title: Physico-chemical profiling of semisynthetic opioids.
abstract: 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.
authors.affiliation: Semmelweis University, Department of Pharmaceutical Chemistry, Research Group of Drugs of Abuse and Doping Agents, Hungarian Academy of Sciences, Hőgyes E. u. 9., H-1092 Budapest, Hungary. Electronic address: mazak.karoly@pharma.semmelweis-univ.hu.
authors.forename: Károly
authors.initials: K
authors.lastname: Mazák
authors.affiliation: Semmelweis University, Department of Pharmaceutical Chemistry, Research Group of Drugs of Abuse and Doping Agents, Hungarian Academy of Sciences, Hőgyes E. u. 9., H-1092 Budapest, Hungary.
authors.forename: Sándor
authors.initials: S
authors.lastname: Hosztafi
authors.affiliation: Semmelweis University, Department of Pharmaceutical Chemistry, Research Group of Drugs of Abuse and Doping Agents, Hungarian Academy of Sciences, Hőgyes E. u. 9., H-1092 Budapest, Hungary.
authors.forename: Márta
authors.initials: M
authors.lastname: Kraszni
authors.affiliation: Semmelweis University, Department of Pharmaceutical Chemistry, Research Group of Drugs of Abuse and Doping Agents, Hungarian Academy of Sciences, Hőgyes E. u. 9., H-1092 Budapest, Hungary.
authors.forename: Béla
authors.initials: B
authors.lastname: Noszál
mesh_terms: D000701:Analgesics, Opioid / Q000737:chemistry*; D055598:Chemical Phenomena; D004090:Dihydromorphine / Q000737:chemistry*; D004091:Hydromorphone / Q000737:chemistry*; D009266:Nalbuphine / Q000737:chemistry*; D009269:Nalorphine / Q000737:chemistry*
chemical_list: D000701:Analgesics, Opioid; D004090:Dihydromorphine; D009266:Nalbuphine; D004091:Hydromorphone; D009269:Nalorphine
keywords: Dihydromorphine; Hydromorphone; Lipophilicity; Microscopic protonation constant; Nalbuphine; Nalorpine