Complexation in Formulation of Parenteral Solutions: Solubilization of the Cytotoxic Agent Hexamethylmelamine by Complexation with Gentisic Acid Species

The apparent solubility of hexamethylmelamine in aqueous solutions suitable for intravenous use was increased by complexation with gentisic acid. Studies were carried out in the pH 0–8 range. Unprotonated hexamethylmelamine did not form complexes with the gentisate ion, while the hexamethylmelammonium ion appeared to form several different complexes with both the gentisate ion and gentisic acid. Two different solid complexes were isolated and characterized. The solubility increases observed at pH 3.5–5.0 are described by mathematical relationships involving the stability constants of some postulated complex species. From these results, suitable formulations for use as parenteral solutions are proposed. The increase in the apparent aqueous solubility of hexamethylmelamine in such formulations may range from five- to 90-fold, depending upon the pH and total gentisate-ion concentrations.