Detection method of rupatadine fumarate related substances
Through high-performance liquid chromatography and gradient elution technology, the impurity monitoring problem during the synthesis of lupatadin fumarate was solved, and fast and accurate quality control was achieved, and product yield and purity were improved.
Patent Information
- Application Number
- CN202510369438.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-03-27
- Publication Date
- 2025-07-04
AI Technical Summary
The prior art is difficult to effectively monitor impurities during the synthesis of lupatadin fumarate, affecting product yield and purity.
Using high-performance liquid chromatography, using silica gel-bonded octadecylsilane column and gradient elution technology, combined with triethylamine phosphate buffer and pure organic solvent, impurity separation detection of lupatadine fumarate and intermediate 4 was performed.
It realizes rapid and accurate quality control of Lupatading fumarate, improves product yield and purity, and ensures the quality of the final product.
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Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of chemical drugs and food analysis, and particularly relates to a detection method for analyzing and determining related substances of rupatadine fumarate and rupatadine fumarate (intermediate 4) by liquid chromatography; Background Art
[0002] Seasonal allergic rhinitis is a chronic disease caused by allergies, mainly manifested as runny nose, accompanied by allergic symptoms such as itchy eyes and itchy skin. Although allergic rhinitis itself is not fatal, its long-term effects and potential hazards cannot be ignored; chronic urticaria has a high incidence rate in the cardiovascular system, respiratory system and skin symptoms. Some patients may have serious complications or develop infections or other serious diseases due to the decline of immune system function, thus endangering life. Currently, research data shows that rupatadine fumarate is a second-generation antihistamine with dual effects of antihistamine and anti-platelet activating factor (PAF), and it is mainly used to treat allergy-related diseases.
[0003] Rupatadine fumarate, its molecular formula is C 30 H 30 ClN3O4, and the molecular weight is 532.03:
[0005] In the process of synthesizing and preparing rupatadine fumarate, quality analysis is crucial for the impurity control of rupatadine fumarate. And a method for analyzing related substances of rupatadine fumarate and rupatadine fumarate (intermediate 4) can guide and detect the synthesis and preparation of rupatadine fumarate, improve the yield and purity of the final product, and thus has important practical significance in the quality control of the synthesis process of rupatadine fumarate. Summary of the Invention
[0006] The present invention provides a method for analyzing and detecting related substances of rupatadine fumarate and rupatadine fumarate (intermediate 4), so as to quickly, effectively and accurately monitor the related substances of rupatadine fumarate and realize the quality control of its final product bulk drug.
[0007] The present invention provides a method for detecting related substances of rupatadine fumarate and rupatadine fumarate (intermediate 4). The high performance liquid chromatography method is adopted, with a silica gel-bonded octadecylsilane column as the chromatographic column. Mobile phase A contains a phosphate buffer with triethylamine, and mobile phase B is a pure organic solvent for gradient elution. The gradient elution program is as follows: Time (min) A％ B％ 0.00 80 20 3 80 20 8 70 30 16 60 40 30 25 75 35 25 75 35.1 80 20 43 80 20
[0008] Preferably, the organic phase is pure acetonitrile.
[0009] Preferably, the provided chromatographic column is Waters C18 (4.6 mm × 150 mm, 5 μm).
[0010] The analytical determination method described in the present invention can be tested according to the following method: Example 1 1) Diluent: Mobile phase A: Methanol (40:60). 2) System suitability solution: Take appropriate amounts of rupatadine fumarate, rupatadine fumarate (intermediate 2), rupatadine fumarate (intermediate 3), and reference substances of impurities (B, C, D, E, F, G, H, I, J, K). Dissolve them in the diluent and prepare a mixed solution containing 0.5 mg of rupatadine fumarate, 0.5 μg each of rupatadine fumarate (intermediate 2), rupatadine fumarate (intermediate 3), and reference substances of impurities (B, C, D, E, F, G, H, I, J, K) per 1 ml. 3) The flow rate of the mobile phase is preferably designed to be 1.0 mL / min, the ultraviolet wavelength is 220 nm, the column oven temperature is 30 °C, and the injection volume is 10 μl. 4) Elution method: Gradient elution 5) High-performance liquid chromatograph: 1260Ⅱ; 6) Precisely measure 10 μl of the solutions in 1) and 2) above, inject them into the liquid chromatograph respectively, and record the chromatogram. Example 2 1) Diluent: Mobile phase A: Methanol (40:60). 2) System suitability solution: Take appropriate amounts of rupatadine fumarate (intermediate 4) and reference substances of intermediate 4 (A, B, C, D, E, F). Dissolve them in the diluent and prepare a mixed solution containing 0.5 mg of rupatadine fumarate (intermediate 4) and 0.5 μg each of reference substances of intermediate 4 (A, B, C, D, E, F) per 1 ml. 3) The flow rate of the mobile phase is preferably designed to be 1.0 mL / min, the ultraviolet wavelength is 220 nm, the column oven temperature is 30 °C, and the injection volume is 10 μl. 4) Elution method: Gradient elution 5) High-performance liquid chromatograph: 1260Ⅱ; 6) Precisely measure 10 μl of the solutions in 1) and 2) above, inject them into the liquid chromatograph respectively, and record the chromatogram
[0011] The present invention uses Waters Under the chromatographic conditions such as a C18 chromatographic column, mobile phase A containing phosphate buffer with triethylamine, mobile phase B being acetonitrile, and an ultraviolet absorption wavelength of 220 nm, rupatadine fumarate and rupatadine fumarate (intermediate 4) and their impurities can be effectively and completely separated. The present invention uses an HPLC analysis method to solve the problem of separation and determination of rupatadine fumarate and rupatadine fumarate (intermediate 4) and their impurities, thereby reducing the occurrence of side reactions, improving the yield and purity of the product, and ensuring the quality controllability of rupatadine fumarate and its impurities. Description of the Drawings
[0012] Figure 1 It is the HPLC chart when Example 1 is carried out.
