Characterization and in silico Mutagenic Assessment of a New Betahistine Degradation Impurity

Murilo De Mello,João Lopes,Fernanda Ferreira,Caroline De Oliveira,Fernando Gama,Miller De Freitas,Alessandra Mascarello,Tiago Lourenço,Mariah Ultramari,Cristiano Guimarães,Carlos Cunha,Giuliano Clososki,Antonio De Oliveira

doi:10.21577/0103-5053.20190037

Abstract

Currently, the pharmaceutical industry devotes great attention to drug degradation products because these compounds can offer risks to patients. A previous degradation study of betahistine (N-α-methyl-2-pyridylethylamine) conducted under different stress conditions detected three main impurities named A, B and C. Degradation products were analyzed by high-resolution mass spectrometry in electrospray source and time of flight analyzer (ESI-TOF) and nuclear magnetic resonance (NMR). Impurity mutagenicity was evaluated by Derek Nexus and Sarah Nexus softwares. Liquid chromatography hyphenate with tandem mass spectrometry (LC-MS/MS) analysis of the betahistine forced degradation sample indicated the presence of a new impurity, which was named impurity C1. 2D NMR experiments allowed the complete structural characterization of the new entity. The active pharmaceutical ingredient and degradation impurities were classified as inactive in the in silico mutagenic studies. Systematic investigation of a forced degradation sample led to the characterization of a new betahistine impurity. The in silico mutagenicity study of the betahistine degradation impurities may be useful in the risk assessment of the drug products.

Highlights

Betahistine (1) (N-α-methyl-2-pyridylethylamine), a histamine (2) analog (Figure 1), has long been reported as an effective drug for the treatment of vascular problems such as Ménière’s disease,[1,2,3] an inner ear disorder that is clinically characterized by recurrent vertigo, tinnitus, and hearing loss episodes and which is linked to endolymphatic drops.[4]
At the end of the long-term stability study (30 °C, 75% relative humidity) in betahistine tablets, the impurity C and an unknown impurity with relative retention time (RTT) of 1.74 min were found in levels higher than those stated in the International Conference on Harmonization (ICH) Q3B24 for identification and qualification, 3.26 and 0.77%, respectively
Systematic investigation of a forced degradation betahistine sample led to the detection and structural characterization of a new entity, which was named betahistine impurity C1

Summary

Introduction

Betahistine (1) (N-α-methyl-2-pyridylethylamine), a histamine (2) analog (Figure 1), has long been reported as an effective drug for the treatment of vascular problems such as Ménière’s disease,[1,2,3] an inner ear disorder that is clinically characterized by recurrent vertigo, tinnitus, and hearing loss episodes and which is linked to endolymphatic drops.[4]. A previous betahistine degradation study conducted under different stress conditions detected these impurities.[27]

Results

Conclusion