Aqueous Solubility in Discovery, Chemistry, and Assay Changes

This chapter is not simply a treatise on the highest capacity methods for measuring aqueous solubility in a discovery setting that most closely approximate a lower capacity thermodynamic solubility measurement. Rather it is the author s viewpoint that dealing with the problem of poor drug solubility in an early discovery setting requires an appreciation of recent changes in three related but distinct areas. The areas to be considered are  

Changes in the chemistry method of synthesis and therefore in resultant physical form and aqueous solubility. 

Drug Bioavailability Estimation of Solubility, Permeability, Absorption and Bioavailability. Edited by Han van de Waterbeemd, Hans Lennernas and Per Artursson Copyright 2003 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim ISBN 3-527-30438-X 

Changes in the method of compound distribution for biological assays and therefore changes in apparent aqueous solubility and compound concentration. 

These three areas will be discussed as they relate to aqueous solubility. This will be followed by a general discussion of experimental approaches to measuring aqueous solubility in a discovery setting. Detailed descriptions of varied discovery solubility assays can be found in the excellent review by Kerns [1], 

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Aqueous Solubility in Discovery, Chemistry, and Assay Changes... 

Lipinski CA. Aqueous solubility in discovery, chemistry, and assay changes. Methods and Principles in Medicinal Chemistry 2003 18 215-231. 

Figure 8.19 Minimum acceptable solubilities for compounds with low, medium, and high permeability at a clinical dose. The middle three bars are for a 1 mpk dose where, with medium permeability, a solubility of 52 p,g/mL is required (Reproduced with permission from Lipinski, C. Aqueous Solubility in Discovery, Chemistry, and Assay Changes , Chapter 9 in van de Waterbeemd, H., Lennernas, H., Artursson, P., Eds. Drug Bioavailability, (Wiley-VCH Verlag GmbH Co. KGaA) p. 222, copyright 2003.).

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