Species-specific acid-base and partition equilibrium constants were experimentally determined for the therapeutically important semisynthetic opioid receptor agonist hydromorphone, dihydromorphine, and mixed agonist-antagonist nalorphine and nalbuphine. The acid-base microequilibria were characterized by combining pH-potentiometry and deductive methods using synthesized auxiliary compounds. Independent of the pH, there are approximately 4.8 times as many zwitterionic microspecies than non-charged ones in nalbuphine solutions, while for nalorphine it is the non-charged form that predominates by the same ratio. The non-charged microspecies is the dominant one also in the case of hydromorphone, although its concentration exceeds only 1.3 times that of its zwitterionic protonation isomer. The pH-independent partition coefficients of the individual microspecies were determined by a combination of experimentally measured, pH-dependent, conditional distribution constants and a custom-tailored evaluation method, using highly similar auxiliary compounds. The pH-independent contribution of the zwitterionic microspecies to the distribution constant is 1380, 1070, 3160 and 72,440 times smaller than that of the inherently more lipophilic non-charged one for hydromorphone, dihydromorphine, nalbuphine and nalorphine, respectively.
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