Separation, qualitative and quantitative detection method for related substances in rupatadine fumarate

Abstract

The invention belongs to the technical field of pharmaceutical analysis, and particularly relates to a separation, qualitative and quantitative detection method for related substances in rupatadine fumarate. According to the method, main components and related impurities in rupatadine fumarate are separated by adopting a high performance liquid chromatography, and the method comprises the following steps: carrying out gradient elution by taking octadecylsilane chemically bonded silica as a chromatographic column filler, taking a phosphate solution as a mobile phase A and taking acetonitrile as a mobile phase B, and carrying out detection by adopting a detection wavelength of 210 nm and / or 250 nm; and finally, according to the measured chromatogram, calculating the content of each impurity by adopting a correction factor-added principal component self-contrast method. The method solves the problem of separation and determination of main components in rupatadine fumarate and a plurality of impurities such as an impurity G, an impurity D, an impurity E and an impurity F which cannot be solved in the prior art, and has the characteristics of short analysis time, low detection limit, good durability, good reproducibility and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of drug analysis, and in particular relates to a method for separation, qualitative and quantitative detection of related substances in rupatadine fumarate. Background Art

[0002] Rupatadine fumarate is a dual antagonist of histamine and platelet aggregation, and is mainly used in the treatment of seasonal and perennial allergic rhinitis and urticaria. Its chemical name is 8-chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridyl)methyl]-4-piperidinyl]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine fumarate, and its structural formula is shown in Formula I.

[0003]

[0004] According to the synthetic process of rupatadine fumarate, the impurities introduced or produced by degradation in the production process may include: impurity A, impurity B, impurity C, impurity D, impurity E, impurity F, impurity G, impurity H, carbamylated loratadine, diethyl fumarate, impurity Z 3a 、Impurity Z 3d , impurity SM1, a total of 13 known impurities. In order to ensure the quality of rupatadine fumarate and the safety of medication, it is necessary to control the content of the above 13 known impurities and other individual impurities.

[0005] There have been many studies on the detection of related substances of rupatadine fumarate in this field, including the detection method of related substances of rupatadine fumarate in the EP Pharmacopoeia; "HPLC Determination of Related Substances of Rupatadine Fumarate Tablets", Chen Yeqing's team proposed a detection method of related substances of rupatadine fumarate; CN112903859B patent discloses a detection method of related substances of rupatadine fumarate, etc. However, our research found that these methods cannot effectively separate and determine the above 13 known impurities. Summary of the invention

[0006] Based on this, one of the purposes of the present invention is to provide a method for separating rupatadine fumarate and its related impurities, which achieves the separation of impurities A, impurity B, impurity C, impurity D, impurity E, impurity F, impurity G and its enantiomers, impurity H, carbamylated loratadine, diethyl fumarate, impurity Z in rupatadine fumarate. 3a and its enantiomers, impurity Z 3d The separation of 13 known impurities including impurity SM1 and impurity SM4 provides new ideas for the qualitative and quantitative detection of the above impurities.

[0007] To achieve the above object, the present invention adopts the following technical solutions:

[0008] The invention discloses a method for separating rupatadine fumarate and related impurities thereof, wherein the main component rupatadine and related impurities thereof are separated by high performance liquid chromatography; the related impurities include impurity A, impurity B, impurity C, impurity D, impurity E, impurity F, impurity G and its enantiomers, impurity H, carbamylated loratadine, diethyl fumarate, impurity Z 3a and its enantiomers, impurity Z 3d , any one or more of impurities SM1; the high performance liquid chromatography method uses octadecylsilane bonded silica gel as a chromatographic column filler, phosphate solution as mobile phase A, acetonitrile as mobile phase B, and separates impurities B, impurity A, impurity H, impurity SM1, diethyl fumarate, impurity F, carbamylated loratadine, impurity D, impurity Z in sequence by gradient elution. 3d , Rupatadine, Impurity G and its enantiomers, Impurity E, Impurity Z 3a and its enantiomers and / or impurity C;

