The spectroscopic and solution properties of a series of amidated acids (delivery agents), which promote the gastrointestinal absorption of USP heparin and other drugs that show poor oral bioavailability, are investigated using Raman and NMR spectroscopy. The results show evidence for self-association at low concentrations of delivery agents that increases as the concentration of the delivery agent is increased. The self-associate is characterized by ring-ring stacking interactions, and the best geometrical arrangement for the stacking is the parallel-shifted arrangement of the rings. In addition, the amide group participates in the formation of intermolecular hydrogen bonds in the self-associate. Unlike the rigid ring, the tails of these delivery agents remain relatively flexible in the self-associate. It is suggested that the limited solubility of the delivery agents at physiological pH arises from a percentage of protonated carboxyls. Their presence promotes the formation of intermolecular hydrophobic and ring stacking interactions, which are otherwise weakened by an ionized carboxyl group.
Copyright 2002 John Wiley & Sons, Inc.