Rate and Equilibrium Constants for the Epimerization of the Endothelin Receptor Antagonist J-104,132 Aqueous Solution

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  • BRAY Michelle L.
    Pharmaceutical Research and Development, Merck Research Laboratories
  • GORBACHEVA Daniela
    Pharmaceutical Research and Development, Merck Research Laboratories
  • JAHANSOUZ Hossain
    Pharmaceutical Research and Development, Merck Research Laboratories
  • KAUFMAN Michael J.
    Pharmaceutical Research and Development, Merck Research Laboratories
  • ISHIKAWA Kiyofumi
    Pharmaceutical Research and Development, Laboratories for Technology Development, Banyu Pharmaceutical Co., Ltd.
  • HARADA Nobuo
    Pharmaceutical Research and Development, Laboratories for Technology Development, Banyu Pharmaceutical Co., Ltd.
  • SUZUKI Kimimasa
    Pharmaceutical Research and Development, Laboratories for Technology Development, Banyu Pharmaceutical Co., Ltd.

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  • Rate and Equilibrium Constants for the Epimerization of the Endothelin Receptor Antagonist J-104,132 in Aqueous Solution.

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The degradation of [5S-[5α, 6β, 7α(R*)]]-2-butyl-5-(1, 3-benzodioxol-5-yl)-7-[(2-carboxypropyl)-4-methoxy-phenyl]-6-dihydro-5H-cyclopenta[b]pyridine-6-carboxylic acid (J-104, 132) was studied in aqueous solution as a function of temperature and pH. The degradation reaction does not proceed to completion; rather, a stable equilibrium is attained in which approximately 2% of the degradate is produced. Kinetic data for the formation of the degradate are analyzed using an integrated form of the rate law for a reversible first-order reaction, and the forward and reverse rate constants and overall equilibrium constants are presented. Isolation and spectroscopic structural determination indicate that the degradate is the C7 β-epimer of the drug. A mechanism for the epimerization reaction involving a novel enamine-like intermediate is proposed and shown to be consistent with the kinetic data. The rate and equilibrium constants are used to predict the room temperature stability of an injectable formulation of J-104, 132, and these predictions are compared to actual data from long-term stability studies. It is concluded that the preformulation kinetic studies provide essential data needed for optimum drug product development.

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