Evaluation of Solution Oxygenation Requirements for Azonitrile-Based Oxidative Forced Degradation Studies of Pharmaceutical Compounds
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.
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2013, Journal of Pharmaceutical SciencesCitation 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.