Evaluation of Solution Oxygenation Requirements for Azonitrile-Based Oxidative Forced Degradation Studies of Pharmaceutical Compounds

https://doi.org/10.1002/jps.20626Get rights and content

ABSTRACT:

AIBN and ACVA oxidative forced degradation models are examined for two drug molecules whose predominant oxidation chemistries arise from different reaction mechanisms (i.e., free radical vs. nucleophilic). Stress was conducted under a variety of initiator concentrations, and under ambient and pressurized oxygen atmospheres. In each case examined, the azonitrile initiator solutions served as a good predictive model of the major oxidative degradation products observed in pharmaceutical formulations. At low to moderate inititator concentrations, the degradation product distributions and degree of reactivity were similar for samples stored in ambient and pressurized oxygen environments. These results are rationalized with reference to the oxygen consumption kinetics of AIBN and ACVA solutions as a function of initiator concentration. The data suggests that ambient air provides sufficient oxygen to enable chain propagation of peroxy radicals in azonitrile solutions of concentrations appropriate to the forced degradation of pharmaceutical compounds. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association.

Section snippets

INTRODUCTION

Pharmaceutical scientists tasked with the development of stability-indicating analytical methods for new drug products face a difficult challenge in that they must develop a method that is selective for all the degradants occuring in the formulation before information is available about what these degradants actually are. The understanding of the degradation chemistry of a pharmaceutical compound is thus an important first step in the development of a stability-indicating method. The ultimate

EXPERIMENTAL

Solutions of compounds 1 and 2 were prepared at ∼0.1 mg/mL concentrations (approximately 0.2 mM) together with 1, 5, 25, and 50 mM AIBN or ACVA in 50% water/50% acetonitrile solution. The low drug concentrations used in this study are consistent with the milligrams quantities available in early drug development when initial forced stress studies are most commonly initiated.3 It should be noted that this low drug concentration maximizes the percent degradation for a given amount of initiator,

Oxygen Consumption Kinetics of AIBN and ACVA Solutions

Figure 1 shows the headspace oxygen concentration for 1–50 mM AIBN solutions in 50/50 acetonitrile/water as a function of time at 40°C. Higher concentrations of initiator give approximately linear increases in oxygen consumption, as expected assuming a first order rate of initiator decomposition. Figure 1 shows that less than 10% of the oxygen in the headspace is consumed over 1 week in the 1 and 5 mM AIBN cases, while nearly 80% of the headspace oxygen is consumed in the 50 mM AIBN case in the

Use of Ambient Oxygen Atmospheres in AIBN and ACVA Initiated Oxidation

The practice of using pressurized oxygen headspace4,8 during the azonitrile-initiated stress experiment has presumably arisen from a desire to maximize the formation of alkyl hydroperoxy radicals in the belief that such species provide the most representative model of autoxidiation. Indeed, this is a reasonable procedure and is consistent with the current understanding of peroxy radicals as the central species involved in solid-state oxidative degradation in pharmaceutical formulations.11 In

CONCLUSIONS

Azonitrile-type radical initiators hold much promise in their ability to quickly and simply generate relevant oxidative degradation profiles to aid in the development of stability-indicating chromatographic methods. However, clear understanding of the impact of experimental variables is required to achieve the maximum insight from the forced degradation experiment. This work represents a critical evaluation of one of the key experimental variables, the oxygenation of solutions during the forced

Acknowledgements

The authors wish to thank Kim Gallagher for helpful discussions of this subject matter and Dr. Rajiv Mahajan for help with some of the experiments. Further thanks are due to Parminder Sidhu, Andrey Peresypkin, James Qin, Allen Templeton, Hui Xu, Steven Pitzenberger, and Andreas Abend for background work pertaining to the test molecules used in this research.

REFERENCES (40)

  • M.J. Kaufman

    Applications of oxygen polarography to drug stability testing and formulation development: Solution-phase oxidation of hydromethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors

    Pharm Res

    (1990)
  • G. Boccardi

    Oxidative susceptibility testing

  • P.J. Jansen et al.

    Stress testing: Analytical considerations

  • L.M. Arnett et al.

    Vinyl polymerization with radioactive aliphatic azobisnitrile initiators

    J Am Chem Soc

    (1952)
  • J.C. Bevington et al.

    The termination reaction in radical polymerizations. Polymerizations of methyl methacrylate and styrene at 25°

    J Polym Sci

    (1954)
  • J.C. Bevington

    Aspects of the chemistry of azobisisobutyronitrile

    J Polym Mater

    (1993)
  • Harmon PA, Kosuda KM, Nelson ED, Mowery MA, Reed RA. A novel peroxy radical based oxidative stressing system for...
  • F. Lombardo et al.

    How do we study oxidative chemical stability in discovery? Some ideas, trials, and outcomes

  • A.A. Miller et al.

    Oxidation of unsaturated compounds. I. The oxidation of styrene

    J Am Chem Soc

    (1956)
  • F.R. Mayo

    The oxidation of unsaturated compounds. V. The effect of oxygen pressure on the oxidation of styrene

    J Am Chem Soc

    (1958)
  • Cited by (27)

    • Mechanistic study of the oxidative degradation of the triazole antifungal agent CS-758 in an amorphous form

      2013, Journal of Pharmaceutical Sciences
      Citation Excerpt :

      Such stressing systems are used to evaluate drug candidates during the early drug development stage. The literature available regarding approaches for studying oxidation mechanisms is extensive.14–20 Indeed, these approaches have been used in the pharmaceutical industry, and in many cases, the data obtained about oxidative decomposition have been helpful in the drug development process.

    View all citing articles on Scopus
    View full text