Characterization of the self-association properties of a leukotriene D-4 receptor antagonist, MK-0476

The development of a liquid dosage form requires a comprehensive understanding of physicochemical properties unique to solutions. The objective of this study was to investigate the behaviour of MK-0476, a potent leukotriene D-4 receptor antagonist, using determination of solubility characteristics, surface tension measurements: static and dynamic light scattering, and near-UV spectroscopy. More specifically, the self-association behaviour of aqueous solutions of MK-0476 was investigated as a function of ionic strength, pH and temperature, The observed pH-solubility profile deviated markedly from the expected profile suggesting a self-association behaviour. The ionic strength influenced the solubility and surface activity. The critical micelle concentration (cmc) determined by tensiometry at pH 10.0 decreased from 162 mu M to 14 mu M with increasing ionic strength, and a linear relationship between logarithm of cmc and the logarithm of the total counterion concentration was obtained. The cmc determined from surface tension measurements was marginally affected by pH in the range of 8.8 to 10.8 in a constant ionic strength (mu = 0.05) glycine-KOH buffer. Results from surface tension measurements showed that temperature had no effect on the self-association phenomenon in the range 25 degrees-37 degrees C. Light scattering data indicated that at low ionic strength and basic pH, micelles of an average hydrodynamic radius of 1.6 nm exist. The addition of 150 mM of NaCl increased micelle size to approximately 40 nm. The radius of gyration of these aggregates measured by the angular dissymmetry method were larger than the hydrodynamic radii calculated from dynamic light scattering measurements, indicating an elongated shape. Understanding the surface active behaviour of MK-0476 and establishing the critical parameters affecting its self association provided valuable insight towards the development of a liquid dosage form.