Equilibria, kinetics and mechanism for the degradation of the cytotoxic compound L-NG-nitroarginine

Pham Van Quyet, Bernice Mei Jin Tan, Celine Valeria Liew, Lai Wah Chan, Quan Sing Ng, Paul Wan Sia Heng

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L-NG-nitroarginine (LNNA), an analog of L-arginine, is a competitive inhibitor of nitric oxide synthase which causes the selective reduction of blood flow to tumor cells. Despite the potential of LNNA to function as an adjuvant in cancer therapies, its poor solubility and stability have hindered the development of an injectable formulation of LNNA that is suitable for human administration. This work, for the first time, details a systematic study on the determination of equilibrium Kconstants and the rate law of LNNA degradation. The four Kvalues of LNNA were determined to be 1.03, 1.10 × 10−2, 2.51 × 10−10, and 1.33 × 10−13M. From the kinetic and equilibrium studies, we have shown that the deprotonated form of LNNA is the main form of LNNA that undergoes degradation in aqueous media at room temperature. The rate law of LNNA degradation was found to be first order with respect to OHconcentration and first order with respect to LNNAconcentration. The rate constant at 25 °C and 1 atm was determined to be 0.04453 M−1min−1. A base catalyzed mechanism of LNNA degradation was proposed based on the kinetic study. The mechanism was found to be very useful in explaining the discrepancies and changes of the rate law at different pH values. It is thus recommended that LNNA should be formulated as a concentrated solution in acidic conditions for maximum chemical stability during storage and be diluted with a basic solution to near physiological pH just before administration.

Original languageEnglish
Pages (from-to)624-631
Number of pages8
JournalDrug Development and Industrial Pharmacy
Issue number4
Publication statusPublished - 2018
Externally publishedYes


  • degradation kinetics
  • equilibrium constants
  • L-N-nitroarginine
  • rate law
  • solubility enhancement

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