Method for detecting related substances of rupatadine fumarate intermediate

Abstract

The invention discloses a method for detecting related substances of a rupatadine fumarate intermediate, which is characterized in that a high performance liquid chromatography method is adopted, a chromatographic column is a silica gel bonded octadecylsilane column, a chromatographic column is a silica gel bonded octadecylsilane column, a chromatographic column is a silica gel bonded octadecylsilane column, a chromatographic column is a silica gel bonded octadecylsilane column, a chromatographic column is a silica gel bonded octadecylsilane column, and a chromatographic column is a silica gel bonded octadecylsilane column. A certain proportion of inorganic salt buffer solution-organic phase is used as a mobile phase, and a gradient elution mode is adopted for separation and detection. According to the method for preparing the related substances of the rupatadine fumarate intermediate, the quality of a medicine can be effectively controlled, and the safety of the medicine is ensured.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical drug analysis, and in particular to an analytical method for analyzing and determining rupatadine fumarate intermediates and related impurities thereof by liquid chromatography. Background Art

[0002] The intermediate of rupatadine fumarate is called loratadine, with the chemical formula of ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate. Its English name is Ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine-1-carboxylate, its molecular formula is C22H23ClN2O2, and its molecular weight is 382.883.

[0003]

[0004] Loratadine is a second-generation antihistamine. It is a highly effective and long-lasting tricyclic antihistamine. It is a selective peripheral H1 receptor antagonist that can relieve various symptoms caused by allergic reactions.

[0005] During the synthesis of rupatadine fumarate, introduced intermediates may affect the drug's purity and quality due to incomplete removal. Testing for these substances can help control drug quality and safety. Therefore, separating loratadine from other related impurities is of great practical significance for quality control during the synthesis of rupatadine fumarate. Summary of the Invention

[0006] The present invention provides a method for analyzing related substances of a rupatadine fumarate intermediate, thereby enabling rapid, effective and accurate monitoring of the purity and content of the related substances of the rupatadine fumarate intermediate, thereby achieving quality control of the final product raw material.

[0007] The present invention provides a method for analyzing related substances of rupatadine fumarate intermediates, which adopts high performance liquid chromatography, uses a silica gel-bonded octadecylsilane column as a chromatographic column, uses a certain proportion of an inorganic salt buffer solution as mobile phase A and an organic phase as mobile phase B, and performs isocratic elution.

[0008] The present invention provides a method for analyzing related substances of rupatadine fumarate intermediates, wherein the gradient elution procedure is:

[0009] Preferably, the inorganic salt buffer solution is phosphate, specifically potassium dihydrogen phosphate, with a concentration of 0.025 mol / L.

[0010] Preferably, the organic phase is acetonitrile.

[0011] Preferably, the chromatographic column provided is Shim-pack GIS C18 (4.6 mm×250 mm, 5 μm).

[0012] The separation and determination method of the present invention can be achieved by the following method: 1) Take an appropriate amount of loratadine reference substance and dissolve the sample in a diluent to prepare a sample solution containing 0.2 mg of loratadine 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, with the optimal detection wavelength being 210 nm, and the column oven temperature to 20-40°C, with the optimal column oven temperature being 30°C. 3) Take 10-30 μl of the sample solution from 1) above and inject it into a liquid chromatograph to separate and determine loratadine and related substances. High-performance liquid chromatograph: Agilent 1260 InfinityII; Chromatographic column: Shim-pack GIS C18 (4.6 mm × 250 mm, 5 µm); Mobile phase A: 0.025 mol / L potassium dihydrogen phosphate buffer solution (containing 0.02% phosphoric acid) Mobile phase B: acetonitrile; Elution was performed according to the following gradient:

[0013] Flow rate: 1.0 mL / min; Column temperature: 30°C; Detection wavelength: 210nm; Injection volume: 20 μl; The invention utilizes a Shim-pack GIS C18 (250 x 4.6 mm, 5 μm) chromatographic column to effectively separate loratadine and its related substances. This solves the problem of separating and determining loratadine and its related impurities, improves the content and purity of the product, and ensures the controllable quality of the final rupatadine fumarate product. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 This is the HPLC chart of the blank solvent of loratadine in Example 1.

[0015] Figure 2This is the HPLC chart of loratadine intermediate and its related impurities in Example 1. DETAILED DESCRIPTION The following examples are provided to further understand the present invention, but are not intended to limit the scope of this invention.

[0016] Example 1 Instruments and conditions High-performance liquid chromatograph: Agilent 1260 InfinityII; Chromatographic column: Shim-pack GIS C18 (4.6 mm × 250 mm, 5 µm); Mobile phase A: 0.01 mol / L potassium dihydrogen phosphate buffer solution (containing 0.02% phosphoric acid) Mobile phase B: acetonitrile; Elution was performed according to the following gradient:

[0017] Flow rate: 1.0 mL / min; Column temperature: 30°C; Detection wavelength: 210nm; Injection volume: 20 μl; The HPLC detection steps of loratadine related substances are as follows: Take an appropriate amount of loratadine and its impurity reference substances, dissolve the sample with a diluent, and prepare a sample solution containing 0.2 mg / mL of loratadine and about 2 µg / mL of its impurities.

[0018] Take 20µl of the above solution and inject it into the liquid chromatograph, record the chromatogram, and the results are shown in the attached Figure 2 , Figure 2 The chromatographic peak with a retention time of 19.349 min is loratadine, and the other chromatographic peaks are the chromatographic peaks of various impurities.

[0019] In summary, the present invention can separate loratadine from its impurities, accurately perform quantitative detection, effectively control the purity and content of loratadine, and thus effectively control the product quality of the final product, rupatadine fumarate.

Claims

1. A method for detecting related substances of rupatadine fumarate intermediates, comprising high performance liquid chromatography (HPLC), a silica gel-bonded octadecylsilane column, and a mobile phase consisting of an aqueous solution and an organic phase in a certain ratio, for gradient elution.

2. The method for analyzing and detecting related substances in the rupatadine fumarate intermediate according to claim 1, wherein the organic phase is selected from one of the following compounds: methanol and acetonitrile.

3. The method for analyzing and detecting related substances in the rupatadine fumarate intermediate according to claim 1, characterized in that: The inorganic salt buffer solution is selected from one of the following inorganic salts: phosphate, perchlorate, and carbonate.

4. The method for analyzing and detecting related substances in the rupatadine fumarate intermediate according to claim 1, wherein the gradient process is a gradient elution process of:

5. The method for analyzing and detecting related substances in the rupatadine fumarate intermediate according to claim 1, wherein the chromatographic column preferably has a length of 254 mm, a diameter of 4.6 mm, and a filler particle size of 5 µm.

6. The method for analyzing and detecting related substances in the rupatadine fumarate intermediate according to claims 1 and 3, characterized in that: The inorganic salt buffer solution is preferably phosphate, and its optimal concentration is 0.025 mol / L.

7. The method for analyzing and detecting related substances of the rupatadine fumarate intermediate according to claims 2 and 4, wherein the organic phase is preferably acetonitrile.

8. The method for analyzing and detecting related substances in the rupatadine fumarate intermediate 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°C; and ④ setting the injection volume to 10-30 µl.

9. The method for analyzing and detecting related substances in the rupatadine fumarate intermediate 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°C; and ④ the injection volume is preferably 20 µl.

10. The method for analyzing related substances in loratadine, an intermediate of rupatadine fumarate, according to claim 1, wherein the related substance impurities are:

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