Thermodynamics and Molecular Orbital Calculations for the Parabens

Kenneth S. Alexander, University of Rhode Island


The intent of this study was to follow two approaches of scientific methodology in the investigation of a chemically related series of pharmaceutical preservatives, the parabens (esters of para-hydroxybenzoic acid). One approach involved the experimental determination of the solubilities of these compounds and also included their partition coefficient determination. The other approach, strictly theoretical in nature, was manifest by the utilization of molecular orbital theory in the determination of molecular parameters and their possible correlation with physico-chemical parameters and/or drug action.

The solubilities of a series of solutes related to each other by their increasing size in alkyl chain in an ester moiety are determined and compared. These compounds include benzoic acid, para-hydroxybenzoic acid and the methyl, ethyl, propyl, and butyl esters of parahydroxybenzoic acid. The effect of temperature upon the solubilities of these compounds in a series of n-alkanols allows for the calculation of thermodynamic parameters for these systems. Since heat of fusion values are available in the literature, then this leads to the determination of other theoretically important thermodynamic quantities which have been presented. This coupled with the experimentally evaluated thermodynamic elements, allows for some insight into the solubility mechanism. Previously enunciated empirical theory of dielectric requirements may be placed on a more quantitative basis.

The rather extensive experimental support of the multiplicity of solubility peak maxima for a single solute can be interpreted on a thermodynamic basis. The partition coefficient, an important physicalchemical property of biologically active drugs, was determined from a biphasic system of n-octanol-water at 25°C for each of the solutes. Correlation of this work with the previous work of Hansch and with rank order of activity

With respect to the determination of molecular parameters, appropriate computer programs were utilized to obtain the desired results for the following: aniline, para-aminobenzoic acid, phenol, benzoic acid, parahydroxybenzoic acid, methyl and ethyl esters of parahydroxybenzoic acid. It should be pointed out that the computer elements utilize the Iterated Extented Ruckel Theory (IEHT) approach, which contains assumptions of various types. For any series of molecules these assumptions are self consistent, however, so that comparisons can easily be made.

The approach taken in this portion of the study was to characterize these systems in terms of atomic charge distributions, effect of hydroxy (-OH) and ester groups (both sterically and electronically), preferred molecular conformations and distinguishing features of the molecular orbitals. A hypothesis as to the possible site of action leading to biological activity of these compounds has been proposed.