A quantitative kinetic study of polysorbate autoxidation: the role of unsaturated fatty acid ester substituents.
OBJECTIVE
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 degrees 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) x 10(-2) M(-1/2) s(-1/2)) was found to be 2.65 times greater than polysorbate 20 ((0.404 +/- 0.080) x 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[O(2)]/dt = k(p)[RH](R(i)/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.
Yao
Jia
J
Amgen, Inc., Pharmaceutical Research and Development, Thousand Oaks, California, USA.
Dokuru
Dushyanth K
DK
Noestheden
Matthew
M
Park
SungAe S
SS
Kerwin
Bruce A
BA
Jona
Janan
J
Ostovic
Drazen
D
Reid
Darren L
DL
D004353:Drug Evaluation, Preclinical / Q000379:methods; D004952:Esters; D005231:Fatty Acids, Unsaturated / Q000737:chemistry* / Q000502:physiology*; D007700:Kinetics; D008823:Micelles; D008956:Models, Chemical; D010084:Oxidation-Reduction; D011136:Polysorbates / Q000737:chemistry* / Q000378:metabolism*
D004952:Esters; D005231:Fatty Acids, Unsaturated; D008823:Micelles; D011136:Polysorbates