[0009] The structural formula of rupatadine is shown in Formula 1, the structural formula of impurity A is shown in Formula 2, the structural formula of impurity B is shown in Formula 3, the structural formula of impurity C is shown in Formula 4, the structural formula of impurity D is shown in Formula 5, the structural formula of impurity E is shown in Formula 6, the structural formula of impurity F is shown in Formula 7, the structural formula of impurity G is shown in Formula 8, the structural formula of impurity H is shown in Formula 9, the structural formula of carbamylated loratadine is shown in Formula 10, the structural formula of diethyl fumarate is shown in Formula 11, and the impurity Z is shown in Formula 12. 3a The structural formula is shown in Formula 12, and the impurity Z 3d The structural formula of is shown in Formula 13, and the structural formula of the impurity SM1 is shown in Formula 14;

[0010]

[0011]

[0012] Furthermore, in the phosphate solution, the mass volume ratio of sodium dihydrogen phosphate dihydrate, water and triethylamine is 3.12g:1000ml:1ml.

[0013] The method of the invention controls the pH value of the mobile phase by specifying the concentration of buffer salt in the mobile phase and the amount of triethylamine added.

[0014] Further, the gradient elution procedure is as follows:

[0015] At 0 minutes, the volume fraction of the mobile phase A is set to 73%-77%, and the volume fraction of the mobile phase B is set to 27%-23%;

[0016] At 2 minutes, the volume fraction of the mobile phase A is set to 73%-77%, and the volume fraction of the mobile phase B is set to 27%-23%;

[0017] At 15 minutes, the volume fraction of the mobile phase A is set to 65%, and the volume fraction of the mobile phase B is set to 35%;

[0018] At 45 minutes, the volume fraction of the mobile phase A is set to 40%, and the volume fraction of the mobile phase B is set to 60%;

[0019] At 60 minutes, the volume fraction of the mobile phase A is set to 30%, and the volume fraction of the mobile phase B is set to 70%;

[0020] At 61 minutes, the volume fraction of the mobile phase A is set to 73%-77%, and the volume fraction of the mobile phase B is set to 27%-23%;

[0021] At 70 minutes, the volume fraction of the mobile phase A was set to 73%-77%, and the volume fraction of the mobile phase B was set to 27%-23%.

[0022] Preferably, the gradient elution procedure is as follows:

[0023] At 0 minute, the volume fraction of the mobile phase A is set to 75%, and the volume fraction of the mobile phase B is set to 25%;

[0024] At 2 minutes, the volume fraction of the mobile phase A is set to 75%, and the volume fraction of the mobile phase B is set to 25%;

[0025] At 15 minutes, the volume fraction of the mobile phase A is set to 65%, and the volume fraction of the mobile phase B is set to 35%;

[0026] At 45 minutes, the volume fraction of the mobile phase A is set to 40%, and the volume fraction of the mobile phase B is set to 60%;

[0027] At 60 minutes, the volume fraction of the mobile phase A is set to 30%, and the volume fraction of the mobile phase B is set to 70%;

[0028] At 61 minutes, the volume fraction of the mobile phase A was set to 75%, and the volume fraction of the mobile phase B was set to 25%;

[0029] At 70 minutes, the volume fraction of the mobile phase A was set to 75%, and the volume fraction of the mobile phase B was set to 25%.

[0030] Preferably, the flow rate of the mobile phase is 1.1 ml / min-1.3 ml / min, more preferably 1.2 ml / min; the column temperature of the chromatographic column is 33° C.-37° C., more preferably 35° C.

[0031] Preferably, the injection volume is 50 μl.

[0032] The second object of the present invention is to provide a method for identifying rupatadine fumarate and its related impurities, which realizes the qualitative identification of various impurities such as impurity C and impurity G in rupatadine fumarate, solves the problem of separation and identification of various related impurities in rupatadine fumarate that cannot be solved in the prior art, and provides a new idea and direction for the qualitative identification of rupatadine fumarate and its related impurities.

