Chapter 25 - Solubility Methods

Abstract

Solubility plays a crucial role in drug absorption in the gastrointestinal tract, accurate biological assays in vitro, and dosage form selection for in vivo administration. With this central role, measurement of solubility is a frequent activity of discovery scientists, and attention should be paid to accurate and relevant analyses. This chapter provides an overview of in silico and in vitro solubility methods. The total solubility of an ionizable compound at a particular pH can be estimated using its intrinsic solubility. Several software products for solubility are commercially available. One widely distributed software, QikProp, predicts several absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) properties based on regression models using molecular descriptors. Kinetic solubility is most appropriate for drug discovery for the following reasons. The purpose of kinetic solubility measurements is to identify compounds that do not have good kinetic solubility even in aqueous buffer containing DMSO, to guide modification of structures to improve solubility, and to guide formulation selection for animal dosing. Thermodynamic solubility data are most appropriate for crystalline material that is studied in detail during late drug discovery and development. Thermodynamic solubility studies are often performed to assist discovery and development formulation and in preparation for clinical development. Such studies provide perspectives on compound solubility in various physiological fluids to aid absorption studies, in various formulary solvents to aid formulation, and in solvents that are used to measure lipophilicity.