Improvement in aqueous solubility in small molecule drug discovery programs by disruption of molecular planarity and symmetry.

Aqueous solubility is essential for drug candidates. Poor aqueous solubility is likely to result in poor absorption, even if the permeation rate is high, since the flux of a drug across the intestinal membrane is proportional to the concentration gradient between the intestinal lumen and the blood. The Biopharmaceutical Classification System (BCS) was introduced in the mid-1990s to classify drug substances with respect to their aqueous solubility and membrane permeability. Drug substrates, for which solubility enhancement can improve the oral bioavailability, are classified in class 2 (poorly soluble/ permeable) and class 4 (poorly soluble/poorly permeable). The FDA regulations concerning oral medications require more extensive investigation of compounds with low solubility, and low solubility may have an even greater impact in the case of iv dosage forms. In addition, risk assessment of poorly soluble compounds is challenging because exposure may be difficult to define and test sensitivity may be reduced. Further, high concentrations of poorly soluble drugs in organisms may result in crystallization and acute toxicity, as in the case of uric acid and gout. Overall, poor solubility of drug candidates has been identified as the cause of numerous drug development failures. According to the simplest definition, the thermodynamic solubility of a compound in a solvent is the maximum amount of the most stable crystalline form of the compound that can remain in solution under equilibrium conditions. The most stable form is invariably the form that has the highest melting point. The importance of thermodynamic assessment is greater in late discovery/early development, when it is useful to confirm earlier kinetic solubility results, to rule out potential artifacts, and to generate high-quality solubility data. The kinetic solubility of a molecule depends on its crystal form, and crystal polymorphs of a molecule can show different kinetic solubility. Therefore, crystal modification can produce an increase in dissolution rate and a temporary or apparent increase of solubility. However, it cannot produce a permanent alteration of solubility. Given sufficient time, the undissolved solute will revert to its most stable crystal form, and the solubility will approach the true thermodynamic solubility. Therefore, the role of crystal modification is confined to increasing the dissolution rate of drugs. Appropriate formulation can help in addressing these problems, but the extent of absorption and solubility enhancement that can realistically be achieved is severely limited. Stability and manufacturing problems also have to be taken into account, since it is likely that an insoluble drug candidate may not be formulated as a conventional tablet or capsule and will require a less conventional approach such as, for example, a soft gel capsule. Thus, it would be better to generate drug candidates with sufficient aqueous solubility at the drug discovery stage. In other words, it is much better to improve solubility by chemical means, i.e., by modification of the molecule itself. But on the other hand, application of combinatorial chemistry and highthroughput screening (HTS) systems has tended to change the profile of compound libraries in the direction of greater hydrophobicity and higher molecular weight, and this in turn has resulted in a profile of lower solubility. This is a problem for medicinal chemists, and improvement of the aqueous solubility of bioactive molecules is a major and common issue in medicinal chemistry. In general, the aqueous solubility of small molecules depends on their hydrophobicity (log P). The partition coefficient, logP, is defined as follows: logP = log[(solute in n-octanol)/ (solute in water)]. Increase of aqueous solubility leads to an increase of the denominator of the above equation and a decrease of log P. Thus, decrease of log P by chemical modification, i.e., introduction of hydrophilic group(s) into molecules, is a classical and general strategy for improving aqueous solubility. But this approach is not universally effective because the introduced hydrophilic group(s) sometimes interferes with the target proteindrug interaction. In addition, this strategy is not effective when both solubility and hydrophobicity need to be increased, for example, to improve the oral bioavailability of highly hydrophilic compounds with insufficient solubility. Furthermore, compounds with poor solubility in both octanol and water sometimes retain poor absolute values of aqueous solubility despite a decrease of log P values, because log P values are just ratios. Therefore, a novel and general strategy to increase the aqueous solubility of drug candidates would have a great impact on drug discovery and medicinal chemistry. Here, we review an alternative strategy for improving aqueous solubility by means of disruption of molecular planarity and symmetry.