Extent and mechanism of solvation and partitioning of isomers of substituted benzoic acids: a thermodynamic study in the solid state and in solution

J Pharm Sci. 2008 Sep;97(9):3883-96. doi: 10.1002/jps.21260.

Abstract

Temperature dependency of saturated vapour pressure and thermochemical characteristics of fusion processes for 2-, 3- and 4-methoxybenzoic acids (anisic acids) were measured and thermodynamic functions of sublimation, fusion, and evaporation calculated. A new approach to split specific and nonspecific energetic terms in the crystal lattice was developed. For methoxybenzoic acid isomers as well as for a number of analogous molecules, a parameter describing molecular packing density by the ratio of free volume of the molecules in the crystal lattice and van der Waals molecular volume is defined. Its relationship to Gibbs energy of sublimation and to the respective melting points was analysed. Temperature dependencies of solubility in buffers with pH 2.0 and 7.4, n-octanol and n-hexane were measured. The thermodynamic functions of solubility, solvation and transfer processes were deduced. Concentration dependence of partition coefficients for the outlined isomers was measured. Specific and nonspecific solvation terms were distinguished using the transfer from the 'inert' n-hexane to the other solvents. Comparison analysis of specific and nonspecific interactions in the solid state and in solution was carried out. A diagram enabling analysis of the mechanism of the partitioning process was applied. It was found that position of substituents essentially affects the mechanism of partitioning in buffer pH 2.0, however, at pH 7.4, the mechanism is independent of the position of the substituent.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzoates / chemistry*
  • Calorimetry, Differential Scanning
  • Isomerism
  • Pharmacokinetics
  • Solubility
  • Solutions / chemistry*
  • Thermodynamics

Substances

  • Benzoates
  • Solutions