DEGRADATION KINETICS OF DMP-777, AN ELASTASE INHIBITOR

Purpose. The objective was to evaluate the degradation profile of the elastase inhibitor DMP 777 and lay the foundation for formulation deve lopment Methods. The pK(a) was determined by potentiometric titration in mixed-aqueous solvents. The degradation kinetics were studied as a function of pH, buffer concentration, ionic strength, methanol concent ration and temperature using a stability-indicating HPLC assay. The de gradation products were identified. by LC-MS, NMR, and by comparison w ith authentic samples. Results. The pK(a) for the protonated piperazin e nitrogen was estimated to be 7.04. The pH-rate profile is described by specific acid-, water-, and specific base-catalyzed pathways. The p H of maximum stability is in the range of 4 to 4.5 where water is the principal catalyst in the reaction. Buffer catalysis, primary salt eff ects and medium effects were observed. The proposed mechanism for acid catalyzed degradation is the rarely observed AAL1 which involves alky l-nitrogen heterolysis. The driving force for the reaction appears to lie in the stability of the benzylic carbocation. The proposed mechani sm for base catalyzed degradation is B(AC)2 which involves beta-lactam ring opening. The beta-lactam ring of DMP 777, a monolactam, appears to be as reactive as that in benzylpenicillin in the k(OH) controlled region where a similar mechanism of hydrolysis should be operative. A contributing factor to this increased reactivity may lie in the reduce d basicity of the beta-lactam nitrogen making it a good leaving group. Conclusions. The degradation profile indicates that development of a solution dosage form of DMP 777 with adequate shelf-life stability at room temperature is feasible.