Effect of Polymer Additives on the Transformation of BMS-566394 Anhydrate to the Dihydrate Form

Abstract

To investigate the effect of polymer additives on the transformation of BMS-566394 anhydrate to the dihydrate form and to propose the possible mechanisms for inhibition of conversion of the anhydrate to the dihydrate form. The conversion of anhydrate to dihydrate was monitored using differential scanning calorimetry, powder X-ray diffraction and polarized light microscopy. Solubility and intrinsic dissolution studies were performed on anhydrate and dihydrate. IR and NMR spectroscopy were used to probe the molecular interactions between BMS-566394 and cellulose ether polymers. The anhydrate form of BMS-566394 was readily transformed into the more stable dihydrate form in aqueous suspension. The kinetic solubility and intrinsic dissolution rate of the anhydrate were ca. fourfold that of the dihydrate. Addition of cellulose ether polymers (HPC, HPMC, MC) inhibited anhydrate to dihydrate transformation in aqueous suspensions. Hydrogen bonding interaction between the polar groups of the drug and polymers was inferred from infrared spectroscopy. Solution NMR also indicated a hydrophobic interaction between the drug and polymer backbone. The anhydrate form of BMS-566394 is stabilized in the presence of cellulose ether polymers. Spectroscopic evidence is offered to postulate a molecular interaction between drug and polymers.