ABSTRACT
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417 Classical Salts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 418 Organic Salts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419 Polymeric and Macromolecular Salts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422 Predictability of Solubility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422 Formulation Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427 Salt-Selection Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432
In formulation development or in the in vivo performance of the dosage form, the occasion may arise when the inherently low aqueous solubility of a drug does not meet the solution concentration required. If the aqueous solubility of a drug is less than 10 mg/mL, bioavailability or absorption problems are likely to exist (Greene, 1979). If the drug to be formulated as a liquid product possesses ionizable groups, adjustment of the pH in which the drug is to be dissolved might be sufficient to enhance the solubility. The solubility of an organic molecule is frequently enhanced more by an ionized functional group than by any other single means. This is understandable since there are strong interactions between the solute ion and the ions and dipoles of water, possibly overcoming the drawback of a large hydrophobic portion of the drug molecule. However, weak acids and weak bases may require extremes in pH that are outside acceptable physiological limits, or at which stability problems arise (Anderson, 1985; Ansel et al., 1995). In general, aqueous solubility is a function of chemical structure, and salts represent the class of drugs that are most likely to attain the desired extent of solubility in water (Motola and Agharkar, 1984). The salt form of a drug is usually more soluble than the nonionized form in an aqueous medium, although it should be noted that not all salts have an improved solubility in water when compared to the uncharged form of the drug. Procaine penicillin is often cited as an example of a poorly soluble salt (Amidon, 1981).
