The treatise by Grant and Higuchi [37] comprehensively covers pre-1990 solubility literature. In this chapter, we present a concise, multimechanistic [1] solubility equilibrium model ("not just a number''; see Section 1.6) and stress what is new since 1990 [39]; we also cite some important classic works. Many protocols have been described in the literature for measuring solubility-pH profiles, using various detection systems [12,26,37-39,459-503]. Classical approaches are based on the saturation shake-flask method [37-39]. New methods are usually validated against it. The classical techniques are slow and not easily adapted to the high-throughput needs of modern drug discovery research. At the early stages of research, candidate compounds are stored as DMSO solutions, and solubility measurements need to be performed on samples introduced in DMSO, often as 10 mM solutions. It is known that even small quantities of DMSO (<5%) in water can increase the apparent solubility of molecules, and that it is a challenge to determine the true aqueous solubility of compounds when DMSO is present. To this end, a new method has been developed which extracts true aqueous solubility from DMSO-elevated values [26].

The accurate prediction of the solubility of new drug candidates still remains an elusive target [1,12,502]. Historical solubility databases used as ''training sets'' for prediction methods contain a large portion of oil substances, and not enough crystalline, drug-like compounds. Also, the quality of the historical data in the training sets is not always easy to verify. Such methods, for reasons of uncertain training

Absorption and Drug Development: Solubility, Permeability, and Charge State. By Alex Avdeef ISBN 0-471-423653. Copyright © 2003 John Wiley & Sons, Inc.

data, often perform poorly in predicting solubilities of crystalline drug compounds [504-506].


The basic relationships between solubility and pH can be derived for any given equilibrium model. In this section simple monoprotic and diprotic molecules are considered [26,472-484,497].

The protonation reactions for ionizable molecules have been defined in Section 3.1. When a solute molecule, HA (or B), is in equilibrium with its precipitated form, HA(s) (or B(s)), the process is denoted by the equilibrium expression

and the corresponding equilibrium constant is defined as

or S0

By convention, [HA(s)] = [B(s)] = 1. Eqs. (6.1) represent the precipitation equilibria of the uncharged species, and are characterized by the intrinsic solubility equilibrium constant, S0. The zero subscript denotes the zero charge of the precipitating species. In a saturated solution, the effective (total) solubility S, at a particular pH is defined as the sum of the concentrations of all the compound species dissolved in the aqueous solution:

where [HA] is a constant (intrinsic solubility) but [A~] is a variable. It's convenient to restate the equation in terms of only constants and with pH as the only variable. Substitution of Eqs. (3.1) [or (3.2)] into (6.3) produces the desired equation.

0 0

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