[0013] Figure 2 It is the HPLC chart when Example 2 is carried out.
[0014] Figure 3 For Figure 1 and Figure 2 comparison chart Detailed Implementation Modes The following examples are used to further understand the present invention, but are not limited to the scope of this implementation.
[0016] The examples use Instruments and Conditions High-performance liquid chromatograph: 1260Ⅱ Chromatographic column: Waters C18 (4.6 mm × 150 mm, 5 μm); Mobile phase A: (0.03 mol / L sodium dihydrogen phosphate + 3 ml triethylamine, adjusted to pH 5.20 with phosphoric acid): Methanol (900:100); Mobile phase B: Acetonitrile Column oven temperature: 30°C; Injection volume: 10 μl; Ultraviolet wavelength: 220 nm; Elution method: Gradient elution Time (min) A％ B％ 0.00 80 20 3 80 20 8 60 30 16 60 40 30 25 75 35 25 75 35.1 80 20 43 80 20 Figure 1 Solution preparation: Weigh appropriate amounts of reference substances of rupatadine fumarate, rupatadine fumarate (intermediate 2), rupatadine fumarate (intermediate 3), and impurities (B, C, D, E, F, G, H, I, J, K), add a diluent to dissolve and prepare a system suitability solution containing 0.5 mg of rupatadine fumarate and 0.5 μg each of rupatadine fumarate (intermediate 2), rupatadine fumarate (intermediate 3), and impurities (B, C, D, E, F, G, H, I, J, K) per 1 ml. Carry out high-performance liquid chromatography analysis according to the above conditions and record the chromatogram. Figure 1 The elution order of rupatadine fumarate and its impurities is impurity J, impurity K, rupatadine fumarate (intermediate 3), rupatadine fumarate (intermediate 2), impurity D, impurity I, impurity G, impurity F, impurity B, impurity E, main peak, impurity H, impurity C; Figure 2 Solution preparation: Take appropriate amounts of rupatadine fumarate (intermediate 4) and reference substances of intermediate 4 (A, B, C, D, E, F), dissolve them with a diluent and prepare a mixed solution containing 0.5 mg of rupatadine fumarate (intermediate 4) and 0.5 μg of each of the reference substances of intermediate 4 (A, B, C, D, E, F) per 1 ml. Figure 2 The elution order of rupatadine fumarate (intermediate 4) and its impurities is intermediate 4-E, intermediate 4-F, intermediate 4-D, intermediate 4-C, intermediate 4-B, main peak, intermediate 4-A;
[0017] In Figure 3 medium, Figure 2 the rupatadine fumarate intermediate (2) in Figure 1 is intermediate 4-F in Figure 2 the rupatadine fumarate intermediate (3) in Figure 1 is intermediate 4-E in Figure 3 It shows that: with the same HPLC analysis method, the method of the present invention can completely separate the rupatadine fumarate in Figure 2 and Figure 1 the impurities to be monitored in rupatadine fumarate (intermediate 4) in, and can accurately perform quantitative detection, thereby effectively controlling the product quality of rupatadine fumarate.
Claims
1. A method for the analysis and detection of related substances of rupatadine fumarate, which uses high performance liquid chromatography. The chromatographic column is a silica gel bonded octadecylsilyl column, and an ultraviolet detector is used. Phosphate is used as the buffer salt and an organic solvent is used as the mobile phase for gradient elution, which can completely separate rupatadine fumarate and its impurities.
2. According to the analysis and detection method described in claim 1, the buffer salt is selected from sodium dihydrogen phosphate or potassium dihydrogen phosphate, and the organic phase is selected from acetonitrile or methanol.
3. According to the analysis and detection method described in claim 1, rupatadine fumarate and its impurities (intermediate 4) all have ultraviolet absorption wavelengths at 190 - 400 nm, so an ultraviolet detector is selected.
4. According to the analysis and detection method described in claim 1, the elution gradient process is as follows:
5. According to the analysis and detection method described in claim 1, the preferred length of the chromatographic column is 150 mm, the diameter is 4.6 mm, and the particle size of the packing is 5 µm.
6. According to the analysis and detection method described in claim 2, mobile phase A is preferably sodium dihydrogen phosphate, and mobile phase B is preferably pure acetonitrile.
7. According to the analysis and detection methods described in claims 1 and 3, it includes the following steps: ① Set the flow rate to 0.5 - 1.5 ml / min;; ② The column temperature of the chromatographic column is 30 - 50 °C; ④ The injection volume is 5 - 20 µl.
8. According to the analysis and detection method described in claim 7, the chromatographic conditions are optimized as follows: ① The flow rate is preferably 1.0 ml / min;; ③ The column temperature is preferably 30 °C; ④ The injection volume is preferably 10 µl.
9. According to the analysis and detection method described in claim 3, the structural formula of the impurities of rupatadine fumarate is:
10. According to the analysis and detection method described in claim 3, the structural formula of the impurities of rupatadine fumarate (intermediate 4) is: