Solubilization of Metronidazole by Water-Miscible Multi-Cosolvents and Water-Soluble Vitamins

Abstract

In the systemic treatment of anaerobic infections, a parenteral mode of administration of metronidazole is preferable. The practical way of administering a parenteral dose(500 mg/dose) of metronidazole in a single injectable dosage form(10 ml) can be achieved by incorporating two or more water-miscible co-solvents, e.g., ethanol,N, N-dimethylacetamide, propylene glycol or solketal, in the aqueous solution. The aqueous solubility of metronidazole was found to increase, exponentially, as increasing the volume fraction of the co-solvents. A maximum solubility of metronidazole was observed in the aqueous solutions with a dielectric constant in the range of 41.49#x00B1; 1.76. The importance of dielectric constant in determining the aqueous solubility of slightly water-soluble metronidazole, which consists of lipophilic and hydrophilic functional groups, was discussed. The aqueous solubility of metronidazole can also be enhanced by solubilizing with a water-soluble vitamin, e.g., nicotinamide, ascorbic acid or pyridoxine HCl. A cage-like structure was postulated to rationalize the observation that 9 molecules of vitamin are required to solubilize every molecule of metronidazole in the aqueous solution.