Separation, Identification, Isolation and Characterization of Degradation Product of Osimertinib Tablets by UPLC-QTOF-MS/MS and NMR: Evaluation of &amp;lt;i&amp;gt;In-Silico&amp;lt;/i&amp;gt; Safety Assessment for Osimertinib (OSM) and Degradation Product (DP)

Arun D Bhutnar,Seema R Saple,Vikas V Vaidya

doi:10.4236/abc.2021.111003

Abstract

The present work encompasses identification and characterization of major degradation product (DP) of OSM observed in base hydrolytic stress study. The separation of DP was carried out on a non-polar stationary phase by using high-performance liquid chromatography system (HPLC). Using waters X-bridge (250 mm × 4.6 mm, 5 μm) C18 column with gradient elution program. For the characterization study, stress samples were subjected to HPLC and UPLC-QTOF-MS/MS and based on mass fragmentation pattern, plausible structure was deduced. Further, the DP was isolated using semi-prepara- tive liquid chromatography and concentrated the fractions using lyophilization. The isolated DP was subjected to extensive 1D (1H, 13C, and DEPT-135) and 2D (COSY, HSQC and HMBC) nuclear magnetic resonance (NMR) studies to authenticate the structure. The impurity was unambiguously named as N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-metho-xy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-3-methoxypropanamide. Add- itionally, the In-Silico structure activity relation (QSAR) assessed through statistical based software’s DEREK NexusTM, and MultiCASE, Case UltraTM widely accepted and respected software’s for DP and OSM.

Highlights

Osimertinib Mesylate (OSM) (Figure 1; IUPAC name: “N-(2-{2 dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2yl]amino}phenyl)prop-2-enamide mesylate salt” molecular formula: C28H33N7O2∙CH4O3S; molar mass: 596 g/mol [1]
The OSM Mesylate drug substance and drug products are a non-compendial product and no literature was found on the public domain for Degradation products
A novel analytical method developed to separate degradation product (DP), and the same method adopted for further identification with the aid of UPLC-ESI-Q-TOF-Mass spectrometric (MS)

Summary

Introduction

Osimertinib Mesylate (OSM) (Figure 1; IUPAC name: “N-(2-{2 dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2yl]amino}phenyl)prop-2-enamide mesylate salt” molecular formula: C28H33N7O2∙CH4O3S; molar mass: 596 g/mol [1]. The tablet formulation of OSM Mesylate (TagrissoTM) developed by Astra-Zeneca has been granted accelerated approval by the United States Food and Drug Administration (US-FDA) in November 2015, for the therapy of patients with metastatic EGFR T790M mutation-positive NSCLC who have progressed on or after the first and second generation of EGFR TKI therapy [9]. The impurity profiling is the one of the critical quality attributes for the pharmaceutical preparations which ensures the pure and safe drug to the patient [11]. For the finished product or raw materials self-life would be assigned based on the stability studies and trend data of degradation products on various intervals of testing. Degradation studies of drugs are paramount importance to forecast

Methods

Results

Conclusion