Chapter 1
Physicochemistry
Abbreviations
CPC | Centrifugal partition chromatography |
CoMFA | Comparative field analysis |
CsA | Cyclosporine A |
3D-QSAR | Three-dimensional quantitative structureâactivity relationships |
HDM | Hexadecane membrane |
IUPAC | International Union of Pure and Applied Chemistry |
MLP | Molecular lipophilicity potential |
PAMPA | Parallel artificial membrane permeability assay |
PGDP | Propylene glycol dipelargonate |
PSA | Polar surface area |
RP-HPLC | Reversed-phase high-performance liquid chromatography |
SF | Shake flask, referring to traditional method of measuring log P or log D |
TPSA | Topological polar surface are |
Symbols
APSUV | Absorption potential measured in small unilamellar vesicles (SUV) |
Îlog D | Difference between log D in octanol/water and log D in alkane/water |
Îlog P | Difference between log P in octanol/water and log P in alkane/water |
f | Rekker or Leo/Hansch fragmental constant for log P contribution |
Ka | Ionization constant |
Î | Polarity term, mainly related to hydrogen bonding capability of a solute |
log P | Logarithm of the partition coefficient (P) of neutral species |
log D | Logarithm of the distribution coefficient (D) at a selected pH, usually assumed to be measured in octanol/water |
log Doct | Logarithm of the distribution coefficient (D) at a selected pH, measured in octanol/water |
log Dchex | Logarithm of the distribution coefficient (D) at a selected pH, measured in cyclohexane/water |
log D7.4 | Logarithm of the distribution coefficient (D) at pH 7.4 |
MW | Molecular weight |
Ď | Hansch constant; contribution of a substituent to log P |
pKa | Negative logarithm of the ionization constant Ka |
1.1 Physicochemistry and Pharmacokinetics
The body can be viewed as primarily composed of a series of membrane barriers dividing aqueous filled compartments. These membrane barriers are principally comprised of the phospholipid bilayers that surround cells and form intracellular barriers around the organelles present in cells (mitochondria, nucleus, etc.). These are formed with the polar ionized head groups of the phospholipid facing toward the aqueous phases and the lipid chains providing a highly hydrophobic inner core. To cross the hydrophobic inner core, a molecule must also be hydrophobic and able to shed its hydration sphere. Many of the processes of drug disposition depend on the ability or inability to cross membranes and hence there is a high correlation with measures of lipophilicity. Moreover, many of the proteins involved in drug disposition have hydrophobic binding sites further adding to the importance of the measures of lipophilicity [1].
At this point, it is appropriate to define the terms hydrophobicity and lipophilicity. According to published IUPAC recommendations, both terms are best described as follows [2]:
Hydrophobicity is the association of nonpolar groups or molecules in an aqueous environment that arises from the tendency of water to exclude nonpolar molecules.
Lipophilicity represents the affinity of a molecule or a moiety for a lipophilic environment. It is commonly measured by its distribution behavior in a biphasic system, either liquidâliquid (e.g., partition coefficient in 1-octanol/water) or solidâliquid (retention on reversed-phase high-performance liquid chromatography or thin-layer chromatography (TLC) system).
Key physicochemical properties that are associated with hydrophobicity and lipophilicity include solubility, hydrogen bonding capacity, and the ionization state [3]. All these properties have a strong influence on membrane permeability that affects absorption [4], distribution, and balance of elimination by transporter-mediated processes and metabolism [5].
1.2 Partition and Distribution Coefficients as Measures of Lipophilicity
The inner hydrophobic core of a membrane can be modeled by using an organic solvent. Similarly, a water or aqueous buffer mimics the aqueous media surrounding cells or present within cells. If the organic solvent is not miscible with water, then a two-phase system can be used to study the relative preference of a compound for the aqueous (hydrophilic) or organic (hydrophobic and lipophilic) phase.
For an organic compound, lipophilicity can be described in terms of its partition coefficient P (or log P as it is generally expressed). This is defined as the ratio of concentrations of the compound at equilibrium between the organic and the aqueous phases:
The partition coefficient (log P) describes the intrinsic lipophilicity of the collection of functional groups and carbon skeleton, which combine, to make up the structure of the compound, in the absence of dissociation or ionization. Methods to measure partition and distribution coefficients have been described [6, 7].
Every component of an organic compound has a defined lipophilicity, and calculation of partition coefficient can be performed from a designated structure. Likewise, the effect on log P of the introduction of a substituent group into a compound can be predicted by a number of methods as pioneered by Hansch [8â11] (Ď-values), Rekker [12, 13] (f-values), and Leo and Hansch [8â10, 14, 15] (f â˛-values). These values break molecules down into fragments allowing the total lipophilicity to be calculated.
Partitioning of a compound between aqueous and lipid (organic) phases is an equilibrium process. When in addition the compound is partly ionized in the aqueous phase, a further (ionization) equilibrium is set up since it is assumed that under normal conditions only the unionized form of the drug penetrates the organic phase [16]. This traditional view is shown schematically in Figure 1.1.
This model is consistent with many observations, but partitioning of some compounds into octanol has been shown to occur as an ion pair [17]. Such ion pairs include chloride with basic compounds and sodium with acidic compounds. Whether such behavior can occur with a biological membrane is still not clear, some evidence exists for this with the strongly acidic drug proxicromil. The lipophilicity of the drug above pH 6 in octanolâbuffer partition experiments depends on ion p...