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 under standing of physicochemical properties unique to solutions. The object ive of this study was to investigate the behaviour of MK-0476, a poten t leukotriene D-4 receptor antagonist, using determination of solubili ty characteristics, surface tension measurements: static and dynamic l ight scattering, and near-UV spectroscopy. More specifically, the self -association behaviour of aqueous solutions of MK-0476 was investigate d as a function of ionic strength, pH and temperature, The observed pH -solubility profile deviated markedly from the expected profile sugges ting a self-association behaviour. The ionic strength influenced the s olubility and surface activity. The critical micelle concentration (cm c) 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 concentrat ion 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 consta nt ionic strength (mu = 0.05) glycine-KOH buffer. Results from surface tension measurements showed that temperature had no effect on the sel f-association phenomenon in the range 25 degrees-37 degrees C. Light s cattering data indicated that at low ionic strength and basic pH, mice lles of an average hydrodynamic radius of 1.6 nm exist. The addition o f 150 mM of NaCl increased micelle size to approximately 40 nm. The ra dius of gyration of these aggregates measured by the angular dissymmet ry method were larger than the hydrodynamic radii calculated from dyna mic light scattering measurements, indicating an elongated shape. Unde rstanding 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.