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A Quantitative Kinetic Study of Polysorbate Autoxidation: The Role of Unsaturated Fatty Acid Ester Substituents

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Abstract

Purpose

To study the role of unsaturated fatty acid ester substituents in the autoxidation of polysorbate 80 using quantitative kinetics.

Methods

Oxidation kinetics were monitored at 40°C in aqueous solution by tracking head space oxygen consumption using a fiber optic oxygen sensor with phase shift fluorescence detection. Radical chain initiation was controlled using an azo-initiator and assessed by Hammond’s inhibitor approach, allowing oxidizability constants (k p /(2k t )1/2) to be isolated. Reaction orders were determined using modified van’t Hoff plots and mixed polysorbate micelles.

Results

The oxidizability constant of polysorbate 80 ((1.07 ± 0.19) × 10−2 M−1/2 s−1/2) was found to be 2.65 times greater than polysorbate 20 ((0.404 ± 0.080) × 10−2 M−1/2 s−1/2). The additional reactivity of polysorbate 80 was isolated and was first-order in the unsaturated fatty acid ester substituents, indicating that the bulk of the autoxidative chain propagation is due to these groups. This data, and the observation of a half-order dependence on the azo-initiator, is consistent with the classical autoxidation rate law (-d[O2]/dt = k p [RH](Ri/2k t )1/2).

Conclusions

Polysorbate 80 autoxidation follows the classical rate law and is largely dependent on the unsaturated fatty acid ester substituents. Clarification of the substituents’ roles will aid formulators in the selection of appropriate polysorbates to minimize oxidative liabilities.

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Abbreviations

AAPH:

2,2′-azobis-2-methyl-propanimidamide, dihydrochloride

API:

Active pharmaceutical ingredient

CMC:

Critical micelle concentration

d[O2]/dt:

Rate of oxygen uptake

e :

Efficiency factor

EDTA:

Ethylenediaminetetraacetic acid

k i :

Initiation rate constant

k p :

Propagation rate constant

k p /(2k t )1/2 :

Oxidizability constant

k p1 :

Propagation rate constant for fatty acid ester substituents

k p2 :

Propagation rate constant for ethylene oxide substituents

PS-20:

Polysorbate 20, polyoxyethylene sorbitan monolaurate

PS-80:

Polysorbate 80, polyoxyethylene sorbitan monooleate

Ri :

Initiation rate

ROS:

Reactive oxygen species

Rp :

Propagation rate

Rt :

Termination rate

Trolox:

6-hydroxy-2,5,7,8-tetramethyl chroma-2-carboxylic acid

τ:

Inhibition time

2k t :

Termination rate constant

2k t1 :

Termination rate constant for fatty acid ester autoxidation

2k t2 :

Termination rate constant for ethylene oxide autoxidation

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ACKNOWLEDGEMENTS

The authors would like to thank Amgen Inc. for funding, Jodi Liu for discussions regarding statistical analysis of the data, and the reviewers for critical reading of this manuscript and their suggestions, especially to highlight the potential importance of linoleic and linolenic fatty acid ester substituents. J. Y. thanks Amgen Inc. for a summer graduate internship.

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Author notes

  1. Jia Yao

    Present address: Amgen, Inc., Analytical Research and Development, Thousand Oaks, California, USA

Authors and Affiliations

  1. Amgen, Inc., Pharmaceutical Research and Development, Thousand Oaks, California, USA

    Jia Yao, Dushyanth K. Dokuru, Matthew Noestheden, Janan Jona, Drazen Ostovic & Darren L. Reid

  2. Amgen, Inc., Formulation & Analytical Resources, Thousand Oaks, California, USA

    SungAe S. Park

  3. Amgen, Inc., Analytical & Formulation Sciences, Seattle, Washington, USA

    Bruce A. Kerwin

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  1. Jia Yao
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Correspondence to Darren L. Reid.

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Yao, J., Dokuru, D.K., Noestheden, M. et al. A Quantitative Kinetic Study of Polysorbate Autoxidation: The Role of Unsaturated Fatty Acid Ester Substituents. Pharm Res 26, 2303–2313 (2009). https://doi.org/10.1007/s11095-009-9946-7

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