PMID- 34225039
OWN - NLM
STAT- MEDLINE
DCOM- 20210721
LR  - 20210721
IS  - 1873-264X (Electronic)
IS  - 0731-7085 (Linking)
VI  - 203
DP  - 2021 Sep 5
TI  - QBD-driven HPLC method of eltrombopag olamine: Degradation pathway proposal, 
      structure elucidation, and in silico toxicity prediction.
PG  - 114231
LID - S0731-7085(21)00342-3 [pii]
LID - 10.1016/j.jpba.2021.114231 [doi]
AB  - Eltrombopag olamine is prescribed for chronic immune (idiopathic) 
      thrombocytopenic purpura (ITP). This work aims to investigate the formation of 
      potential degradants of the drug and determine their toxicity in silico. A 
      stability-indicating high performance liquid chromatography (HPLC) method was 
      developed to separate six oxidative degradation impurities and three thermal 
      degradation impurities employing the quality by design (QBD) approach. The 
      degradation impurities were resolved with minimum resolution of 1.5 using a 
      phenyl column with 0.1 % trifluoroacetic acid (TFA) and acetonitrile as the 
      mobile phase and quantified at 245 nm. The structure and degradation pathway for 
      the degradants was proposed by employing liquid chromatography with tandem mass 
      spectrometry (LC-MS/MS), among the identified degradation pathways demethylation 
      and decarboxylation are common reactions observed during oxidation resulted in 
      majority of degradation products. All the degradation products are characterized 
      with help of the daughter ions and product ion obtained upon LC-MS/MS analysis. 
      The HPLC method parameters such as column temperature, flow rate, TFA 
      concentration and organic concentration are identified as critical method 
      attributes (CMA), a design of experiments (DOE) mediated design space was 
      established through use of design experts. The resolution between sets of 
      adjacent peaks was identified as a critical quality attribute; among the 
      investigated CMAs, column temperature and flow rate significantly affected the 
      resolution. Furthermore, the toxicology of the degradation products was predicted 
      with the help of in silico TOPKAT analysis, the carcinogenicity of the impurities 
      was discussed.
CI  - Copyright (c) 2021 Elsevier B.V. All rights reserved.
FAU - Jayagopal, Balaji
AU  - Jayagopal B
AD  - Department of Chemistry, School of Advanced Sciences, Vellore Institute of 
      Technology University, Vellore-14, Tamil Nadu, India.
FAU - Murugesh, Shivashankar
AU  - Murugesh S
AD  - Department of Chemistry, School of Advanced Sciences, Vellore Institute of 
      Technology University, Vellore-14, Tamil Nadu, India. Electronic address: 
      mshivashankar@vit.ac.in.
LA  - eng
PT  - Journal Article
DEP - 20210629
PL  - England
TA  - J Pharm Biomed Anal
JT  - Journal of pharmaceutical and biomedical analysis
JID - 8309336
RN  - 0 (Benzoates)
RN  - 0 (Hydrazines)
RN  - 0 (Pyrazoles)
RN  - S56D65XJ9G (eltrombopag)
SB  - IM
MH  - Benzoates
MH  - Chromatography, High Pressure Liquid
MH  - Chromatography, Liquid
MH  - Computer Simulation
MH  - *Drug Contamination
MH  - Drug Stability
MH  - Hydrazines
MH  - Pyrazoles
MH  - *Tandem Mass Spectrometry
OTO - NOTNLM
OT  - Degradation impurities
OT  - Eltrombopag
OT  - MS/MS structure elucidation
OT  - QBD
COIS- Declaration of Competing Interest The author declare that there are no conflicts 
      of interest.
EDAT- 2021/07/06 06:00
MHDA- 2021/07/22 06:00
CRDT- 2021/07/05 20:22
PHST- 2021/03/01 00:00 [received]
PHST- 2021/06/19 00:00 [revised]
PHST- 2021/06/23 00:00 [accepted]
PHST- 2021/07/06 06:00 [pubmed]
PHST- 2021/07/22 06:00 [medline]
PHST- 2021/07/05 20:22 [entrez]
AID - S0731-7085(21)00342-3 [pii]
AID - 10.1016/j.jpba.2021.114231 [doi]
PST - ppublish
SO  - J Pharm Biomed Anal. 2021 Sep 5;203:114231. doi: 10.1016/j.jpba.2021.114231. Epub 
      2021 Jun 29.