PREFORMULATION STUDIES OF A NOVEL HIV PROTEASE INHIBITOR, AG1343

AG1343 is a novel human immunodeficiency virus (HIV) protease inhibitor designed using protein structure-based techniques and intended for chronic oral administration in the treatment of AIDS-related conditions. The compound is the mesylate salt of a basic amine with a molecular weight of 663.90, pK(a) of 6.0, and partition coefficient (log P) of 4.1. Examination of the physicochemical properties of a bench-scale lot of the bulk drug was undertaken in order to establish a preformulation database and to begin development of an oral formulation suitable for phase I clinical trials. A stability-indicating gradient HPLC method was developed, and initial stability studies indicated that the compound is relatively stable under accelerated conditions. Water solubility and intrinsic dissolution rate studies, however, revealed the potential for dissolution rate-limited absorption. Alternative salts were prepared and evaluated for water solubility relative to the mesylate. A pH-solubility profile for AG1343 was generated and its solubility in various pharmaceutical solvents was determined. Formulation into several prototypical oral dosage forms for in-vitro evaluation in animal models prior to phase I clinical trials resulted in a several-fold difference in bioavailability between these formulations.