Physicochemical Properties of Drug Molecules

Water can interact with ionic or polar substances and may destroy their crystal lattices. Since the resulting hydrated ions are more stable than the crystal lattice, solvation results. Water has a very high dielectric constant (80 Debye units [D] versus 21 D for acetone), which counteracts the electrostatic attraction of ions, thus favoring further hydration. The dielectric constant of a medium can be defined as a dimensionless ratio of forces the force acting between two charges in a vacuum and the force between the same two charges in the medium or solvent. According to Coulomb s law. 

Solubility is a function of many molecular parameters. Ionization, molecular structure and size, stereochemistry, and electronic structure all influence the basic interactions between a solvent and solute. As discussed in the previous section, water forms hydrogen bonds with ions or with polar nonionic compounds through -OH, -NH, -SH, and -C=0 groups, or with the nonbonding electron pairs of oxygen or nitrogen atoms. The ion or molecule will thus acquire a hydrate envelope and separate from the bulk solid that is, it dissolves. The interaction of nonpolar compounds with lipids is based on a different phenomenon, the hydrophobic interaction, but the end result is the same formation of a molecular dispersion of the solute in the solvent. 

The effect of solubility on drug action is, however, usually a question of equilibration of the drug between the aqueous phase and the lipid phase of the cell membrane. This leads us to a discussion of partition coefficients. 

The partition coefficient of a drug is defined as the equilibrium constant 

The partition coefficient and concepts derived from it are particularly important in explaining the mode of action of neurological drugs, such as anticonvulsants (chapter 8, section 8.1.5) and general anesthetics, which must penetrate the blood-brain barrier prior to exerting their biological effect. 

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UV/visible spectrophotometry is a standard method for determining the physicochemical properties of drug molecules prior to formulation and for measuring their release from formulations. The type of properties which can be usefully determined by the UV method are listed as follows. 

Figure 13.2 Relationships of basic physicochemical properties of drug molecules, as observed by Lipinski etal. [13]. The green arrows suggest limits for the respective properties that were proposed in the Lipinski rules. ...

The real breakthrough came in 1964 when Hansch and Fujita [4] described the logarithm of the biological activity within a series of compounds as a linear combination of different physicochemical properties of drug molecules. The lipophilicity was quantified as the partition coefficient, log P, in the system octanol-water. The authors also defined the contribution to the lipophilicity n, of substituents X ... 

Blake, J. F. Chemoinformatics -predicting the physicochemical properties of drug-like molecules. Curr. Opin. Biotechnol. 2000, 11, 104-107. 

Using molecular mechanics calculations to assess the three-dimensional shape of a molecule, various surface properties such as polarity and size can be calculated. The dynamic molecular surface properties can be determined from the (low energy) conformation(s) of the drug molecule obtained by molecular mechanics calculations of conformational preferences. The potential advantage of this method is that the calculated surface character-sitics determine numerous physicochemical properties of the molecules including lipophilicity, the energy of hydration and the hydrogen bond formation capacity [187-... 

To this point, various physicochemical properties of drugs such as lipophilicity, ionization, and partition coefficient have been discussed. While these are certainly major factors, there is an additional factor that can influence drug distribution, namely chirality. Chirality is a relatively unique structural characteristic of certain molecules that can exist in two asymmetric, nonsuperimposable isomers (enantiomers) due to the presence of a chiral center (a carbon atom that is attached to four different functional groups (see Chapters 5 and 13). 

The physicochemical properties of a molecule which affect its absorption across the nasal epithelium are broadly the same as those affecting transepithelial absorption at any site and have been discussed extensively in Section 1.3.4. These factors influence the mechanism and rate of drug absorption through the nasal epithelium. 

In this way it is possible to analyze how each of the physicochemical properties of the molecule is concerned with the drug action. Some examples are shown in Equations 4-11. In these equations, n is the number of points used in the regression, s is the standard deviation, and r is the correlation coefficient. 

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