High throughput solubility measurement in drug discovery and development☆
Introduction
Experimental determination of drug solubility is not a single event but is performed multiple times along the drug discovery and development process, the assays and their focus varying with the phase. Among the five key physicochemical screens in early compound screening, pKa, solubility, permeability, stability and lipophilicity, poor solubility tops of the list of undesirable compound properties (Fig. 1). Compounds with insufficient solubility carry a higher risk of failure during discovery and development since insufficient solubility may compromise other property assays, mask additional undesirable properties, influence both pharmacokinetic and pharmacodynamic properties of the compound, and finally may affect the developability of the compound [1], [2], [3]. Ideally solubility liabilities should be known prior to any functional evaluations.
Section snippets
“Solubility” — what does it mean?
Conceptually, solubility is an easy parameter to measure but its meaning and concept of use is often different for discovery and development scientists and this can be a source of misunderstandings and controversy. In a broad sense, solubility may be defined as the amount of a substance that dissolves in a given volume of solvent at a specified temperature. More specifically, compound solubility can be defined as unbuffered, buffered, and intrinsic solubility. Unbuffered solubility, usually in
Solubility screening in discovery
Solubility assays in discovery and development focus on different key questions (Fig. 2). In lead identification, solubility assays are routinely used to rank-order hits, to flag compounds with potential liabilities, and to validate hits by comparing hit dose response values with apparent solubility values. Low solubility may indicate a response due to nonspecific inhibition by aggregate or precipitation formation. Further, compound solubility is measured under bioassay conditions to optimize
Key elements of solubility assays in discovery and development
The environment in which a solubility assay is run and the primary focus of the assay, basically dictate how assays are currently set-up and performed in discovery and development (Fig. 3). Qualitative and quantitative changes along the drug discovery and development process further determine how assays can be setup and run, which type of solubility can be measured, and how reliable solubility data can be (Fig. 4).
In discovery, during the period from lead identification to clinical candidate
Needs and trends in solubility measurement
The historically strict boundaries between solubility assays performed in discovery and in development are starting to blur. Many organizations now realize that new workflows and technologies are required to fulfill the needs and interests of chemists, biologists and formulators in high quality solubility data with the ultimate goal to support, to improve and to speed up the compound and formulation selection processes. While a single, consistent methodology for solubility studies throughout
Acknowledgements
We have to acknowledge the work of Virginie Micallef, Isabelle Parrilla and Björn Wagner, Stefanie Bendels and Holger Fischer in the field of early stage compound profiling. Without their continuous efforts in order to improve and adapt existing solubility assays to newest technological achievement, current overview would not have been possible. We also wish to acknowledge helpful discussions with colleagues in Preformulation R&D at Roche, especially Dr. Nicole Wyttenbach.
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This review is part of the Advanced Drug Delivery Reviews theme issue on “Drug solubility: How to measure it, how to improve it”.