Population, basicity and partition of short-lived conformers. Characterization of baclofen and pregabalin, the biaxial, doubly rotating drug molecules

Tamás Pálla, Gergő Tóth, Márta Kraszni, Arash Mirzahosseini, B. Noszál

Research output: Contribution to journalArticle

Abstract

Populations, protonation constants and octanol-water partition coefficients were determined and assigned specifically to fast interconverting individual conformers, exemplified in baclofen and pregabalin, the GABA-related drug molecules of biaxial, double rotations. Rotamer statuses along both axes in water and octanol were elucidated from 1H NMR vicinal coupling constants. Conformer abundances were obtained by the appropriate combination of the rotamer populations in the two adjacent moieties in the molecule. The bulky aromatic group in baclofen versus the aliphatic side chain of pregabalin explains why baclofen exists mainly in trans-trans conformeric form, throughout the pH range, unlike pregabalin that has no any highly dominant form. Characteristically enough, for pregabalin, the lipophilicity of the conformers is primarily influenced by the conformation state. Conformers in gauche state are of higher lipophilicity. The conformers of the two compounds were ranked by their membrane-influx and –outflow propensities.

Original languageEnglish
Pages (from-to)327-334
Number of pages8
JournalEuropean Journal of Pharmaceutical Sciences
Volume123
DOIs
Publication statusPublished - Oct 15 2018

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Baclofen
Octanols
Pharmaceutical Preparations
Population
Water
gamma-Aminobutyric Acid
Membranes
Pregabalin

Keywords

  • Double-axis
  • Microspeciation
  • Rotamer

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Population, basicity and partition of short-lived conformers. Characterization of baclofen and pregabalin, the biaxial, doubly rotating drug molecules. / Pálla, Tamás; Tóth, Gergő; Kraszni, Márta; Mirzahosseini, Arash; Noszál, B.

In: European Journal of Pharmaceutical Sciences, Vol. 123, 15.10.2018, p. 327-334.

Research output: Contribution to journalArticle

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