ABSTRACT

Symbols 46 References 47

Solubility of compounds is of great importance in pharmaceutics, and the subject has been subdivided into the foregoing subtopics.

3.1. EQUILIBRIUM SOLUBILITY Whenever the term solubility is employed, it is tacitly assumed that it is equilibrium solubility. In other words, it assumes that a (stable) solid (the solute) is placed in contact with a liquid (the solvent), and the system is allowed to be agitated for a long while, or by other means allowed to reach a state of equilibrium, characterized by the fact that the concentration of solute has reached a constant level. This definition is by no means easy to establish in practice. Such things as small

temperature fluctuations, and that solubility may be a function of particle size, makes the experimental establishment of solubility of a compound difficult to achieve. Add to that the fact that solids of higher energetics (metastable polymorphs or amorphates) have higher apparent solubilities also confounds the issue. At times (e.g., in the case of benzodiazepam), the drug substance, as first produced (in clinical trials), turned out to be a metastable polymorph. Apparent equilibrium solubilities were established and were thought to be true equilibrium solubilities because the figures were reproducible, until one day the more stable form happened to be produced, and this had a lower solubility. Because it is never really certain that any drug substance produced is actually the stable polymorph, the term equilibrium solubility is clouded to some degree with uncertainty. In this chapter to follow it is going to be assumed that solubility is exactly what the foregoing italicized definition purports it to be.