High performance liquid chromatography for determining N-nitrosodimethylamine in ranitidine and solid preparation thereof

A high-performance liquid chromatography and nitrosodimethylamine technology, which is applied in the field of high-performance liquid chromatography measurement of N-nitrosodimethylamine, can solve the problems of mass spectrometry detectors, increased inspection costs, and relatively low impact on measurement results. Large and other problems, to achieve the effect of simple maintenance cycle, long maintenance cycle and less adjustment of detection parameters

Pending Publication Date: 2022-08-09
湖南省药品检验检测研究院
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] There are certain defects in this patent, which cannot meet the measurement requirements, as follows:
[0011] ①The mobile phase contains non-volatile salts and cannot be used in conjunction with a mass spectrometer detector
Publication number is CN112526005A patent method mobile phase aqueous phase adopts phosphoric acid and sodium hydroxide preparation (get phosphoric acid 6.8ml and place in 900ml water, add the sodium hydroxide solution 8.6ml that mass concentration is 50%, add water to 2000ml, use phosphoric acid or mass Concentration is 50% sodium hydroxide solution to adjust the pH value to 7.10 ± 0.05, see the 17th paragraph of this patent), all are non-volatile salts, cannot be combined with the mass spectrometry detector, cause the HPLC method of establishment to be difficult to verify, and cannot Qualified samples need to be verified by mass spectrometry using existing methods
[0012] ②The mobile phase is unfriendly to the chromatographic column
The mobile phase A of the patented method with the publication number CN112526005A only contains 2% acetonitrile, which is lower than the minimum 5% requirement of the organic phase in the mobile phase of the C18 chromatographic column, which can lead to a rapid decline in the performance of the chromatographic column and increase the inspection cost
[0013] ③The feasibility of this method is poor
Measure the sample according to the patented method whose publication number is CN112526005A, and find that its feasibility is poor and accurate measurement results cannot be obtained
Specifically: the drying process can lead to the degradation of ranitidine to produce NDMA, the water content has a great influence on the measurement results, the repeatability is poor, and dichloromethane as a solvent causes a large extension of the chromatographic peak

Method used

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  • High performance liquid chromatography for determining N-nitrosodimethylamine in ranitidine and solid preparation thereof
  • High performance liquid chromatography for determining N-nitrosodimethylamine in ranitidine and solid preparation thereof
  • High performance liquid chromatography for determining N-nitrosodimethylamine in ranitidine and solid preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] Take an appropriate amount of ranitidine or its solid preparation (about 1.5g of ranitidine), add 2.5ml of water precisely, dissolve it by ultrasonic for 2 minutes, precisely add 0.5ml of 0.35g / ml sodium hydroxide solution, shake well, and add 1g of precision 2ml / ml silver nitrate solution, shake well, accurately add 1ml of 0.2g / ml sodium chloride solution, shake well, stand for 10 minutes, centrifuge and filter. The filtrate should be clear and colorless. If it is turbid, it can be frozen at -20°C for 10 minutes, then centrifuged and filtered.

[0076] After repeated verification, under the above proposed operation, ranitidine hydrochloride is almost completely precipitated, and the test solution can change from a pale yellow viscous liquid before precipitation to a clear and non-viscous state. The filtrate of each test batch showed no turbidity after dropwise addition of sodium chloride solution, indicating that the silver ions were completely removed. After more tha...

Embodiment 2

[0093] like Figure 8 As shown, collect the ranitidine hydrochloride capsules of new factory, deal with according to the embodiment of the present invention 1, detect the NDMA lower than the limit, its content determination result is consistent with the current mass spectrometry method detection result, again shows that the inventive method is effective to NDMA. The detection ability reaches the level of mass spectrometry.

Embodiment 3

[0095] Take the same batch of newly manufactured ranitidine hydrochloride capsules and place them at 80°C for 6 hours. Figure 9 As shown, processing according to the present invention results in about 1000 times the detection limit of NDMA. It shows that the method has good specificity and high sensitivity, and also shows that the tendency of ranitidine to degrade in high temperature environment to generate NDMA is extremely obvious.

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Abstract

The invention discloses a high performance liquid chromatography method for determining N-nitrosodimethylamine in ranitidine and a solid preparation thereof, a chromatographic column is used for respectively performing chromatographic analysis on a treated test solution and a contrast solution, and the conditions of the high performance liquid chromatography are as follows: the wavelength is 235nm, the flow velocity is 1ml / min, the column temperature is 30 DEG C, and the sample introduction is 20mu l; the mobile phase of the high performance liquid chromatography comprises a mobile phase A and a mobile phase B, the mobile phase A is an alkaline aqueous mobile phase, the pH value of the alkaline aqueous mobile phase is more than 7 and less than or equal to 10.5, and the mobile phase B is an organic phase. The mobile phase system is alkaline, ranitidine is adsorbed by the stationary phase in a stable molecular state, and a better separation degree is achieved. An ammonia-ammonium bicarbonate buffer system can meet the alkalinity requirement of the system, the baseline noise is low, and the system is compatible with mass spectrum.

Description

technical field [0001] The invention relates to high-performance liquid chromatography for measuring N-nitrosodimethylamine, in particular to a high-performance liquid chromatography for determining N-nitrosodimethylamine in ranitidine and its solid preparations. Background technique [0002] N-nitrosodimethylamine (NDMA) is a strong carcinogenic and toxic impurity contained in ranitidine and its preparations. Its acceptable limit is extremely low. Only NDMA is allowed to contain less than 300ng per gram of ranitidine. . Due to the low limit of NDMA, mass spectrometry with higher sensitivity is generally used for detection according to the prior art, and the limit of quantification is about 33ppb. Although mass spectrometry has high sensitivity, the instrument is expensive, depends on imports, and the inspection cost is high, and it requires high professional competence of the inspectors, resulting in most pharmaceutical companies of ranitidine and its preparations have no ...

Claims

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Application Information

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IPC IPC(8): G01N30/02G01N30/06G01N30/72
CPCG01N30/02G01N30/06G01N30/72
Inventor 李帅廖彬李钰鑫陈鸿玉刘雁鸣唐桂鹏高洋
Owner 湖南省药品检验检测研究院
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