Degradation Pathway Proposal, Structure Elucidation, and In Silico Toxicity Prediction of Dapagliflozin Propane Diol Hyd
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ORIGINAL
Degradation Pathway Proposal, Structure Elucidation, and In Silico Toxicity Prediction of Dapagliflozin Propane Diol Hydrolytic Degradation Products Prashant S. Devrukhakar1 · M. Shiva Shankar1 Received: 16 April 2020 / Revised: 14 July 2020 / Accepted: 20 July 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Dapagliflozin (DAP) is therapeutic agent for diabetes mellitus type II patients with insufficient glycemic control by exercise and diet. Stability-indicating LC–MS method was developed and validated on C8 column and method was able to separate DAP and three major hydrolytic degradation products. Structure elucidation of three major identified hydrolytic degradation products (DPs) and establishment of degradation pathway were executed with the combine application of liquid chromatography-positive mode electrospray ionization tandem mass spectrometry and high-resolution mass spectrometry. Further ProTox-II was used to predict in silico toxicity for each DPs and compared with DAP. Keywords Forced degradation study · Dapagliflozin propanediol · Degradation pathway · Degradation products · Stability indicating method · LC–MS and HRMS
Introduction Type II Diabetes mellitus (T2DM) is the most terrific health challenge of twenty-first century [1]. Dapagliflozin (DAP) is SGLT2 inhibitor and promotes urinary glucose excretion and lower plasma glucose. DAP can be useful to treat T2DM patients across the different stages of clinical progression. Chemical name for DAP is(2S,3R,4R,5S,6R)-2-[4-chloro3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl) oxane-3,4,5-triol [2, 3]. Forced degradation (FD) study is critical for stability study as a part of drug development cycle. It portrays an entire picture about intrinsic stability of molecule in short period of time [4]. The stability study of molecule gives information about storage conditions and shelf life period. There are various factors that impact the quality of molecule with time and intensity of degradation reactions, such as hydrolysis (pH-related degradation), oxidation and photolysis. The advantage of FD study is a) to find plausible degradation products which mimic actual long-term stability study * M. Shiva Shankar [email protected] 1
School of Advance Sciences, Vellore Institute of Technology (VIT), Katpadi, Vellore, Tamil Nadu 632014, India
b) to propose ultimate feasible degradation pathways, and c) to identify most obvious fragmentation pattern [5]. LC–MS/ MS is one of the best tool to separate chromatographically degradation products and to identify them. Similarly, highresolution mass spectrometry (HRMS) can be supportive and confirmative tool to LC–MS/MS for structure elucidation [6–11]. Few of the literature findings suggest validated stability indicating assay method for DAP [12, 13], whereas few provides information about LC method for estimation of DAP alone or with combination of other drugs in either API form or dosage form [14–23] and other literature suggests UHPLC separation method for DAP in the p
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