Realistic prediction of solid pharmaceutical oxidation products by using a novel forced oxidation system.
This study investigated a novel solid-state-based forced oxidation system to enable a realistic prediction of pharmaceutical product oxidation, a key consideration in drug development and manufacture. Polysorbate 80 and ferric(III) acetylacetonate were used as an organic hydroperoxide source and a transition metal catalyst, respectively. Homogeneous solutions of target compounds and these reagents were prepared in a mixed organic solvent. The organic solvent was removed rapidly under reduced pressure, and the oxidation of the resulting dried solid was investigated. Analysis of the oxidation products generated in test compounds by this proposed forced oxidation system using HPLC showed a high similarity with those generated during more prolonged naturalistic drug oxidation. The proposed system provided a better predictive performance in prediction of realistic oxidative degradants of the drugs tested than did other established methods. Another advantage of this system was that the generation of undesired products of hydrolysis, solvolysis, and thermolysis was prevented because efficient oxidation was achieved under mild conditions. The results of this study suggest that this system is suitable for a realistic prediction of oxidative degradation of solid pharmaceuticals.
Analytical and Quality Evaluation Research Laboratories, Pharmaceutical Technology Division, Daiichi Sankyo, Hiratsuka, Kanagawa, 254-0014, Japan.
Eiji
E
Ueyama
Kousuke
K
Tamura
Kousei
K
Mizukawa
Kenji
K
Kano
D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D005290:Ferric Compounds / Q000737:chemistry*; D006861:Hydrogen Peroxide / Q000737:chemistry*; D006868:Hydrolysis; D013058:Mass Spectrometry; D008956:Models, Chemical; D016877:Oxidants / Q000737:chemistry*; D010084:Oxidation-Reduction; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011136:Polysorbates / Q000737:chemistry*; D012997:Solvents
D005290:Ferric Compounds; D016877:Oxidants; D004364:Pharmaceutical Preparations; D011136:Polysorbates; D012997:Solvents; D006861:Hydrogen Peroxide
HPLC; X-ray diffractometry; degradation products; ferric(III) acetylacetonate; oxidation; polysorbate; solid state; stress testing