Background: High-Performance Liquid Chromatography (HPLC) method has been used to
detect related impurities of perampanel. However, the detection of impurities is incomplete, and the
limits of quantification and detection are high. A sensitive, reliable method is badly needed to be
developed and applied for impurity detection of perampanel bulk drug.
Objective: Methodologies utilising HPLC and Gas Chromatography (GC) were established and validated
for quantitative determination of perampanel and its related impurities (a total of 10 impurities
including 2 genotoxic impurities).
Methods: The separation was achieved on a Dikma Diamonsil C18 column (250 mm × 4.6 mm, 5 μm)
with the mobile phase of 0.01 mol/L potassium dihydrogen phosphate solution (A) and acetonitrile (B)
in gradient elution mode. The compound 2-bromopropane was determined on an Agilent DB-624 column
(0.32 mm × 30 m, 1.8 μm) by electron capture detector (μ-ECD) with split injection ratio of 1:5
and proper gradient temperature program.
Results: Both HPLC and GC methods were established and validated to be sensitive, accurate and robust
according to the International Council for Harmonization (ICH) guidelines. The methods developed
were linear in the selected concentration range (R2≥0.9944). The average recovery of all impurities
was between 92.6% and 103.3%. The possible production mechanism of impurities during the synthesis
and degradation processes of perampanel bulk drug was also discussed. Five impurities were
analyzed by liquid chromatography–mass spectrometry (LC-MS). Moreover, two of them were simultaneously
characterized by LC-MS, IR and NMR.
Conclusion: The HPLC and GC methods were developed and optimized, which could be applied for
quantitative detection of the impurities, and further stability study of perampanel.