[0033] To achieve the above object, the present invention adopts the following technical solutions:

[0034] The method for identifying rupatadine fumarate and its related impurities comprises: using the above separation method to separate rupatadine fumarate and its related impurities, entering a detector for detection, and recording a chromatogram; the impurity A, impurity B, impurity D, impurity E, impurity F, impurity G and its enantiomers, impurity H, carbamylated loratadine, diethyl fumarate, impurity Z 3a and its enantiomers, impurity Z 3d And / or the detection wavelength of impurity SM1 is 210 nm; and / or the detection wavelength of impurity C is 250 nm.

[0035] Furthermore, whether the product contains the relevant impurities is determined by the consistency of the chromatographic retention behaviors of the sample to be tested and the reference substance.

[0036] As a preferred technical solution, the chromatographic column has a specification of 4.6 mm × 150 mm, 5 μm; the mobile phase A is composed of sodium dihydrogen phosphate dihydrate, water, and triethylamine in a mass volume ratio of 3.12 g: 1000 ml: 1 ml; the mobile phase B is acetonitrile; the mobile phase flow rate is 1.2 ml / min, and the column temperature of the chromatographic column is 35 ° C; the impurities A, B, D, E, F, G and its enantiomers, H, carbamylated loratadine, diethyl fumarate, and Z 3a and its enantiomers, impurity Z 3d and / or the detection wavelength of the impurity SM1 is 210 nm; and / or the detection wavelength of the impurity C is 250 nm;

[0037] Separation was performed according to the following gradient elution procedure, and a chromatogram was obtained;

[0038] At 0 minute, the volume fraction of the mobile phase A is set to 75%, and the volume fraction of the mobile phase B is set to 25%;

[0039] At 2 minutes, the volume fraction of the mobile phase A is set to 75%, and the volume fraction of the mobile phase B is set to 25%;

[0040] At 15 minutes, the volume fraction of the mobile phase A is set to 65%, and the volume fraction of the mobile phase B is set to 35%;

[0041] At 45 minutes, the volume fraction of the mobile phase A is set to 40%, and the volume fraction of the mobile phase B is set to 60%;

[0042] At 60 minutes, the volume fraction of the mobile phase A is set to 30%, and the volume fraction of the mobile phase B is set to 70%;

[0043] At 61 minutes, the volume fraction of the mobile phase A was set to 75%, and the volume fraction of the mobile phase B was set to 25%;

[0044] At 70 minutes, the volume fraction of the mobile phase A was set to 75%, and the volume fraction of the mobile phase B was set to 25%.

[0045] Further, the impurity B is at a retention time of 10.0±0.5min, the impurity A is at a retention time of 10.9±0.5min, the impurity H is at a retention time of 15.2±0.5min, the impurity SM1 is at a retention time of 17.6±0.5min, the impurity fumarate is at a retention time of 19.2±0.5min, the impurity F is at a retention time of 22.9±0.5min, the impurity loratadine is at a retention time of 23.6±0.5min, the impurity D is at a retention time of 28.9±0.5min, and the impurity Z is at a retention time of 29.7±0.5min. 3d The retention time of 35.7±0.5min is rupatadine, the retention time of 37.6±0.5min is impurity G or its enantiomer, the retention time of 40.4±0.5min is impurity E, and the retention time of 44.6±0.5min is impurity Z. 3a Or its enantiomer, the one with retention time at 56.0±0.5min is impurity C.

[0046] The third object of the present invention is to provide a method for determining the content of rupatadine fumarate and its related impurities, which method can achieve the content determination of rupatadine fumarate and its related impurities within 70 minutes, and has the characteristics of short analysis time, high sensitivity and good durability.

