Detection method of rupatadine fumarate genotoxic impurities

Abstract

The invention relates to a method for detecting genotoxic impurities of rupatadine fumarate, which is characterized in that a phosphate buffer solution is matched with acetonitrile, a high performance liquid chromatography method is adopted, a chromatographic column is a silica gel bonded octadecylsilane column, a gradient program is adopted for elution, and the content of the rupatadine fumarate genotoxic impurities in the rupatadine fumarate genotoxic impurities in the rupatadine fumarate genotoxic impurities is detected. Effective separation between rupatadine fumarate and genotoxic impurities and between genotoxic impurities can be achieved, accurate quantitative analysis can be achieved, and the quality of drugs can be effectively controlled.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical analysis and quality control technology, specifically to a method for detecting genotoxic impurities of rupatadine fumarate using liquid chromatography. Background Technology

[0002] The chemical formula of rupatadine fumarate is 8-chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridyl)methyl]-4-piperidylidene]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine fumarate, and its English name is 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridyl)methyl]-4-piperidylidene]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine fumarate. Its molecular formula is C26H26ClN3·C4H4O4, and its molecular weight is 532.03.

[0003]

[0004] Loratadine Fumarate is a third-generation tricyclic antihistamine developed by the Spanish pharmaceutical company Uriach. It was first launched in Spain in 2003. It is currently the only drug with dual antihistamine and platelet-activating factor (PAF) antagonistic effects.

[0005] In the synthetic production process of rupapatadine fumarate, genotoxic impurities introduced during the process may affect the purity and quality of the drug if not completely removed. This impact extends beyond directly threatening long-term patient safety; it also affects drug quality control. Therefore, achieving the separation of rupapatadine fumarate from genotoxic impurities is of significant practical importance for quality control during its synthesis. Summary of the Invention

[0006] This invention proposes a method for detecting genotoxic impurities in rupatadine fumarate, which enables rapid, effective, and accurate monitoring of the purity and content of genotoxic impurities in rupatadine fumarate, thereby achieving quality control of the final product.

[0007] The present invention proposes a method for detecting the genotoxic impurity of rupatadine fumarate, which employs high performance liquid chromatography (HPLC) with a silica-bonded octadecylsilane column, using a certain proportion of phosphate buffer solution as mobile phase A and an organic phase as mobile phase B for gradient elution.

[0008] The method for detecting the genotoxic impurity of rupatadine fumarate provided by this invention, wherein the gradient elution procedure is as follows:

[0009] Preferably, the salt buffer solution is sodium dihydrogen phosphate buffer solution with an optimal concentration of 0.05 mol / L and an optimal pH of 5.5.

[0010] Preferably, the organic phase is acetonitrile.

[0011] Preferably, the chromatographic column provided is an XBridge® C18 (4.6 mm × 150 mm, 3.5 µm).

[0012] The separation and determination method described in this invention can be implemented according to the following method: 1) Take an appropriate amount of rupatadine fumarate reference standard, dissolve the sample with diluent, and prepare a sample solution containing 0.5 mg of rupatadine fumarate per 1 ml; 2) Set the mobile phase flow rate to 0.5-1.5 mL / min, preferably 1.0 mL / min, the detection wavelength to 220-240 nm, the optimal detection wavelength to 210 nm, and the column oven temperature to 20-40 °C, with the optimal temperature to 30 °C. 3) Take 20 μl of the sample solution from 1) above and inject it into the liquid chromatograph to complete the separation and determination of rupatadine fumarate and genotoxic impurities.

[0013] This invention utilizes an XBridge® C18 (150 × 4.6 mm, 3.5 μm) chromatographic column, which effectively separates rupatadine fumarate and its genotoxic impurities. This invention solves the problem of separating and determining rupatadine fumarate and its genotoxic impurities, improves the content and purity of the product, and ensures the quality control of the final rupatadine fumarate product. Attached Figure Description

[0014] Figure 1 The image shows the HPLC chromatogram of rupatadine fumarate blank solvent in Example 1.

