Percentage cosolvent

Figure 10.5 (a) Dilution profiles for three solutions (I, II and III) in pure cosolvent containing 1, 2 and 3 mg cm 3 drug, respectively. (b) Curves from (a) plotted on semilog scale along with typical solubility line.

Reproduced from S. H. Yalkowsky and S. Valvani, Drug Intell. Clin. Pharm., 11, 417 (1997).

buffered with sodium benzoate and benzoic acid and preserved with benzyl alcohol. Addition of this formulation to normal saline results in the formation of a precipitate. The maximum dilution that produces an observable precipitate after mixing is about 15-fold; a precipitate also forms on addition of the diazepam solution to human plasma.

A graphical technique has been described to predict whether a solubilised drug system will become supersaturated and thus have the potential to precipitate. When a drug dissolved in a cosolvent system is diluted with water, both drug and cosolvent are diluted. The logarithm of the solubility of a drug in a cosolvent system generally increases linearly with the percentage of cosolvent present (Fig. 10.5a). On dilution, the drug concentration falls linearly with a fall in the percentage of cosolvent. The aim of the graphical method is to plot dilution curves and solubility curves on the same graph. This is achieved in Fig. 10.5(b), where the dilution curves have been plotted semilogarithmically for three systems containing initially 1, 2 and 3 mg cm 3 of drug substance (plots I, II and III, respectively). With solution III, dilution below about 30% cosolvent causes the system to be supersaturated; with solution II, below 20% cosolvent the solubility line and the dilution line touch. Only with solutions containing 1 mg cm 3 can there be dilution without precipitation.

10.3 Cation-anion interactions

The interaction between a large organic anion and an organic cation may result in the formation of a relatively insoluble precipitate.

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