[0047] To achieve the above object, the present invention adopts the following technical solutions:

[0048] A method for determining the content of rupatadine fumarate and related impurities thereof, the method comprising the following steps:

[0049] (1) separating rupatadine fumarate and its related impurities by the method described in any one of claims 1 to 4;

[0050] (2) using the method described in any one of claims 5 to 8 to detect rupatadine fumarate and its related impurities, and obtaining a chromatogram;

[0051] (3) Based on the chromatogram obtained in step (2), the content of each impurity is calculated using the principal component self-comparison method with a correction factor added.

[0052] Furthermore, before step (1), a solvent is used to prepare the test solution; the solvent is composed of the mobile phase A and acetonitrile in a volume ratio of 70:30.

[0053] Preferably, the method comprises the following specific steps:

[0054] 1. Sample solution / test solution: Take an appropriate amount of rupatadine fumarate / this product to be tested, weigh accurately, add solvent to dissolve by ultrasonication and dilute to make a solution with a concentration of 0.64 mg / mL;

[0055] 2. Control solution: Accurately measure 1 ml of the test solution prepared in step 1 and place it in a 100 ml volumetric flask, dilute it to the mark with solvent, shake well, then accurately measure 1 ml and place it in a 10 ml volumetric flask, dilute it to the mark with solvent, shake well, and obtain;

[0056] 3. Accurately measure the test solution and control solution, such as 50 μl, and inject them into the liquid chromatograph respectively, and record the chromatogram;

[0057] 4. According to the chromatogram measured in step 3, calculate the content of each impurity by peak area using the main component self-reference method with correction factor added.

[0058] The impurity content calculation formula is as follows:

[0059]

[0060] Where: Ax——peak area of ​​each impurity peak in the chromatogram of the test solution;

[0061] Ad——the main peak area in the chromatogram of the reference solution;

[0062] RRF - Impurity correction factor.

[0063] The beneficial effects of the present invention are:

[0064] 1. The present invention adopts an efficient and durable chromatographic method to achieve the separation of fumaric acid, rupatadine and 13 known impurities that may exist, and provides the separation and determination of multiple impurities such as impurity G, impurity D, impurity E, impurity F in rupatadine fumarate that cannot be solved by the prior art. The analytical method has strong specificity, good durability, good reproducibility, and the method is simple and feasible to operate.

[0065] 2. The high performance liquid chromatography method proposed in the present invention has a short analysis time and can simultaneously separate and detect 13 impurities in rupatadine fumarate within 70 minutes.

[0066] 3. The detection limits of the main component rupatadine and other known impurities in rupatadine fumarate in the method of the present invention are as low as 0.07 μg / ml, and the method has high sensitivity. BRIEF DESCRIPTION OF THE DRAWINGS

[0067] Figure 1 This is the chromatogram detected by the EP Pharmacopoeia related substance method;

[0068] Figure 2 This is the chromatogram of the related substance detection method in the literature "HPLC Determination of Related Substances in Rupatadine Fumarate Tablets";

[0069] Figure 3 The chromatogram is a mixed solution in Example 1 under the condition of a detection wavelength of 210 nm;

[0070] Figure 4 The chromatogram is a mixed solution in Example 1 under the condition of a detection wavelength of 250 nm;

[0071] Figure 5 The chromatogram is the detection limit solution in Example 2 under the condition of a detection wavelength of 210 nm;

[0072] Figure 6 The chromatogram is the detection limit solution in Example 2 under the condition of a detection wavelength of 250 nm;

[0073] Figure 7 is the chromatogram of durability-mixed solution-normal conditions in Example 3;

[0074] Figure 8 This is the chromatogram under the conditions of durability-mixed solution-column temperature 33°C in Example 3;

[0075] Fig. 9 This is the chromatogram under the conditions of durability-mixed solution-column temperature 37°C in Example 3;

[0076] Fig.10 This is the chromatogram under the conditions of durability-mixed solution-flow rate 1.1 ml / min in Example 3;

[0077] Fig.11 This is the chromatogram under the conditions of durability-mixed solution-flow rate 1.3 ml / min in Example 3;

[0078] Fig.12 The chromatogram is shown in Example 3 under the condition of durability-mixed solution-mobile phase initial ratio A:B=77:23;

[0079] Fig.13 This is the chromatogram under the conditions of durability-mixed solution-mobile phase initial ratio A:B=73:27 in Example 3. DETAILED DESCRIPTION

[0080] The technical solution of the present invention will be further described clearly and completely in conjunction with specific embodiments below. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. Therefore, based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work belong to the protection scope of the present invention.

