Preformulation Selection of a Proper Salt for a Weak Acid-Base (Rs-82856) - A New Positive Inotropic Agent

Abstract

The solubility, hygroscopicity and intrinsic dissolution rate of the various salts of a weak acid-base (RS-82856) were evaluated. The phosphate salt was a mixture of monobasic and dibasic salts and was not physically stable. The hydrogen sulfate, and chloride salts were less hygroscopic and more soluble in water than the cation salts tested (sodium and potassium). All salts studied showed only slightly better intrinsic dissolution rates (∼two-fold) than the parent drug at pH 3.1 and 7.0; only the hydrogen sulfate salt and the potassium salt had better dissolution rates at pH 1.2. This unusual dissolution behavior of the salts can be explained by the extremely low buffering effect of the salts in the dissolution medium. The hydrogen sulfate salt was recommended for development and was supported by the ∼two-fold increase in bioavailability in a dog study when compared to the parent drug.