TY - JOUR
T1 - Identification of the Major Degradation Pathways of Selumetinib
AU - Bouchema, Tahar Sif eddine
AU - Annereau, Maxime
AU - Vieillard, Victoire
AU - Boquet, Raphael
AU - Coelho, Gisele Abreu
AU - Castelli, Florence
AU - Solgadi, Audrey
AU - Paul, Muriel
AU - Yagoubi, Najet
AU - Secretan, Philippe Henri
AU - Do, Bernard
N1 - Publisher Copyright:
© 2022 by the authors.
PY - 2022/12/1
Y1 - 2022/12/1
N2 - Selumetinib is administered orally in capsule form and is indicated for the treatment of neurofibromatosis. To facilitate dosage adjustments, liquid preparations, such as solutions or suspensions, are to be developed. This led, first, to determine the stability profile of soluble or dispersed selumetinib and, secondly, to look for ways to stabilize the active substance. The degradation kinetics of selumetinib as a function of stress conditions were determined and compared. The degradation products were detected and identified by LC-HRMSn. In solution, selumetinib is sensitive to oxidation and degrades by photooxidation. In both cases, the side chain represented by the oxoamide group is concerned, leading to the formation of an amide derivative for the first case and an ester derivative for the second. The identification of such degradation mechanisms allowed us to study, in a targeted way, processes aiming at stabilizing the active molecule.
AB - Selumetinib is administered orally in capsule form and is indicated for the treatment of neurofibromatosis. To facilitate dosage adjustments, liquid preparations, such as solutions or suspensions, are to be developed. This led, first, to determine the stability profile of soluble or dispersed selumetinib and, secondly, to look for ways to stabilize the active substance. The degradation kinetics of selumetinib as a function of stress conditions were determined and compared. The degradation products were detected and identified by LC-HRMSn. In solution, selumetinib is sensitive to oxidation and degrades by photooxidation. In both cases, the side chain represented by the oxoamide group is concerned, leading to the formation of an amide derivative for the first case and an ester derivative for the second. The identification of such degradation mechanisms allowed us to study, in a targeted way, processes aiming at stabilizing the active molecule.
KW - ESI-MS fragmentation pathways
KW - degradation pathways
KW - intrinsic stability
KW - oxidation
KW - photooxidation
KW - pre-formulation studies
KW - protein kinase inhibitor
UR - http://www.scopus.com/inward/record.url?scp=85144877718&partnerID=8YFLogxK
U2 - 10.3390/pharmaceutics14122651
DO - 10.3390/pharmaceutics14122651
M3 - Article
AN - SCOPUS:85144877718
SN - 1999-4923
VL - 14
JO - Pharmaceutics
JF - Pharmaceutics
IS - 12
M1 - 2651
ER -