Supramolecular behavior of the amphiphilic drug (2R)-2-ethylchromane-2-carboxylic acid arginine salt (a novel PPARalpha/gamma dual agonist).

Purpose: This study was conducted to evaluate the aggregation properties of an amphiphilic drug.

Methods: Aggregation of the drug was studied by various methods including phase-contrast and polarized microscopy, spectrophotometry, surface tensiometry, atomic force microscopy, and dynamic light scattering. Lymph-cannulated rats were used to assess fractions of drug that were absorbed into lymphatics.

Results: During the pharmaceutical development of an alpha/gamma dual PPAR agonist, a derivative of a chromane-2-carboxylic acid (compound 1), it was discovered that the compound was able to form various aggregates in aqueous media from pH 6.5 to 7.1, whereas aggregating predominantly into micelles at higher pH values. Critical micelle concentrations seemed to be quite low, about 0.25 mM (0.17 mg/mL) in deionized water as determined by spectrophotometric (dye) and surface tensiometry (du Nuoy) methods. Aggregation of compound 1 into large supramolecular aggregates was visualized via phase-contrast microscopy and atomic force microscopy. The observed aggregates ranged from 250 nm to greater than 10 microm in size. Formation of liquid crystalline phases was observed by polarized microscopy as the material was gradually hydrated with water. Lymph studies in rats indicated that up to 6.9% of the orally administered dose of compound 1 in pH 6.5 buffer appeared in lymph, suggesting that supramolecular aggregation may also occur in vivo leading to partitioning between the portal and the lymph routes.

Conclusions: The aforementioned supramolecular aggregation was found to have a profound effect on the pharmaceutical development of the drug and potentially on in vivo absorption of the drug.