Quantitative determination of genotoxic impurities by Xevo TQD

Quantitative determination of genotoxic impurities by Xevo TQD

Joanne Mather, Dominic Moore, Robert S. Plumb and Paul Rainville
Waters Corporation (Milford, MA, USA)

Introduction:

Alkyl sulfonic acids, especially methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, are commonly used as alkylating agents and catalysts in the pharmaceutical industry and are used in the chemical synthesis of APIs. Used in the purification step. In addition, in order to improve chemical properties or improve bioavailability, these sulfonic acids are also often used as the final salt of the drug.

The presence of any residual alcohol in the synthesis reaction or recrystallization step may result in the formation of an alkyl ester of a sulfonic acid. Many of these mesylate, besylate or tosylate are considered to be genotoxic, while other esters may also be genotoxic and therefore need to be monitored in drugs and pharmaceuticals.

Typical methods used in the past to analyze such alkyl sulfonates are based on GC/MS or HPLC/UV/MS, where the derivatization step typically requires a run time of about 20 to 30 minutes. Previously, we have shown how to achieve good results in less than 5 minutes of running time by using UPLC?/MS.

In this application note, we will describe how the latest advances in instrumentation provide greater analytical capabilities and ease of use for these genotoxic impurities. We will also show how to use the high sensitivity of the Xevo TQD with positive and negative ion switching to reduce the analysis time of such impurities. In addition, using RADAR? to reduce matrix interference helps speed up the method development process.

experiment:

Liquid chromatography conditions:

LC system: ACQUITY UPLC
Column: ACQUITY UPLC HSS T3 column,
2.1 x 50 mm, 1.8 μm
Column temperature: 45 ?C
Injection volume: 15 μL (20 μL loop, partial loop mode)
Mobile phase A: 98 H20 2% MeOH 0.1% formic acid mobile phase B: 98 MeOH 2% H2O 0.1% formic acid

Negative ion mode:

Capillary voltage: 0.8 kV
Function type: 3-channel MRM

Positive ion mode:

Capillary voltage: 0.5 kV

Results and discussion:

A 1 mg/mL standard solution was prepared using acetonitrile for various known genotoxic impurities, and then diluted to a concentration of 0.1 to 500 ng/mL with 5% acetonitrile. In addition, a sample solution was prepared: 10 mg of amlodipine besylate tablets were ground and dissolved, and then 1.5 μg of genotoxic impurities were added as standard.

With the help of IntelliStart, each standard solution is used to help tune the MS. Co-elution can occur even at the best chromatographic performance. Simultaneous mass spectrometry data from the matrix is ​​acquired while collecting multiple reaction monitoring (MRM) quantitative mass spectrometry data to help monitor possible interfering compounds, ensuring robustness and reproducibility of the assay.

In the RADAR mode, the entire range of MS full scan spectra in both positive and negative ion modes can be acquired while acquiring MRM data. This process has essentially no impact on MRM data quality. As a result, you can track the composition of other sample matrices while accurately quantifying the target compound, giving you a deeper understanding of the sample.

The RADAR function is achievable based on the Xevo TQD's ultra-fast switching speeds in MS, MS/MS, positive ion and negative ion modes without compromising performance. Developed using the RADAR-assisted LC/MS/MS method to analyze impurities in the spiked tablet solution. Use the final developed method to verify the linearity and sensitivity of this liquid system for genotoxic impurities detection

in conclusion:

Used in conjunction with UPLC, the tandem quadrupole detector Xevo TQD is the best tool for genotoxic impurity analysis. UPLC/Xevo TQD provides excellent sensitivity and fast analysis methods. With its many features, such as IntelliStart and RADAR, positive and negative ion switching, and "all data in all time" generation, the analytical method of detection can be developed quickly and easily. This will significantly increase laboratory efficiency in response to growing research and regulatory needs.

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