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Degradation of BMS-753493, a novel epothilone folate conjugate anticancer agent.
MedLine Citation:
PMID:  23039020     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
BMS-753493 is a folate-targeted candidate being developed for the treatment of cancer. As part of preformulation efforts, our aim was twofold - to understand the major degradation pathways and, study its kinetics of degradation to aid drug product development. Given the complexity of degradation, BMS-748285, the epothilone moiety of BMS-753493 was used as model compound to evaluate the major degradation pathway viz; macrolactone versus aziridine ring hydrolysis. Hydrolysis of BMS-753493 was studied in the pH range of 1.5-9.4 in 0.05 M buffers at 0.5 ionic strength and 5-40°C. Three major pathways were identified; carbonate ester hydrolysis and hydrolysis of aziridine and macrolactone rings resulting in addition products with identical masses (m/z = 794) in the pH range of 5-7.5. Similarly, two addition products, D1 and D2 (m/z = 555) were also formed on hydrolysis of BMS-748285 under neutral pH conditions. The reaction products from BMS-748285 were isolated and characterized using LC-MS and LC-SPE-NMR (1-D (1)H and 2-D HMBC, heteronuclear single quantum coherence) analyses. LC-NMR analysis indicated an intact aziridine ring and opened macrolactone ring, resulting in D1 and D2, an isomeric hydroxy acid pair resulting from an alkyl oxygen cleavage. By analogy to BMS-748285, BMS-753493 was also postulated to undergo alkyl cleavage of the macrolactone, forming two epimeric hydroxy acids under neutral pH. The pH-stability data were also consistent with these findings. Additionally, the degradation kinetics for BMS-753493, indicated a U-shaped pH-stability profile with maximum stability at pH 7. Based on the stability and solubility considerations, the pH range of 6-7 was optimal for an injectible drug product development.
Authors:
Madhushree Gokhale; Ajit Thakur; Frank Rinaldi
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-10-8
Journal Detail:
Title:  Drug development and industrial pharmacy     Volume:  -     ISSN:  1520-5762     ISO Abbreviation:  Drug Dev Ind Pharm     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-8     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7802620     Medline TA:  Drug Dev Ind Pharm     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Exploratory Pharmaceutical Sciences, Bristol Myers Squibb Company , New Brunswick , USA.
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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