An unexpected pH effect on the stability of moexipril lyophilized powder.
Because of the limited stability of moexipril (RS-10085; 1) in aqueous solution, lyophilized parenteral formulations were evaluated as a function of pH in this study. In general, the lyophilized powder of 1 showed about two orders of magnitude less reactivity at 50 degree C than in aqueous solution at pH values below 3 or above 6. At pH 5.1, however, the lyophilized powder had maximum reactivity, with the rate actually comparable to that observed in aqueous solution. When the distribution of the two major products, diketopiperazine (DKP) 2 and ester hydrolysis analogue 3, was compared to the observed kinetics as a function of pH, it was clear that removal of water via lyophilization suppressed the spontaneous k1 cyclization process, the spontaneous k3 hydrolysis process, and the specific base-catalyzed k4 hydrolysis process. The overall spontaneous k2 cyclization process, however, was not affected by lyophilization. The latter result is accounted for by the increased equilibrium constant for the formation of the tetrahedral intermediate, To, as a result of lyophilization. This study demonstrates that stability data in solution can not be used for predicting the stability of moexipril in lyophilized powder form.
Strickley
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Institute of Pharmaceutical Sciences, Syntex Research, Palo Alto, California 94304.
Visor
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GC
Lin
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LH
Gu
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D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D005612:Freeze Drying; D006863:Hydrogen-Ion Concentration; D007546:Isoquinolines / Q000032:analysis; D012995:Solubility; D044005:Tetrahydroisoquinolines; D014867:Water / Q000032:analysis
D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D014867:Water; C058302:moexipril