Site-specific acid-base properties of pholcodine and related compounds

Z. Kovács, S. Hosztafi, B. Noszál

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

The acid-base properties of pholcodine, a cough-depressant agent, and related compounds including metabolites were studied by 1H NMR-pH titrations, and are characterised in terms of macroscopic and microscopic protonation constants. New N-methylated derivatives were also synthesized in order to quantitate site- and nucleus-specific protonation shifts and to unravel microscopic acid-base equilibria. The piperidine nitrogen was found to be 38 and 400 times more basic than its morpholine counterpart in pholcodine and norpholcodine, respectively. The protonation data show that the molecule of pholcodine bears an average of positive charge of 1.07 at physiological pH, preventing it from entering the central nervous system, a plausible reason for its lack of analgesic or addictive properties. The protonation constants of pholcodine and its derivatives are interpreted by comparing with related molecules of pharmaceutical interest. The pH-dependent relative concentrations of the variously protonated forms of pholcodine and morphine are depicted in distribution diagrams.

Original languageEnglish
Pages (from-to)1709-1716
Number of pages8
JournalAnalytical and Bioanalytical Chemistry
Volume386
Issue number6
DOIs
Publication statusPublished - Nov 1 2006

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Keywords

  • Acid-base equilibria
  • Metabolites
  • Microspeciation
  • Pholcodine
  • Protonation

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biochemistry

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