Kinetics and mechanism of the hydrolytic degradation of indinavir: intramolecular catalysis

Journal of Pharmaceutical Sciences
Maria M TotevaDrazen Ostovic

Abstract

The pH-rate profile of first-order rate constants for the lactonization of Indinavir in aqueous solutions with ionic strength I = 1 (KCl) at 40 degrees C is reported. The lactonization reaction is a subject of strong buffer catalysis with a nonlinear dependence of the first-order rate constants on the concentration of the buffer. The pH-rate profile is more complex than the pH-rate profiles for the hydrolysis of simple peptides and for the intramolecular OH-catalyzed hydrolysis of gamma-hydroxyamides. This complexity appears unique to Indinavir and is a result of the cis-aminoindanol leaving group. The mechanistic pathways for the lactonization are discussed. The buffer catalysis data are consistent with kinetic general acid catalysis. The second-order rate constant for the specific-acid catalyzed hydrolysis of Indinavir at 40 degrees C (k(H) = 2.2 x 10(-4) M(-1) min(-1)) is similar to that for a simple peptide indicating similar interactions in the rate limiting transition state for both reactions.

References

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Citations

Sep 21, 2013·Drug Development and Industrial Pharmacy·Julieta C ImperialeAlejandro Sosnik
Jul 11, 2012·Journal of Pharmaceutical Sciences·Roman ShimanovichMatthew L Peterson
Dec 19, 2012·Journal of Pharmaceutical and Biomedical Analysis·R Nageswara RaoS Satyanarayana Raju
Apr 27, 2013·Molecular Pharmaceutics·Catia MarzoliniAnna Seelig

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