The causes of low solubility
High hydrophobicity and low water solubility are common characteristics of hits, leads, development candidates, and ultimately marketed therapeutic products. In spite of attempts to circumvent solubility problems in medicinal chemistry programs, approximately 70% of chemical entities currently under development have been suggested to be poorly water-soluble. The drivers of this solubility problem are clearly multivariate, and have been related to the implementation of high-throughput screening in discovery programs (which are often conducted in nonaqueous media), the search for enhanced receptor binding (which may be accomplished via promotion of hydrophobic interactions) and the identification of unprecedented targets that require lipophilic ligands for effective interaction. The problem of low water solubility has persisted over the years and continues to be a challenge to successful pharmaceutical development.
When does low solubility become a problem?
Although low water solubility presents varied and significant challenges throughout discovery and development, the greatest concern is generally the risk of reduced and variable absorption after oral administration. The value at which limited solubility begins to impact absorption is difficult to state definitively since it is dependent on a number of other system variables, including API permeability across the gastrointestinal (GI) epithelium, the target dose, and the pH and composition of the GI fluids. It is important to note that permeability and solubility are compensatory; that is, high permeability may offset low solubility in determining the maximum dose above which solubility in the GI tract becomes restrictive to absorption. By combining a compound’s GI solubility and permeability values in physiology-based pharmacokinetic (PBPK) models, it is possible to estimate the fraction of the dose that can maximally be absorbed. Knowledge of the maximum absorbable dose in turn is useful in determining which enabling formulation technology is required to overcome the solubility barrier.