Interplay of degradation, dissolution and stabilization of clarithromycin and its amorphous solid dispersions.

Clarithromycin (CLA) is an aminomacrolide antibiotic whose physical properties are fascinating and challenging. It has very poor solubility at neutral intestinal pH, but much better solubility under acidic conditions due to amine protonation. The improved solubility in an acid environment is confounded by the poor chemical stability of clarithromycin that is quite labile toward acid-catalyzed degradation. This creates a complex system under gastrointestinal (GI) conditions: dissolution in the stomach, degradation, potential for precipitation in the small intestine, and interplay with the formulation components. We report herein a study of amorphous solid dispersion (ASD) of CLA with carboxyl-containing cellulose derivatives, which have recently been shown to be excellent ASD matrices for maximizing oral bioavailability. This approach was intended to improve CLA solubility in neutral media while minimizing release in an acid environment, and thereby increase its uptake from the small intestine. Amorphous p...