Degradation kinetics of DMP 777, an elastase inhibitor.
OBJECTIVE
The objective was to evaluate the degradation profile of the elastase inhibitor DMP 777 and lay the foundation for formulation development.


METHODS
The pKa was determined by potentiometric titration in mixed-aqueous solvents. The degradation kinetics were studied as a function of pH, buffer concentration, ionic strength, methanol concentration and temperature using a stability-indicating HPLC assay. The degradation products were identified by LC-MS, NMR, and by comparison with authentic samples.


RESULTS
The pKa for the protonated piperazine nitrogen was estimated to be 7.04. The pH-rate profile is described by specific acid-, water-, and specific base-catalyzed pathways. The pH 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 effects and medium effects were observed. The proposed mechanism for acid catalyzed degradation is the rarely observed AAL1 which involves alkyl-nitrogen heterolysis. The driving force for the reaction appears to lie in the stability of the benzylic carbocation. The proposed mechanism for base catalyzed degradation is BAC2 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 KOH controlled region where a similar mechanism of hydrolysis should be operative. A contributing factor to this increased reactivity may lie in the reduced 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.
Raghavan
K S
KS
Dupont Merck Pharmaceutical Company, Experimental Station, Wilmington, Delaware 19880-0400, USA.
Gray
D B
DB
Scholz
T H
TH
Nemeth
G A
GA
Hussain
M A
MA
D001384:Azetidines; D002021:Buffers; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D009994:Osmolar Concentration; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000737:chemistry*; D012996:Solutions; D013696:Temperature
D001384:Azetidines; D002021:Buffers; D010879:Piperazines; D012996:Solutions; C105999:DMP 777; D010196:Pancreatic Elastase