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AAPS PharmSciTech

, Volume 9, Issue 1, pp 205–216 | Cite as

Influence of Position and Size of Substituents on the Mechanism of Partitioning: A Thermodynamic Study on Acetaminophens, Hydroxybenzoic Acids, and Parabens

  • German L. Perlovich
  • Tatyana V. Volkova
  • Alex N. Manin
  • Annette Bauer-Brandl
Research Article

Abstract

The objective of the present investigation was to study the influence of size, nature, and topology of substituents on the thermodynamic characteristics of sublimation, fusion, solubility, solvation, and partitioning processes of some drug and druglike molecules. Thermodynamic functions of sublimation process 2-acetaminophen and 3-acetaminophen were obtained on the basis of temperature dependencies of vapor pressure by the transpiration method. Thermodynamic characteristics of solubility processes in water, n-octanol, and n-hexane were calculated from the temperature dependencies of solubility using the solubility saturation method. For evaluation of fusion parameters, differential scanning calorimetry was used. A new approach to distinguishing specific and nonspecific energetic terms in the crystal lattice was developed. Specific and nonspecific solvation terms were distinguished using the transfer from the “inert” n-hexane to the other solvents. For the acetaminophen compounds and for some related drug molecules, the correlation between melting points and a parameter describing the ratio between specific and nonspecific interaction in the crystal lattices was obtained. A diagram enabling analysis of the mechanism of the partitioning process was applied. It was found that for isomers of benzoic acids and for acetaminophens, the position of substituents affects the mechanism of the partitioning process but not the extent of partitioning (\(\Delta G_{{\text{tr}}}^{\text{0}}\) values). In contrast to this, an increased size of substituents (parabens) leads to essential changes in \(\Delta G_{{\text{tr}}}^{\text{0}}\) values, but the mechanism of the partitioning process stays the same.

Key words

partitioning solubility solvation sublimation thermodynamics transfer 

Notes

Acknowledgment

This study was supported by the Russian Foundation of Basic Research no. 06-03-96304.

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Copyright information

© American Association of Pharmaceutical Scientists 2008

Authors and Affiliations

  • German L. Perlovich
    • 1
    • 2
  • Tatyana V. Volkova
    • 2
  • Alex N. Manin
    • 2
    • 3
  • Annette Bauer-Brandl
    • 1
  1. 1.Institute of PharmacyUniversity of TromsøTromsøNorway
  2. 2.Institute of Solution ChemistryRussian Academy of SciencesIvanovoRussia
  3. 3.Ivanovo State University of Chemical Sciences and TechnologyIvanovoRussia

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