Method for detecting nitrosamine genotoxic impurities in varenicline intermediate

A detection method and a genotoxicity technology are applied in the field of detection of nitrosamine genotoxic impurities in varenicline intermediates, which can solve the problems of scarcity of detection methods, safety of varenicline medication, etc., and reduce the side effects of medication in patients. Response, avoidance of clinical risk, and the effect of improving detection sensitivity

Pending Publication Date: 2022-02-25
上海皓鸿生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] In order to solve the scarcity of genotoxic impurity detection m...

Method used

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  • Method for detecting nitrosamine genotoxic impurities in varenicline intermediate
  • Method for detecting nitrosamine genotoxic impurities in varenicline intermediate
  • Method for detecting nitrosamine genotoxic impurities in varenicline intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Embodiment 1: method groping

[0061] (1) Chromatographic conditions

[0062] The filler is octadecyl bonded silica gel column,

[0063] The mobile phase is 0.1% formic acid aqueous solution and 0.1% formic acid acetonitrile solution with different volume ratios, and the gradient elution is carried out according to the following table

[0064]

[0065]

[0066] The column temperature is 40°C,

[0067] The mobile phase flow rate is 0.4mL / min,

[0068] The detection wavelength is 214nm.

[0069] (2) Mass Spectrometry Conditions

[0070] The ion source is a heatable electrospray ionization source, and the ion source temperature is 450°C

[0071] The sheath gas flow rate is 55 arbitrary units, and the auxiliary gas flow rate is 15 arbitrary units.

[0072] Collision energy is 50~70(NCE)

[0073] The temperature of the ion transfer tube was 380°C.

[0074] The scan mode is positive ion mode,

[0075] The acquisition mode is parallel reaction monitoring mode. ...

Embodiment 2

[0084] Example 2 Methodological investigation - system applicability

[0085] According to the expert model and the reasoning of the software, it is predicted that the genotoxic impurities A, B, and C are all three types of impurities in ICH. According to the guidelines of ICH M7, it is necessary to carry out impurity research and control. Based on the toxicological threshold (TTC) data of 1.5 μg / day and actual process conditions, it was finally confirmed that the limits of genotoxic impurities A, B, and C were all 3.9 ppm. According to this limit and the solubility of varenicline intermediates, 1 mL of reference solution containing 7.8 ng of genotoxic impurities A, B, and C were prepared respectively. After the system was balanced, 6 injections were repeated, and the mass spectrum was recorded. The system is applicable. The test results are shown in Table 1.

Embodiment 3

[0086] Embodiment 3 methodological investigation-limit of quantitation

[0087] According to the prepared reference substance solution in Example 1, it was diluted 5 times, and it was prepared into a quantitation limit solution containing 7.8ng genotoxic impurity A, 7.8ng genotoxic impurity B and 7.8ng genotoxic impurity C, and the signal-to-noise ratio of each impurity was equal to Greater than 10, the quantitative limit test results are shown in Table 1.

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Abstract

The invention provides a method for detecting nitrosamine genotoxic impurities in a varenicline intermediate. The method comprises the step of determining the content of the nitrosamine genotoxic impurities by adopting a high-resolution liquid chromatography and mass spectrometry technology, and the nitrosamine genotoxic impurities are compounds A, B and C with the chemical structural formulas shown in the specification, and the structure of the varenicline intermediate is shown in the specification. according to the method, the effective separation of the varenicline intermediate and the related genotoxic impurities can be achieved, and the quantitative detection of the micro-content can be achieved so as to effectively control the content of the genotoxic impurities in the bulk drug and ensure the medication safety; and the detection method provided by the invention adopts common reagents, and is simple and convenient to operate, good in separation degree, high in sensitivity and good in reproducibility.

Description

technical field [0001] The invention belongs to the technical field of drug analysis, and in particular relates to a detection method for nitrosamine genotoxic impurities in varenicline intermediates. Background technique [0002] Varenicline is a drug developed by Pfizer of the United States for the treatment of nicotine addiction. At present, there are a lot of reports on the preparation and synthesis of varenicline intermediates, but less attention has been paid to its genotoxic impurities. [0003] In the original research patent CN101410110A, varenicline may have one or more of several mononitro, monoamino, mixed aminonitro, diamino or dinitro intermediate impurities, but no nitroso impurities have been identified. Research. [0004] In June 2021, Pfizer stopped production of the smoking cessation drug Chantix (varenicline), N-nitroso-varenicline, due to unacceptable levels of nitrosamines. Currently, genotoxicity assays in varenicline are receiving increasing attent...

Claims

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Application Information

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IPC IPC(8): G01N30/02G01N30/06G01N30/34G01N30/72G01N30/86
CPCG01N30/02G01N30/06G01N30/34G01N30/7266G01N30/8675G01N2030/047
Inventor 姚会婷宁彩芳王主海徐影高强郑保富
Owner 上海皓鸿生物医药科技有限公司
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