The interaction of a compound with its physical environment determines its physicochemical properties (e.g., solubility and passive permeability). This interaction is determined by the interplay of the structural properties outlined earlier. Taking pKa as an example, the pKa determines the degree of ionization, and it has a major effect on solubility and permeability.
Ionized molecules are more polar and more soluble in aqueous solution than in their neutral form. However, ionized molecules are less permeable than in their neutral form.
Neutral molecules are more lipophilic and permeate via passive diffusion.
For an orally administered CNS drug to be efficacious, it needs to cross two biological barriers, the gastrointestinal (GI) tract and the BBB, before it can reach its intended target. [For a target that is inside the cell, the drug also needs to cross the cell membrane]. While formulation has been an effective tactic to affect dissolution and absorption across the GI tract, solubility remains an important requirement for a CNS drug, as demonstrated by Alelyunas, who determined the solubility of 98 marketed CNS drugs in pH 7.4 buffer . Over 85% of the drugs tested had high aqueous solubility (>100 uM), but only seven drugs had low solubility (<10 uM), two of which had very poor solubility <1 uM. Of the seven drugs with poor solubility, three are no longer on the market, while the remaining four are all administered at relatively low daily doses (e.g., <0.5 mg/kg: quazepam (15 mg); metaclazepam (15 mg); ziprasidone (20 mg); and aripiperazole (10 mg)). Although the structural properties of these compounds generally are within Lipinski rules for oral absorption, the combinations of high MW, high lipophilicity, and low PSA predict the potential for poor solubility. Presumably, the attributes of high potency and high permeability for these four drugs may compensate for their low aqueous solubility.
It should be stressed, however, that these four drugs are very much the exceptions to the norm. Indeed, Lipinski described the estimation, which is used at Pfizer, to determine the minimum acceptable thermodynamic solubility required for an orally active drug with low, medium, and high permeability values at a particular clinical dose. For example, to achieve oral absorption, a compound with medium intestinal permeability and a projected human potency of 1 mg/kg (e.g., 50-100 mg dose) needs a minimum aqueous solubility of 52 mg/ml. Thus, for a drug with a MW of 310 (the average MW for a CNS drug), it would require an aqueous solubility of ~165 uM.
Compound solubility will be determined by LC/MS analysis, after combining 1 mg of test compound with 1 mL of pH 7.4 buffer, and then agitating the mixture for 24h at 37 oC. Aqueous solubility of >10 uM is acceptable (although >100 uM is preferable) for compound advancement to in vivo studies. Poor solubility can hinder compound delivery and exposure in vivo, as well as skew the interpretation of data from in vitro assays. Solubility is an important requirement for a CNS drug, as demonstrated by Alelyunas, who determined the solubility of 98 marketed CNS drugs in pH 7.4 buffer. Over 85% of the drugs tested had high aqueous solubility (>100 uM), but only seven drugs had low solubility (<10 uM).