Separation and detection method of dexrazodone intermediate and impurities

A detection method, the technology of dexrazoxane, is used in material separation, measurement devices, analysis materials, etc., and can solve problems such as unfavorable daily operations, small number of separated impurities, and low column temperature.

Active Publication Date: 2021-09-14
中润药业有限公司
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Problems solved by technology

[0007] This product only has terminal absorption, except for the M1 intermediate and its related impurities, which are slightly less polar, and other intermediates and impurities are very polar, which makes it difficult to analyze and detect
Patents CN104177301A and WO2007062076A2 disclose the preparation method of dexrazoxane, the purity detection part discloses that the analysis method is isocratic elution, the purpose is to detect the content of dexrazoxane in the crude product, and impurities such as intermediates cannot be detected; the dexrazoxane disclosed in patent CN108226309A The Zuosheng chromatographic analysis method uses a reversed-phase C18 chromatographic column and gradient elution. The preferred method Example 1 can only detect and analyze 3 kinds of impurities. The chromatographic column and gradient elution conditions used in Examples 2-9 are the same as those in Example 1. Others In the case of fine-tuning the chromatographic conditions, it is impossible to effectively separate the three impurities, so the number of separated impurities is small and the reproducibility is poor, and the column temperature in Example 1 is only 15°C; ) reported that the detection and analysis of dexrazoxane uses HPLC normalization method, but the process impurities A and B were not detected, and the column temperature is also very low, which is not conducive to daily operation
[0008] The existing technology has weak ability to separate dexrazoxane impurities, the number of separated impurities is small, the reproducibility is poor, and the chromatographic conditions are harsh, such as low column temperature, which is not conducive to daily operation

Method used

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  • Separation and detection method of dexrazodone intermediate and impurities
  • Separation and detection method of dexrazodone intermediate and impurities
  • Separation and detection method of dexrazodone intermediate and impurities

Examples

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preparation example Construction

[0045] Preparation of sample solution: Take 10 mg of dexrazoxane containing impurities, 5 mg of intermediate M2 and intermediate M1, dissolve and dilute with phosphoric acid solution with a volume fraction of 1.0%, precisely dilute to a 10.0 mL volumetric flask, shake well, Place in a water bath at 80°C for 3 hours to obtain the sample solution.

[0046] High performance liquid chromatography detection conditions:

[0047] High performance liquid chromatography: Thermo Fisher U3000, DAD ultraviolet detector;

[0048] Chromatographic column: CAPCELL PAK ADME chromatographic column, 4.6mm×250mm, 5um;

[0049] Mobile phase: A: 1% methanol-0.1% phosphoric acid; B: 40% acetonitrile-0.1% phosphoric acid;

[0050] Injection volume: 10μL;

[0051] Running time: 50min;

[0052] Detection wavelength: 210nm;

[0053] Gradient elution: The elution program is shown in Table 1:

[0054] Table 1 Gradient elution program (volume fraction)

[0055]

[0056]

Embodiment 1～3

[0057] Embodiments 1 to 3: When the column temperature of the chromatographic column is 25°C, the flow velocity of the mobile phase is respectively 0.9mL / min, 1.0mL / min, and 1.1mL / min to detect the sample solution, and record the chromatograms to obtain Figure 1~3 , the retention time and resolution of each peak are shown in Table 2:

[0058] Retention time and resolution of each peak under different flow rates of mobile phase in table 2

[0059]

[0060] As can be seen from Table 2, in Examples 1 to 3, after the flow velocity of the mobile phase of the chromatographic column changes, the retention time of each peak changes accordingly, but within this flow velocity range, dexrazoxane, intermediates M2, M1 and impurity A The separation of impurity F is good, and the overall effect is the best when the mobile phase flow rate is 1.0mL / min, which shows that the method can well control the quality of dexrazoxane samples.

Embodiment 4～6

[0061] Embodiments 4-6: When the flow rate of the mobile phase is 1.0mL / min, the column temperature of the chromatographic column is respectively set to 20°C, 25°C, and 30°C, the sample solution is detected, and the chromatograms are recorded in order to obtain Figure 4~6, the retention time and resolution of each peak are shown in Table 3:

[0062] Table 3 Retention time and resolution of each peak at different column temperatures

[0063]

[0064] As can be seen from Table 3, in Examples 4-6, after the column temperature of the chromatographic column changes, the retention time of each peak changes accordingly, but within this column temperature range, dexrazoxane, intermediates M2, M1 and impurities The separation of A to impurity F is good, and the overall effect is the best when the column temperature is 25°C, which shows that the method can well control the quality of dexrazoxane samples.

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Abstract

The invention provides a separation and detection method of a dexrazodone intermediate and impurities. The method comprises the following steps: (1) diluting dexrazodone containing the intermediates and the impurities by using a diluent to obtain a sample solution; and (2) detecting the sample solution by using a high performance liquid chromatograph, wherein a chromatographic column of the high performance liquid chromatograph is a CAPCELL PAK ADME chromatographic column. According to the separation and detection method disclosed by the invention, the dexrazodone intermediate M2, the intermediate M1, the impurity A, the impurity B, the impurity C, the impurity D, the impurity E and the impurity F can be effectively separated, good base line separation can be realized among peaks, when the flow velocity of a mobile phase or the column temperature of a chromatographic column is properly controlled, the peak separation degrees of most of the intermediates and the impurities are greater than 3.0, and an overall separation degree is high so that the quality of dexrazoxane and the intermediates thereof can be effectively controlled.

Description

technical field [0001] The invention belongs to the technical field of drug analysis, in particular to a method for separating and detecting dexrazoxane intermediates and impurities. Background technique [0002] Dexrazoxane (DEX), the chemical name is (S)-4,4-(1-methyl-1,2-ethanediyl)bis-2,6-piperazinedione, which is racemic Razoxane The D-isomer of is also a lipophilic cyclic derivative of the chelating agent ethylenediaminetetraacetic acid (EDTA), which is clinically used as a chemoprotectant, mainly for the prevention of anthracycline-induced cardiotoxicity. Its structural formula is as shown in (I): [0003] [0004] The synthesis of dexrazoxane involves multi-step reactions such as acid formation and ester formation, wherein M2 (tetraacetic acid) and M1 (tetraethyl ester) are its intermediate products, and the rest are API degradation impurities. The structural formula is as follows: [0005] [0006] [0007] This product only has terminal absorption. Excep...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N30/02G01N30/06G01N30/34G01N30/86
CPCG01N30/02G01N30/06G01N30/34G01N30/8679
Inventor 王辉朱少璇管璐晗万平安刘佳徐成赵冬梅何清
Owner 中润药业有限公司
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