Assessing the physicochemimal properties of drug compounds are typical early steps in drug discovery. A good compound has high enough water solubility to be able to dissolve to blood/plasma and other aqueous bodily fluids, whilst also having certain amount of lipophilicity to permeate across biological membranes, like the intestine wall (especially important for compounds aimed for oral dosing). Lipophilicity is possibly the lost important physicochemical property of a potential drug, it plays a role in solubility, absorption, membrane penetration, plasma protein binding, distribution, CNS penetration and partitioning into other tissues or organs such as the liver and has an impact on the routes of clearance. It is important in ligand recognition, not only to the target protein but also CYP450 interactions, HERG binding, and PXR mediated enzyme induction. Measurement of LogP can be undertaken in a variety of ways, the most common is the shake-flask method, which consists of dissolving some of the solute in question in a volume of octanol and water, shaking for a period of time, then measuring the concentration of the solute in each solvent. This can be time-consuming particularly if there is no quick spectroscopic method to measure the concentration of the molecule in the phases. A faster method of log P determination makes use of high-performance liquid chromatography. The log P of a solute can be determined by correlating its retention time with similar compounds with known log P value doi.
The acid dissociation constant, Ka, is a mesure of the strength of the acid and its typically expressed as pKa (-log10(ka). Drug compounds are almost always weak acids or bases and depending on the pH, they are thus either charged (A- or HB+) or neutral. The neutral form has better lipophilicity and thus better permeability whilst the charged form has better aqueous solubility. pKa values gives the pH above which the compound is neutral (bases; B) or charged (acids; A-) and below which the compound is neutral (acids; HA) or charged (bases; HB+).