# Identification and Characterization of Perampanel Degradation Products: Stability-Indicating HPLC and In Silico Toxicological Assessment

## TL;DR

This study identifies and characterizes perampanel's degradation products under various stress conditions and assesses their toxicity using in silico methods.

## Contribution

The study reports two previously unreported degradation products of perampanel and provides toxicological insights for formulation development.

## Key findings

- Five degradation products of perampanel were identified and structurally characterized.
- Two new degradation products were formed under alkaline conditions.
- Toxicity assessment showed no mutagenic risk for the degradation products.

## Abstract

A stability-indicating
HPLC-UV method enabling the simultaneous
separation and monitoring of perampanel (PER) and all degradation
products was developed and applied, providing adequate resolution
and peak purity. Forced degradation studies were conducted to define
the degradation profile of PER under acidic, alkaline, oxidative,
photolytic, and metal-ion stress conditions. Five degradation products
(DP-1 to DP-5) were identified by HPLC–UV and structurally
characterized by HRMS/MS, and 1D/2D NMR spectroscopy
(1H, 13C, COSY, and HSQC). Acidic hydrolysis
produced a benzamide derivative (DP-1) and a benzoic acid derivative
(DP-2), oxidative stress generated a pyridine N-oxide
derivative (DP-3), and alkaline conditions yielded two previously
unreported products, a ring-cleavage derivative of perampanel (DP-4)
and a hydroxylated pyridone derivative of perampanel (DP-5). DP-1
was also detected during accelerated stability studies of PER tablets
formulated with acidic excipients, demonstrating excipient–drug
incompatibility under stressed storage conditions (40 °C/75%
RH). The toxicity risk of the five degradation products was assessed
using complementary in silico approaches (statistical and expert-rule
methods) in accordance with ICH M7 guidance. None of the degradation
products showed mutagenic concern and were therefore classified as
ICH M7 Class 4 or Class 5 impurities. These results expand the structural
knowledge of PER degradation products, clarify its main degradation
pathways, and provide experimental and toxicological support for formulation
development and impurity control.