Improving Aqueous Solubility of Drug Candidates Through Structural Modifications

Despite demonstrating high potency, many lead compounds fail to advance into clinical development due to suboptimal bioavailability, frequently arising from limited aqueous solubility. Consequently, solubility has become a critical parameter in early phase drug discovery. Achieving improved solubility for poorly soluble drug candidates without compromising their biological activity remains a major challenge in medicinal chemistry. Solubility is not only necessary for compound dissolution but also plays a crucial role in attaining therapeutically relevant systemic concentrations. It is estimated that more than 40% of new chemical entities suffer from poor water solubility, which can hinder both in vitro and in vivo evaluation, thereby increasing the complexity, time, and cost associated with drug development. To overcome this limitation, a broad spectrum of strategies—spanning physical, chemical, and formulation-based approaches—have been employed. Among these, structural modification through rational medicinal chemistry design holds particular promise, offering the potential to enhance solubility while simultaneously optimizing other pharmacokinetic and physicochemical properties. This chapter provides an overview of solubility and its implications for drug discovery, followed by literature examples that illustrate successful structural modification strategies aimed at improving solubility in early stage or, in some cases, in advanced-stage compounds. Key approaches discussed include incorporation of hydrophilic and ionizable functional groups, modulation of hydrogen-bonding capacity, implementation of bioisosteric replacements, prodrug design, and changes to molecular symmetry and planarity. Furthermore, we address the inherent challenges associated with solubility enhancement and highlight emerging in silico tools for solubility prediction. Collectively, this chapter underscores the value of strategic molecular design in overcoming solubility barriers in modern drug discovery.