Physical and Chemical Properties of DMP 504, a Polyalkylammonium-Based Bile Acid Sequestrant

ABSTRACT The purpose of this study was to characterize the physicochemical properties of DMP 504 and lay the foundation for formulation development. Thermal properties were characterized by DSC and TGA and moisture sorption and desorption by TGA. The association rate and equilibrium binding capacity of the polymer for a prototype bile acid was evaluated using cholic acid, and solid state stability was examined at 25°C, 40°C (with and without 5% added water), 60°C, and 600 foot candles/25°C. The solid state excipient compatibility of binary mixtures of DMP 504 and several commonly used pharmaceutical excipients was also evaluated. Thermal analysis of the polymer showed a glass transition temperature at β 95°C and no melting point, indicating a highly amorphous macromolecular structure with thermal stability up to 250°C. Moisture sorption and desorption isotherms at controlled humidity ranging from 11% to 97% RH did not display hysteresis. Cholic acid associated with DMP 504 extremely rapidly so that binding was essentially complete within 5 min. Scatchard analysis of the equilibrium binding of cholic acid to DMP 504 was unconventional, and indicated that the system was exhibiting positive cooperative behavior. Modeling the binding curve for a system exhibiting cooperative behavior indicated a maximum binding capacity of DMP 504 for cholic acid in phosphate buffered saline (pH 7.0) of 4.9 μmol/mg, and a cooperativity value, P, of 2.2 implying that binding of one molecule promotes the binding of additional molecules. DMP 504, a hygroscopic, amorphous cross-linked polymer with a tendency to gain or lose moisture with ease, is stable in the solid state, either drug substance alone or in presence of excipients, at normal storage temperatures and light, and under controlled conditions of humidity.