Objective: To identify and characterize the structures of maillard reaction impurities in tenofovir alafenamide fumarate tablets by 2-dimensional liquid chromatography-tandem mass spectrometry (2D-LC-MS/MS),and establish a method to determine the maillard reaction impurities. Methods: Tenofovir alafenamide fumarate (TAF), lactose were dissolved in a small amount of water and heated at 90 ℃ for 18 h to get the maillard reaction impurities. The separation was carried out on Waters XTerra MS C18 (250 mm×4.6 mm, 5 μm) column with a mobile phase consisting of 0.02 mol·L-1 phosphate buffer (adjusted to pH 6.0 with 1 mol·L-1 potassium hydroxide)-methanol (95∶5) in a gradient mode. The maillard reaction impurities were separated and trapped. Desalination and structural identification was achieved by ultra-high liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The determination of maillard reaction impurities were performed with a ZORBAX Eclipse Plus C18 (3.0 mm×50 mm, 1.8 μm) column by using formic acid solution as mobile phase A and methanol as mobile phase B in a gradient elution. The electrospray was operated with the source ESI under positive ionization multiple reaction monitoring (MRM) mode, the nebulizer was 0.31 MPa, and the drying gas N2 flow rate was 6 L·min-1. The desolation tube temperature was 350 ℃. Results: Based on their multi-level product MS behaviour, three maillard reaction impurities were detected and their structures were identified to be monophenyl tenofovir lactose adduct, tenofovir alafenamide lactose adduct and tenofovir lactose adduct. The quantitative ion pairs were m/z 688.5→406.4, 801.5→477.4, 612.3→288.2. Conclusion: The study provides valid methodological support for prescribing screening and quality control of tenofovir alafenamide fumarate tablets.
ZHANG Hai-yun, SU Liang, XIE Ling-ling, ZHANG Zi-xuan, ZHU Jing, YUAN Xiu-ju
. Structural analysis and determination of maillard reaction impurities in tenofovir alafenamide fumarate tablets by 2-dimensional liquid chromatography-tandem mass spectrometry*[J]. Chinese Journal of Pharmaceutical Analysis, 2023
, 43(6)
: 1026
-1035
.
DOI: 10.16155/j.0254-1793.2023.06.14
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