence we and others have determined experimentally, which is not surprising given the complicated factors driving the acid–base properties of these molecules. Drug Dev Res 72: 416–426, 2011. © 2011 Wiley‐Liss, Inc.