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The science behind the parameters we measure

Progress in drug synthesis has meant that discovery of compounds with high biological activity and strong affinity for receptor sites is no longer the main impediment to the speed of drug development. Instead, pharmacokinetic factors such as absorption/permeability across the GI epithelium have become crucial. The absorption of orally administered drugs is largely determined by their solubility and their permeability across the gastrointestinal (GI) tract.

While a number of routes exist for absorption of drugs through membranes and tissues, transport by passive diffusion is the most common. It has been shown that passive permeability correlates well with lipophilicity. To be absorbed by this route, drugs must be sufficiently lipophilic to penetrate the lipid cores of membranes, but not so lipophilic that they get stuck there. Lipophilicity is expressed by the octanol-water partition coefficient (logP) or distribution coefficient (logD). Although octanol-water partitioning is a surrogate for interaction of drugs with true membranes, it has proved a remarkably enduring concept, probably because it is relatively easy and fast to measure, and because the information encoded is "good enough" to make useful approximations about a drug's behaviour.

Most drugs ionise in aqueous solution, and can therefore exist in a neutral or a charged state, depending on the pH of the local environment. Molecules are more lipophilic when neutral than when charged. Ionisation is expressed by the aqueous ionisation constant pKa. Permeability and aqueous solubility are also pKa-dependent. Lipophilicity, pKa, and aqueous solubility are the three principal physicochemical parameters measured during Physicochemical Profiling. Molecules with appropriate physicochemical properties may be considered suitable candidates for further development. Most pharmaceutical development groups have in-house rules for assessing these properties, often calling for measured pKa, logP and solubility values.