Prediction of Partition Coefficients and Permeability of Drug Molecules in Biological Systems with Abraham Model Solute Descriptors Derived from Measured Solubilities and Water-to-Organic Solvent Partition Coefficients

Modern drug testing and design includes experimental in vivo and in vitro measurements, combined with in silico computations that enable prediction of the drug candidate’s ADMET (adsorption, distribution, metabolism, elimination and toxicity) properties in the early stages of drug discovery. Recent estimates place the discovery and development cost of a small drug molecule close to US $1.3 billion, from the time of inception to the time when the drug finally reaches the market place. Only 20 % of conceived drug candidates proceed to clinical trial stage testing, and of the compounds that enter clinical development less than 10 % receive government approval. Reasons for the low success rate include unsatisfactory efficacy, poor solubility, poor bioavailability, unfavorable pharmacokinetic properties, toxicity concerns and drug-drug interactions, degradation and poor shelf-life stability. Unfavorable pharmacokinetic and ADME properties, toxicity and adverse side effects account for up to two-thirds of drug failures. Traditional ADME analyses relied heavily on whole animal assays and the more labor intensive biochemical studies. High throughput screening methods, fast ADMET profiling assays, and computational approaches have allowed the pharmaceutical industry to identify quickly the less promising drug candidates in the very early development stage so that time and valuable resources are not spent pursuing compounds that have little probability of reaching the general population. Of the fore-mentioned properties, the drug’s aqueous solubility will likely be one of the first properties measured. Aqueous solubility is a major indicator of the drug’s solubility in physiological gastrointestinal fluids and is a major indicator of the drug’s oral bioavailability. Approximately 40 % of the proposed new pharmaceutical candidates are rejected in the very early stages of drug discovery because of their poor aqueous solubility resulting in bioavailability problems (Lukyanov and Torchilin, 2004; Keck et al., 2008). The