[0081] In the embodiment of the present invention, the technical solution is as follows:

[0082] (1) Preparation of solution

[0083] Mobile phase A (phosphate solution): Take 3.12 g of sodium dihydrogen phosphate dihydrate, add 1000 ml of water to dissolve it, then add 1 ml of triethylamine and mix well.

[0084] Solvent: a mixed solution of mobile phase A and acetonitrile, wherein the volume ratio of mobile phase A to acetonitrile is 70:30.

[0085] Test solution: Take an appropriate amount of the product (rupatadine fumarate), weigh accurately, add solvent to dissolve by ultrasonication and dilute to make a solution containing about 0.64 mg per 1 ml.

[0086] Control solution: Accurately measure 1 ml of the test solution and place it in a 100 ml volumetric flask, dilute it to the mark with solvent, shake well, then accurately measure 1 ml and place it in a 10 ml volumetric flask, dilute it to the mark with solvent, shake well.

[0087] (2) Chromatographic conditions

[0088] Octadecylsilane bonded silica gel was used as filler (Shim-pack Scepter C18-120 4.6mm×150mm, 5μm or chromatographic column of equivalent performance); phosphate solution was used as mobile phase A, acetonitrile was used as mobile phase B, and gradient elution was performed according to Table 1 below; detection wavelengths were 210nm and 250nm (for detection of impurity C); column temperature was 35°C; flow rate was 1.2ml per minute; injection volume was 50μl.

[0089] Table 1. Gradient elution program

[0090] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 75 25 2 75 25 15 65 35 45 40 60 60 30 70 61 75 25 70 75 25

[0091] Note: 61-70 minutes is the initial ratio equilibrium period, which can be adjusted to different lengths according to the dead volume of the instrument.

[0092] (3) Determination method

[0093] Accurately measure the test solution and control solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0094] Limit: Each component is located by using systematic reference substances and impurity location solutions. If there are impurity peaks in the test solution, in addition to the blank solvent peak, gradient elution peak and fumaric acid peak, the content of each impurity is calculated by the principal component self-reference method with correction factors.

[0095] In the embodiment of the present invention, impurity C is detected at a detection wavelength of 250 nm, and the other 12 impurities (impurity A, impurity B, impurity D, impurity E, impurity F, impurity G, impurity H, carbamylated loratadine, diethyl fumarate, impurity Z 3a 、Impurity Z 3d , impurity SM1) is detected using a detection wavelength of 210nm.

[0096] Embodiment 1, specificity

[0097] Impurities that may exist in rupatadine fumarate include: impurity A, impurity B, impurity C, impurity D, impurity E, impurity F, impurity G, impurity H, carbamylated loratadine, diethyl fumarate, impurity Z 3a 、Impurity Z 3d There are a total of 13 impurities, including impurity SM1 and impurity SM2. This example investigates the separation of the above 13 impurities from fumaric acid and rupatadine.

[0098] (1) Preparation of solution

[0099] Test solution: Take an appropriate amount of the product, weigh accurately, add solvent, dissolve by ultrasonication and dilute to make a solution containing approximately 0.64 mg per 1 ml.

[0100] Stock solution of each impurity: Accurately weigh impurity A, impurity B, impurity C, impurity D, impurity E, impurity F, impurity G, impurity H, carbamylated loratadine, diethyl fumarate, impurity Z 3a 、Impurity Z 3d , impurity SM1 reference substance, each in appropriate amount, dissolved in methanol or acetonitrile and diluted to make a solution of about 0.5 mg per 1 ml.

