An excess amount of drug is placed in a vial along with a specific amount of the solvent. The tightly closed vial is then agitated at constant temperature and the amount of drug in solution is determined by a suitable analytical method. The solubility is generally expressed in mg of solute per ml of solvent at 25°C or per 100 ml. The solubility of a drug depends on the temperature, solvent, pH and chemical nature of the molecule. By modifying these parameters, the solubility of a drug can be manipulated according to the requirement of designing the dosage form.

pH

The solubility of drugs is influenced by the pH of the environment. When a weakly acidic drug is dissolved in water it remains in three states, namely undissolved, dissolved and ionized forms. The relationship between the equilibrium solubility of a weakly acidic drug and the pH is expressed by Henderson–Hasselbalch equation:

pH = pK_a + log(A^–)/log(AH)

where pK_a is the dissociation constant of the acid, [A^–] is the molar concentration of ionized drug and [AH] is the molar concentration of unionized drug.

To maintain a drug in the soluble state, it must be dissolved in a suitable buffer solution that has adequate buffer capacity in the desired pH range, must be biologically safe for the intended use and must have minimum interference on the stability of the final product. Commonly used buffer systems are ammonium chloride, diethanolamine, carbonic acid, phosphate buffers, glutamic acid, tartaric acid, citric acid buffer and acetic acid buffer.