[0015] Figure 2 The image shows the HPLC chromatogram of rupatadine fumarate and its genotoxic impurities in Example 1.

[0016] Figure 3 This is the HPLC chromatogram of rupatadine fumarate in Example 1.

[0017] Figure 4 This is the HPLC chromatogram of the localization of the base poison impurity A in Example 1.

[0018] Figure 5 This is the HPLC chromatogram of the localization of the base poison impurity B in Example 1.

[0019] Figure 6This is the HPLC chromatogram of the localization of the base poison impurity C in Example 1.

[0020] Figure 7 This is the HPLC chromatogram of the localization of the base poison impurity D in Example 1. Detailed Implementation The following embodiments are provided to further understand the present invention, but are not limited to the scope of these embodiments.

[0021] Example 1 Instruments and conditions High-performance liquid chromatograph: Agilent 1260 Infinity II; Column: XBridge® C18 (4.6mm × 150mm, 3.5µm); Mobile phase A: 0.05 mol / L sodium dihydrogen phosphate buffer solution (pH 5.5) Mobile phase B: Acetonitrile; Elution should be performed according to the following gradient:

[0022] Flow rate: 1.0 mL / min; Column temperature: 30℃; Detection wavelength: 210nm; Injection volume: 20 μl; The HPLC detection procedure for the genotoxic impurity of rupatadine fumarate is as follows: Take an appropriate amount of rupatadine fumarate and its various genotoxic impurities reference standards, dissolve the sample with a diluent, and prepare a sample solution containing 0.5 mg / mL rupatadine fumarate and approximately 10 µg / mL of its various genotoxic impurities.

[0023] Inject 20 µl of the above solution into the liquid chromatograph, record the chromatogram, and the results are shown in the appendix. Figure 2 , Figure 2 The chromatographic peak with a retention time of 21.055 min is rupatadine, and the remaining chromatographic peaks are those of various genotoxic impurities.

[0024] In summary, this invention can separate rupapatedin fumarate from its various genotoxic impurities and accurately perform quantitative detection, effectively control the purity and content of rupapatedin fumarate, and monitor the content of genotoxic impurities, thereby effectively controlling the product quality of the final product, rupapatedin fumarate.

Claims

1. A method for detecting genotoxic impurities of Rupatadine fumarate by high performance liquid chromatography, using a silica bonded octadecylsilane column, with a certain proportion of buffer salt solution and organic phase as mobile phase, and gradient elution.

2. The method according to claim 1, wherein the organic phase is selected from one of the following compounds: methanol, acetonitrile.

3. The method of claim 1, wherein, The said salt buffer solution is selected from one of the following inorganic salts: phosphate, perchlorate.

4. The method according to claim 1, wherein the gradient process is gradient elution as follows:

5. The method according to claim 1, wherein the column is preferably 150 mm in length, 4.6 mm in diameter, and 3.5 µm in particle size.

6. The detection method according to claim 1 and 3, characterized in that, The said salt buffer solution is preferably sodium dihydrogen phosphate buffer, and the optimal concentration is 0.05 mol / L.

7. The detection method according to claim 6, characterized in that, The pH of the said sodium dihydrogen phosphate buffer is 5.0-6.0, preferably 5.

5.

8. The method according to claims 2 and 4, wherein the organic phase is preferably acetonitrile.

9. The method according to claim 1, comprising the following steps: ① setting the flow rate to 0.5-1.5 ml / min; ② setting the detection wavelength to 210-240 nm; ③ setting the column temperature to 20-40℃; ④ setting the injection volume to 10-30 µl.

10. The method according to claim 8, wherein the chromatographic conditions are as follows: ① the flow rate is preferably 1.0 ml / min; ② the wavelength is preferably 210 nm; ③ the column temperature is preferably 30℃; ④ the injection volume is preferably 20 µl.

11. The method for detecting genotoxic impurities of Rupatadine fumarate according to claim 1, wherein the related substance impurities are as follows:

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