A PROFOUND SOLVENT EFFECT ON THE DIKETOPIPERAZINE FORMATION OF THE NEW DIPEPTIDE ANGIOTENSIN-CONVERTING ENZYME-INHIBITOR, MOEXIPRIL

The effect of organic solvents on the degradation kinetics, products and mechanisms of Moexipril (1) was investigated at 25°C. Like those observed in aqueous solution, the degradation kinetics leading to the diketopiperazine (2) and hydrolysis product (3) in mixed solvents were found to be pseudo-first-order. Added organic solvent, however, produced a dramatic effect on the rate and product ratio of the degradation. Thus, the hydrolysis process (k3) was suppressed in solvents with high organic content. The two water or neutral catalyzed cyclizaation processes (k1 and k2) responsible for the diketopiperazine formation, on the other hand, were enhanced by the addition of organic solvent; a maximum increase of 5.5 and 29-fold for k1 and k2, respectively, was observed in 75-90% ethanol solutions. Attempts were made to rationalize such rate enhancement through changes in solvation energy, pKa values of 1 and equilibrium constants of the intermediates with added organics. The application of the results to some of the formulation problems is discussed. © 1990.