Discovery solubility measurement and assessment of small molecules with drug development in mind.

Solubility is a key physicochemical property for the success of any drug candidate. Although the methods used and their rationales for determining solubility are subject to project needs and stages along the drug discovery-drug development pipeline, an artificial boundary can exist at the discovery-development interface. This boundary results in less effective solubility knowledge sharing and data integration among scientists in both drug discovery and drug development. Herein, we present a refreshed perspective on solubility. Solubility experimentation is not a one-size-fits-all measurement; instead, we stress the importance of constructing a seamless solubility understanding of a molecule as it progresses from a new chemical entity into a drug product.

Automated Supersaturation Stability Assay to Differentiate Poorly Soluble Compounds in Drug Discovery.

Increasingly, in vitro assays evaluate a compound's tendency to maintain supersaturation toward improving oral absorption. Throughput remains a challenge and only small sets of compounds are evaluated in reported studies. The present work describes an automated workflow and data analysis approach to determine supersaturation stability after 16 min. Eight increasing concentrations were targeted and supernatant concentration was measured following solvent shift in fasted-state simulated intestinal fluid. The effect of dimethyl sulfoxide both on equilibrium solubility and on induced supersaturation was addressed, whereas the change in concentration was evaluated over time. Our sample set included 24 commercial compounds, along with comparison to literature results. To demonstrate in vivo relevance of in vitro supersaturation, classification of supersaturation stability was proposed based on the target concentration achieved and the percentage of area under the curve dose proportionality in 42 preclinical and clinical studies. Eighty-one percent of low supersaturation stability compounds (target concentrations ≤50 µM) had proportionality <0.8, whereas 100% of high supersaturation stability compounds (target concentrations ≥200 µM) demonstrated proportionality ≥0.8. The robust, automated assay and its impact on dose proportionality downstream make this approach applicable in drug discovery where low-soluble compounds with otherwise attractive properties may be differentiated on the basis of supersaturation stability.