Partition coefficient intrinsic lipophilicity

The procedure takes as input parameters the measured (or calculated) pKa and the measured (or calculated) octanol-water partition coefficient, log P. The latter parameter is used to estimate the intrinsic solubility So, using the Hansch-type expression [38], log So = 1.17 — 1.38 log P, or an improved version for ionizable molecules of moderate lipophilicity (Fig. 6.6) ... 

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 [3,4]. 

The partition coefficient refers to the intrinsic lipophilicity of the drug, in the context of the equilibrium of unionized drug between the aqueous and organic phases. If the drug has more than one ionization center, the distribution of species present will depend on the pH. The concentration of the ionized drug in the aqueous phase will therefore have an effect on the overall observed partition coefficient. This leads to the definition of the distribution coefficient (log D) of a compound, which takes into account the dissociation of weak acids and bases. 

At the other end of the spectrum, however, in transdermal systemic delivery, the molecular attributes required are rather different. In this case, compounds are required to partition into the relatively lipophilic stratum corneum, diffuse rapidly across the stratum corneum and partition easily into the more hydrophilic viable epidermis and dermis prior to vascular removal. The intrinsic requirements of compounds for transdermal delivery are, therefore, a medium polarity (a log octanol-water partition coefficient of 1-3), a low molecular volume and a lack of potential to bind to skin components (e.g., via hydrogen bonding). 

Lipophilicity can be reported as log P, which is the intrinsic partitioning of the drug between octanol and water when the drug is in the neutral state. However, lipophilicity is often reported as log D (distribution coefficient), which represents the distribution of the drug at a specific pH, typically pH 7.4. 

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