Forced degradation studies of rapamycin: Identification of autoxidation products

• Published in: Journal of pharmaceutical and biomedical analysis Vol. 59; pp. 194 - 200
• Main Authors: Oyler, Alan R., Segmuller, Brigitte E., Sun, Yanqiu, Polshyna, Ann, Dunphy, Richard, Armstrong, Barbara L., Achord, Patrick, Maryanoff, Cynthia A., Alquier, Lori, Il’ichev, Yuri V.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 05.02.2012; Elsevier
• Subjects: alcohols; Analysis; Analytical, structural and metabolic biochemistry; Autoxidation; Biological and medical sciences; Chromatography, Gel; Chromatography, High Pressure Liquid; Chromatography, Reverse-Phase; Dimerization; Drug Stability; drugs; Epoxides; Epoxy Compounds - isolation & purification; Fundamental and applied biological sciences. Psychology; General pharmacology; Immunosuppressive Agents - analysis; Immunosuppressive Agents - chemistry; Isomerism; Isomerization; isomers; ketones; Ketones - isolation & purification; Mass Spectrometry; Medical sciences; Molecular Structure; NP-HPLC; Oxidation-Reduction; oxidative stress; Pharmacology. Drug treatments; Sirolimus; Sirolimus - analysis; Sirolimus - chemistry; size exclusion chromatography; Autoxidation; Sirolimus; Epoxides; Isomerization; NP-HPLC; Antineoplastic agent; Chemical stability; HPLC chromatography; Lactone; Macrolide; Macrocycle; Antibiotic; Normal phase chromatography; Storage stability; Epoxide; Qualitative analysis; Protein synthesis inhibitor; Immunosuppressive agent; Degradation product
• ISSN: 0731-7085; 1873-264X
• DOI: 10.1016/j.jpba.2011.10.017

The immunosuppressant drug rapamycin, also known as Sirolimus, underwent autoxidation under mild conditions to give numerous monomeric and oligomeric compounds, which were generally characterized by size-exclusion chromatography and NP-HPLC with UV and MS detection. Some of the more predominant products, epoxides and ketones, were isolated and identified. Two epoxides and 10 S-epimer of rapamycin were described for the first time. Observed rapamycin isomers were also addressed. Computational chemistry was used to provide mechanistic insights. Formation of the majority of the rapamycin products could be rationalized with free radical-mediated autoxidation reactions involving alkene and alcohol sites. Methodological aspects of oxidative stress testing are discussed.