Employment of on-line FT-IR spectroscopy to monitor the deprotection of a 9-fluorenylmethyl protected carboxylic acid peptide conjugate of doxorubicin

A method for accurately determining the end-point, >98% conversion, of the deprotection reaction of a highly toxic 9-fluorenylmethyl (Fm) ester 1b to its corresponding carboxylate 1d in real time by FT-IR spectroscopy is reported. Advantages of this method over analysis by conventional chromatogr...

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Bibliographic Details
Published in:Journal of pharmaceutical and biomedical analysis 2002-04, Vol.28 (1), p.137-144
Main Authors: Cameron, Mark, Zhou, George X, Hicks, Micheal B, Antonucci, Vincent, Ge, Zhihong, Lieberman, David R, Lynch, Joesph E, Shi, Yao-Jun
Format: Article
Language:English
Subjects:
9-fluorenylmethyl ester deprotection
Analysis
Antineoplastic Agents - analysis
Antineoplastic Agents - chemistry
Biological and medical sciences
Calibration
Carboxylic Acids - analysis
Carboxylic Acids - chemistry
Doxorubicin - analysis
Doxorubicin - chemistry
Doxorubicin peptide conjugate
End-point determination
Fluorenes - analysis
Fluorenes - chemistry
FT-IR spectroscopy
General pharmacology
Medical sciences
Oligopeptides - analysis
Oligopeptides - chemistry
On-line
Pharmacology. Drug treatments
Spectroscopy, Fourier Transform Infrared - methods
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Summary:A method for accurately determining the end-point, >98% conversion, of the deprotection reaction of a highly toxic 9-fluorenylmethyl (Fm) ester 1b to its corresponding carboxylate 1d in real time by FT-IR spectroscopy is reported. Advantages of this method over analysis by conventional chromatographic means include real time determination of the end-point of a reaction that is time sensitive to by-product formation, and elimination of sampling a highly toxic reaction mixture. The FT-IR method is based on monitoring, in real time, the disappearance of the Fm ester carbonyl band for 1b at 1737 cm −1, during deprotection by piperidine, and calibration models were established by Partial Least Squares (PLS) regression analysis with high performance liquid chromatography (HPLC) as reference. The best calibration model was built with 5 PLS factors in the spectral range of 1780–1730 and 1551–1441 cm −1 and resulted in a standard error of cross validation (SECV) of 0.63 mM 1b and a standard error of prediction (SEP) of 0.51 mM 1b in the range of 0–25 mM. This error of prediction is approximately 0.8% of the initial concentration of 1b and is well within our specifications of
ISSN:0731-7085
1873-264X
DOI:10.1016/S0731-7085(01)00640-9