[0101] Each impurity location solution: Measure 0.1 ml of each impurity stock solution mentioned above, place it in a 10 ml volumetric flask, add solvent to dilute to the scale, and shake well.

[0102] Mixed solution: Accurately weigh 30 mg of the finished test sample and place it in a 50 ml volumetric flask. Add a solvent and ultrasonicate to dissolve it. Accurately measure impurities A, D, E, G, H, RUP-SM1, and RUP-Z. 3a 、RUP-Z 3d95 μl of each stock solution, 0.3 ml of impurity B stock solution, 60 μl of impurity C, carbamylated loratadine, diethyl fumarate, and impurity F stock solution are placed in the same volumetric flask, diluted to the scale with solvent, and shaken to obtain.

[0103] (2) Detection

[0104] Take 50 μl of each impurity location solution, test solution, and mixed solution, inject them into the liquid chromatograph, and record the chromatogram.

[0105] The results are shown in Table 2. Figure 3-Figure 4 As shown, according to the retention time of fumaric acid, it can be seen that fumaric acid does not interfere with the detection of the main component and impurities; the separation degree between impurity G and the main component is 3.39, and the separation degrees between the known impurities and between the remaining impurities and the main component rupatadine are all greater than 1.5, and the method specificity meets the requirements.

[0106] Table 2. Specificity test results

[0107]

[0108]

[0109] Table 3. Figure 3 Integration result table (detection wavelength is 210nm)

[0110]

[0111] Table 4. Figure 4 Integration result table (detection wavelength is 250nm)

[0112]

[0113]

[0114] Example 2, detection limit

[0115] (1) Preparation of solution

[0116] Impurity stock solution: Accurately weigh impurity A, impurity B, impurity C, impurity D, impurity E, impurity G, impurity H, impurity SM1, impurity Z respectively. 3a 、Impurity Z 3d , carbamylated loratadine, diethyl fumarate, and finished reference substance in appropriate amounts, add methanol or acetonitrile to prepare a stock solution containing approximately 0.5 mg per 1 ml.

[0117] Detection limit solution: Accurately measure impurity A, impurity B, impurity C, impurity D, impurity E, impurity G, impurity H, impurity SM1, impurity Z 3a 、Impurity Z 3d2.5 ml each of carbamylated loratadine and diethyl fumarate stock solutions and 2.5 ml of finished reference solution are placed in the same 50 ml volumetric flask, diluted to the mark with solvent, shake well, accurately measure 0.8 ml, place in a 100 ml volumetric flask, dilute to the mark with solvent, shake well, accurately measure 3.5 ml, place in a 10 ml volumetric flask, dilute to the mark with solvent, shake well, and obtain.

[0118] (2) Detection

[0119] The detection limit solution prepared in step (1) was injected three times continuously, and the ratio of the main peak height to the noise (signal-to-noise ratio) was calculated.

[0120] Results: As shown in Table 2, Figure 5-Figure 6 As shown, under the chromatographic conditions of this analytical method, the detection concentrations of the remaining known impurities and the main component rupatadine were all approximately 0.07 μg / ml, and the method had high sensitivity.

[0121] Table 3. Detection limit determination results

[0122]

[0123]

[0124] Example 3. Chromatographic Conditions Durability

[0125] Use normal mobile phase, different initial proportions of mobile phase, column temperature and column flow rate for the test respectively, the detection wavelength is 210nm, and after the instrument system is stable, test respectively and record the separation degree between each peak.

[0126] Results: As shown in Table 4, Figure 7-Figure 13 As shown, when there is a slight fluctuation in the chromatographic conditions, the peak separation between the main component and the adjacent components is greater than 1.5, and the peak separation between each known impurity and the adjacent component is greater than 1.2, and the chromatographic conditions are durable.

[0127] Table 4. Results of the durability test for changes in chromatographic conditions (resolution)

[0128]

[0129]

[0130] Comparative Example 1

[0131] The present invention reproduces the existing literature methods and EP pharmacopoeia methods for the determination of related substances of rupatadine fumarate, including ① the current EP pharmacopoeia method for related substances of rupatadine fumarate; ② the determination method disclosed in the literature material "HPLC determination of related substances of rupatadine fumarate tablets, Chen Yeqing, Chinese Journal of Pharmaceutical Industry".

