Mechanistic Study of the Oxidative Degradation of the Triazole Antifungal Agent CS-758 in an Amorphous Form

doi:10.1002/jps.23339

Journal of Pharmaceutical Sciences

Volume 102, Issue 1, January 2013, Pages 104-113

https://doi.org/10.1002/jps.23339 Get rights and content

ABSTRACT

In this study, the degradates generated from a pharmaceutical solid were characterized, and a mechanistic pathway underlying their formation was proposed. The chemical stability of a novel triazole antifungal drug, CS‐758, deteriorated significantly when the crystal was disordered, and characteristic degradates were generated. A total of eight degradates in solution and nine degradates in a solid state were isolated by preparative liquid chromatography. Degradates were characterized using high‐performance liquid chromatography–photodiode array, mass spectrometry, and nuclear magnetic resonance. Radical‐mediated oxidation is proposed as the main degradation pathway in the solid state. The initiation step of this pathway is hydrogen atom abstraction from a methine carbon that is adjacent to a dien moiety and the formation of a delocalized vinylic radical intermediate. Molecular oxygen is then added to the radical position to form hydroperoxides. There are three potential oxidation routes based on the proposed autoxidation pathway that lead to the generation of the dioxane ring‐opening hydroxyl form, the 9,10‐epoxide form, or the 11,12‐epoxide form, depending on the substituted position of the added molecular oxygen. The epimer compound generated via the vinylic radical intermediate and sulfoxides was characterized. This degradation mechanism provides the scientific foundation for an oxidative stressing system currently under investigation.

Section snippets

INTRODUCTION

In addition to hydrolysis, oxidation is a major pathway of drug degradation. Several different types of oxidation mechanisms are known, such as autoxidation (mediated by free radicals),¹^,² nucleophilic/electrophilic oxidation (mediated by peroxides),³^,⁴ electron transfer oxidation (mediated by transition metals),⁵ and photochemically induced oxidation (singlet oxidation, etc.).⁶^,⁷ In some cases, an oxidation reaction is triggered by trace amounts of impurities (e.g., peroxides or transition

Materials

CS‐758 was provided by Daiichi‐Sankyo (Tokyo, Japan). All water used was purified using Milli‐Q Gradient A10 system (Millipore, Milford, Massachusetts). The oxygen scavenger Sequl® BP‐100 was kindly donated by NISSO JUSHI (Ibaraki, Japan). All other chemicals were of analytical grade and from commercial sources.

Preparation of Amorphous Sample using the Grinding Method

The drug substance was ground using a vibrational mill (RM‐201; Mitsubishi Chemical Engineering, Tokyo, Japan) for a total of 120 min. The sample was cooled down by occasional

Profile of Degradates

CS‐758 was subjected to acidic, basic, and oxidative conditions in solution. The data obtained from HPLC analysis showed that eight major degradates were generated under these stressing conditions (Fig. 2a). Analytical HPLC showed that the acid degradates, Acid‐D1 and ‐D2, eluted at relative retention times (RRTs) 0.16 and 0.42, respectively; the base degradates, Base‐D1 and ‐D2, eluted at RRTs 0.13 and 0.47, respectively; the H₂O₂ degradates, HP‐D1, ‐D2, and ‐D3, eluted at RRTs 0.49, 0.59, and

Degradation Mechanism

Most degradation of amorphous samples likely occurs via oxidation, as most of the degradates are oxidation products. Proposed solid‐state degradation pathways that lead to the measured degradates are presented in Figures 4 and 5. The oxidation pathway presented in Figure 4 involves radical‐mediated oxidation (autoxidation), in which a hydrogen atom is abstracted from the methine carbon adjacent to the dien moiety to form a delocalized vinylic radical intermediate, with molecular oxygen being

ACKNOWLEDGEMENTS

The authors would like to thank Daiichi Sankyo Company for encouraging publication of this work.

REFERENCES (22)

S.W. Baertschi et al.
Isolation, identification, and synthesis of two oxidative degradation products of olanzapine (LY170053) in solid oral formulations
J Pharm Sci
(2008)
E. Ueyama et al.
Mechanistic study on degradation of azelnidipine solution under radical initiator‐based oxidative conditions
J Pharm Biomed Anal
(2012)
R.A. Seburg et al.
Photosensitized degradation of losartan potassium in an extemporaneous suspension formulation
J Pharm Biomed Anal
(2006)
X. Qin et al.
Liquid chromatography/mass spectrometry (LC/MS) identification of photooxidative degradates of crystalline and amorphous MK‐912
J Pharm Sci
(2001)
BA. Kerwin
Polysorbates 20 and 80 used in the formulation of protein biotherapeutics: Structure and degradation pathways
J Pharm Sci
(2008)
L. Muller et al.
A rationale for determining, testing, and controlling specific impurities in pharmaceuticals that possess potential for genotoxicity
Regul Toxicol Pharmacol
(2006)
D.A. Zhu et al.
A novel accelerated oxidative stability screening method for pharmaceutical solids
J Pharm Sci
(2011)
D.W. Reynolds et al.
The use of N‐methylpyrrolidone as a cosolvent and oxidant in pharmaceutical stress testing
J Pharm Sci
(2012)
Y. Kawaguchi‐Murakami et al.
A prediction system of oxidation reaction as a solid‐state stress condition: Applied to a pyrrole‐containing pharmaceutical compound
J Pharm Biomed Anal
(2009)
E.D. Nelson et al.
Evaluation of solution oxygenation requirements for azonitrile‐based oxidative forced degradation studies of pharmaceutical compounds
J Pharm Sci
(2006)

P.A. Harmon et al.

A novel peroxy radical based oxidative stressing system for ranking the oxidizability of drug substances

J Pharm Sci

(2006)

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Pharmaceutics, Drug Delivery and Pharmaceutical TechnologyMechanistic Study of the Oxidative Degradation of the Triazole Antifungal Agent CS-758 in an Amorphous Form

ABSTRACT

Section snippets

INTRODUCTION

Materials

Preparation of Amorphous Sample using the Grinding Method

Profile of Degradates

Degradation Mechanism

ACKNOWLEDGEMENTS

J Pharm Sci

J Pharm Biomed Anal

J Pharm Biomed Anal

J Pharm Sci

J Pharm Sci

Regul Toxicol Pharmacol

J Pharm Sci

J Pharm Sci

J Pharm Biomed Anal

J Pharm Sci

J Pharm Sci

Pharmaceutics, Drug Delivery and Pharmaceutical Technology
Mechanistic Study of the Oxidative Degradation of the Triazole Antifungal Agent CS-758 in an Amorphous Form