Physicochemical properties of prostaglandin F_2α (tromethamine salt): Solubility behavior, surface properties, and ionization constants

The pH‐solubility profile of the tromethamine salt of PGF_2α was determined. The intrinsic solubility of the free acid is 0.0042 M at 25° and, as expected for a carboxylic acid, the solubility increased as a function of pH. However, at a pH value just above 5, there is a marked increase in solubility, which is significantly greater than would be expected from the ionization constant of the acid. This type of behavior is attributed to the formation of micelles that solubilize the drug once a critical concentration and pH are reached. Independent determination of the critical micellar concentration (CMC) by drop volume or potentiometric techniques demonstrated that PGF_2α tromethamine does form micelles. The CMC increased with the degree of ionization and, therefore, is a function of pH. The pKa of PGF_2α was determined by titration in aqueous media to be 4.90 ± 0.02. The pKa increased above the CMC as a function of concentration to a maximum value of 5.6. When a plot of concentration versus pKa is made, the point of deviation from the true value of 4.90 is in good agreement with the CMC reported by the drop volume technique. The interrelationship between the potentiometric, solubility, and surface properties of PGF_2α tromethamine are presented. Interestingly, these properties are qualitatively similar to those reported for certain bile acids that have similar functional groups present on the parent cholanic acid nucleus.