[0132] Results: The peak of impurity C in the EP Pharmacopoeia related substance method is tailing and cannot be separated from the other impurities by baseline, and impurity G overlaps with the main component peak. Figure 1 ; The literature on the substance method shows that multiple impurity peaks overlap, and G overlaps with the main component peak, see Figure 2 In the process of reproducing the literature method and EP pharmacopoeia method, it was found that the pH range of the mobile phase and the chromatographic column are the key factors affecting the peak separation of impurity G and the main component, other known impurities and adjacent components. In the present invention, impurities D and E are intermediates in the synthetic process route, impurity G is a process impurity that is more easily produced in the process route, impurities F and impurity H are degradation impurities that may exist in the sample, and the remaining impurities loratadine, diethyl fumarate, impurity Z 3a , Z 3d Both SM1 and SM2 are impurities that may exist in the process and are impurities that are more likely to exist in the sample. Therefore, whether the impurities listed in the present invention can be effectively separated and accurately quantified is crucial to product quality control.

Claims

1. A method for separating rupatadine fumarate and its related impurities, characterized in that: The main component rupatadine and its related impurities in rupatadine fumarate are separated by high performance liquid chromatography; the related impurities include impurity A, impurity B, impurity C, impurity D, impurity E, impurity F, impurity G and its enantiomers, impurity H, carbamylated loratadine, diethyl fumarate, impurity Z 3a and its enantiomers, impurity Z 3d , any one or more of impurities SM1; the high performance liquid chromatography method uses octadecylsilane bonded silica gel as a chromatographic column filler, phosphate solution as mobile phase A, acetonitrile as mobile phase B, and separates impurities B, impurity A, impurity H, impurity SM1, diethyl fumarate, impurity F, carbamylated loratadine, impurity D, impurity Z in sequence by gradient elution. 3d , Rupatadine, Impurity G and its enantiomers, Impurity E, Impurity Z 3a and its enantiomers and / or impurity C; The structural formula of rupatadine is shown in Formula 1, the structural formula of impurity A is shown in Formula 2, the structural formula of impurity B is shown in Formula 3, the structural formula of impurity C is shown in Formula 4, the structural formula of impurity D is shown in Formula 5, the structural formula of impurity E is shown in Formula 6, the structural formula of impurity F is shown in Formula 7, the structural formula of impurity G is shown in Formula 8, the structural formula of impurity H is shown in Formula 9, the structural formula of carbamylated loratadine is shown in Formula 10, the structural formula of diethyl fumarate is shown in Formula 11, and the impurity Z is shown in Formula 12. 3a The structural formula is shown in Formula 12, and the impurity Z 3d The structural formula of is shown in Formula 13, and the structural formula of the impurity SM1 is shown in Formula 14; 2. The method according to claim 1, characterized in that In the phosphate solution, the mass volume ratio of sodium dihydrogen phosphate dihydrate, water and triethylamine is 3.12g:1000ml:1ml.

3. The method according to claim 1, characterized in that The gradient elution procedure is as follows: At 0 minutes, the volume fraction of the mobile phase A is set to 73%-77%, and the volume fraction of the mobile phase B is set to 27%-23%; At 2 minutes, the volume fraction of the mobile phase A is set to 73%-77%, and the volume fraction of the mobile phase B is set to 27%-23%; At 15 minutes, the volume fraction of the mobile phase A is set to 65%, and the volume fraction of the mobile phase B is set to 35%; At 45 minutes, the volume fraction of the mobile phase A is set to 40%, and the volume fraction of the mobile phase B is set to 60%; At 60 minutes, the volume fraction of the mobile phase A is set to 30%, and the volume fraction of the mobile phase B is set to 70%; At 61 minutes, the volume fraction of mobile phase A is set to 73%-77%, and the volume fraction of mobile phase B is set to 27%-23%; at 70 minutes, the volume fraction of mobile phase A is set to 73%-77%, and the volume fraction of mobile phase B is set to 27%-23%.

