Influence of position and size of substituents on the mechanism of partitioning: a thermodynamic study on acetaminophens, hydroxybenzoic acids, and parabens

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 (DeltaG(tr)(0) values). In contrast to this, an increased size of substituents (parabens) leads to essential changes in DeltaG(tr)(0) values, but the mechanism of the partitioning process stays the same.

Fig. 1

Structure formula of 2-acetaminophen a, 3-acetaminophen b, N-(2-methylphenyl)acetamide c, and N-(4-methylphenyl)acetamide d

Fig. 2

Relationship between sublimation enthalpies, , and van der Waals volumes, V ^vdw, of selected molecular crystals. Dashed line corresponds to σ interval

Fig. 3

Dependence of the melting points, T _m, vs the ratio between specific and nonspecific terms, , of the crystal lattices. 2-OH-BA 2-Hydroxybenzoic acid, 3-OH-BA 3-hydroxybenzoic acid, 4-OH-BA 4-hydroxybenzoic acid, AcAN acetanilide, ASA acetylsalicylic acid, BA benzoic acid, BuPB butylparaben, EtPB ethylparaben, IBP ibuprofen, MePB methylparaben, Phenac phenacetin, PrPB propylparaben

Fig. 4

Relationship between the ɛ _H values for water vs the ratio between specific and nonspecific enthalpic terms in crystal lattices. The straight line corresponds to bisector. 2-OH-BA 2-Hydroxybenzoic acid, 3-OH-BA 3-hydroxybenzoic acid, 4-OH-BA 4-hydroxybenzoic acid, AcAN acetanilide, BuPB butylparaben, EtPB ethylparaben, MePB methylparaben, Phenac phenacetin, PrPB propylparaben

Fig. 5

Relationship between the ɛ _H values for n-octanol vs the ratio between specific and nonspecific enthalpic terms in crystal lattices. The straight line corresponds to bisector. 2-OH-BA 2-Hydroxybenzoic acid, 3-OH-BA 3-hydroxybenzoic acid, 4-OH-BA 4-hydroxybenzoic acid, AcAN acetanilide, BuPB butylparaben, EtPB ethylparaben, MePB methylparaben, Phenac phenacetin, PrPB propylparaben

Fig. 6

Relationship between the ɛ _H values for the water vs ɛ _H values for the n-octanol. The straight line corresponds to bisector. 2-OH-BA 2-Hydroxybenzoic acid, 3-OH-BA 3-hydroxybenzoic acid, 4-OH-BA 4-hydroxybenzoic acid, AcAN acetanilide, BuPB butylparaben, EtPB ethylparaben, MePB methylparaben, Phenac phenacetin, PrPB propylparaben

Fig. 7

Relationship between the enthalpic and entropic terms of transfer functions from the water to n-octanol. The isoenergetic curves of function are marked by dotted lines. 2-OH-BA 2-Hydroxybenzoic acid, 3-OH-BA 3-hydroxybenzoic acid, 4-OH-BA 4-hydroxybenzoic acid, AcAN acetanilide, BuPB butylparaben, EtPB ethylparaben, MePB methylparaben, Phenac phenacetin, PrPB propylparaben

Scheme 1

A schematic depiction of the relationships of the enthalpic and entropic terms of the transfer processes studied for the various diagram sectors (Fig. 7)