Improving the Water-Solubility of Compounds By Molecular Modification to Disrupt Crystal Packing

Sufficient aqueous solubility is a key requirement for clinical drugs, and improvement of the aqueous solubility of drug candidates is often a major issue for medicinal chemists. The strategy of introducing hydrophilic group(s) into molecules is generally used for this purpose but is not universally effective. This chapter deals with an alternative strategy for molecular modification to improve solubility by focusing on weakening intermolecular interactions in the solid state. Relevant modifications include disruption of intermolecular hydrogen bonds, disruption of molecular planarity (increase in ratio of sp³-hybridized carbons, twisting of molecules, and introduction of substituents at benzylic positions), and bending molecules. Such molecular modifications have the effect of decreasing the efficiency of crystal packing, which in turn results in an increase of aqueous solubility. Improvement of aqueous solubility by as much as 350-fold was achieved in one case.