Interfacial properties of amiodarone: the stabilizing effect of phosphate anions

Amiodarone, a drug used in heart therapy, is poorly soluble in water at room temperature, but forms transparent phases much more concentrated than the critical micellar concentration (CMC), when crystals are heated (above 60 degreesC) in presence of water and cooled down to room temperature. These pseudosolutions were supposed to be made of a complex system of micelles. In order to better understand the effects of pH and ion species on the supramolecular organization of amiodarone, interfacial pressure measurements were performed at the air;water interface on a Langmuir trough. Monolayers spread from chloroformic solutions over non bufferered subphases were insoluble at basic pH (NaOH, pH 10) but soluble at acidic pH (HCl, pH 4). However, a higher ionic strength obtained by adding NaCl (0.15 N) or NaH2PO4 (0.15 N) to the subphase stopped the amiodarone solubilization. On an acidic phosphate subphase (NaH2PO4, pH 4.4, 0.15 N), abnormally high surface pressures (> 1 mN/m) were measured for high molecular areas (80-200 Angstrom (2)/molecule) suggesting a supramolecular organization of the surface film. Insoluble monolayers were also obtained when the amiodarone supramolecular pseudosolution was spread on neutral (NaH2PO4, pH 6.25, 0.15 N) or acidic (NaH2PO4, pH 4.4, 0.15 N) subphases. However, a great instability on basic subphase (phosphate buffer pH 8.8) indicated the breakage of the supramolecular structure during spreading. These results are discussed taking into account the amiodarone state of ionization and the electrostatic interactions with counterions. Combining the use of phosphate counterions and that of acidic pH opens new perspectives in the optimization of amiodarone intravenous formulations. (C) 2001 Elsevier Science B.V. All rights reserved.