The effect of solvents on the potency of chlordiazepoxide, diazepam, medazepam and nitrazepam

Abstract

Abstract ED50 values for loss of righting reflex in mice have been determined for a series of benzodiazepines after intraperitoneal injection of the drugs in various vehicles. The vehicles used greatly modified the ED50 values obtained. The effects obtained were due either to a failure of the vehicle to achieve or maintain complete solubilization of the drug, or to the pharmacological action of the vehicle modifying that of the drug. Diazepam, medazepam and nitrazepam are insoluble in water, but are soluble in dimethylsulphoxide (DMSO) and in aqueous vehicles containing glycofurol or propylene glycol. Chlordiazepoxide hydrochloride is water-soluble. Similar ED50 values were obtained in experiments where the benzodiazepines were injected in an aqueous carboxymethylcellulose suspension and in experiments where the drugs were dissolved in DMSO. Lower ED50 values were obtained when the drugs were dissolved in vehicles containing propylene glycol or glycofurol. The increase in potency of the benzodiazepines could be ascribed either to the solubilization of the drugs or to the synergistic pharmacological activity of the solvents. An ED50 value for diazepam, which was not influenced by the pharmacological activity of the solvent, could be obtained using the vehicles containing either glycofurol or propylene glycol. For medazepam and nitrazepam, the solvent mixtures containing propylene glycol and glycofurol respectively were required to avoid drug-solvent interactions.