4. The method according to claim 1, characterized in that: The flow rate of the mobile phase is 1.1 ml / min-1.3 ml / min, and the column temperature of the chromatographic column is 33° C.-37° C.

5. A method for identifying rupatadine fumarate and its related impurities, characterized in that: The method according to any one of claims 1 to 4 is used to separate rupatadine fumarate and its related impurities, enter the detector for detection, and record the chromatogram; the impurity A, impurity B, impurity D, impurity E, impurity F, impurity G and its enantiomers, impurity H, carbamylated loratadine, diethyl fumarate, impurity Z 3a and its enantiomers, impurity Z 3d And / or the detection wavelength of impurity SM1 is 210 nm; and / or the detection wavelength of impurity C is 250 nm.

6. The method according to claim 5, characterized in that Whether the product contains the relevant impurities is determined by the consistency of the chromatographic retention behavior of the sample to be tested and the reference substance.

7. The method according to claim 5, characterized in that The chromatographic column has a specification of 4.6 mm × 150 mm, 5 μm; the mobile phase A is composed of sodium dihydrogen phosphate dihydrate, water, and triethylamine in a mass volume ratio of 3.12 g: 1000 ml: 1 ml; the mobile phase B is acetonitrile; the mobile phase flow rate is 1.2 ml / min, and the column temperature of the chromatographic column is 35°C; the impurities A, B, D, E, F, G and its enantiomers, H, carbamylated loratadine, diethyl fumarate, and Z 3a and its enantiomers, impurity Z 3d and / or the detection wavelength of the impurity SM1 is 210 nm; and / or the detection wavelength of the impurity C is 250 nm; Separation was performed according to the following gradient elution procedure, and a chromatogram was obtained; At 0 minute, the volume fraction of the mobile phase A is set to 75%, and the volume fraction of the mobile phase B is set to 25%; At 2 minutes, the volume fraction of the mobile phase A is set to 75%, and the volume fraction of the mobile phase B is set to 25%; At 15 minutes, the volume fraction of the mobile phase A is set to 65%, and the volume fraction of the mobile phase B is set to 35%; At 45 minutes, the volume fraction of the mobile phase A is set to 40%, and the volume fraction of the mobile phase B is set to 60%; At 60 minutes, the volume fraction of the mobile phase A is set to 30%, and the volume fraction of the mobile phase B is set to 70%; At 61 minutes, the volume fraction of the mobile phase A was set to 75%, and the volume fraction of the mobile phase B was set to 25%; At 70 minutes, the volume fraction of the mobile phase A was set to 75%, and the volume fraction of the mobile phase B was set to 25%.

8. The method according to claim 7, characterized in that The impurity B is at a retention time of 10.0±0.5min, the impurity A is at a retention time of 10.9±0.5min, the impurity H is at a retention time of 15.2±0.5min, the impurity SM1 is at a retention time of 17.6±0.5min, the impurity fumarate is at a retention time of 19.2±0.5min, the impurity F is at a retention time of 22.9±0.5min, the impurity loratadine is at a retention time of 23.6±0.5min, the impurity D is at a retention time of 28.9±0.5min, and the impurity Z is at a retention time of 29.7±0.5min. 3d The retention time of 35.7±0.5min is rupatadine, the retention time of 37.6±0.5min is impurity G or its enantiomer, the retention time of 40.4±0.5min is impurity E, and the retention time of 44.6±0.5min is impurity Z. 3a Or its enantiomer, the one with retention time at 56.0±0.5min is impurity C.

9. A method for determining the content of rupatadine fumarate and its related impurities, characterized in that: The method comprises the following steps: (1) separating rupatadine fumarate and its related impurities by the method described in any one of claims 1 to 4; (2) using the method described in any one of claims 5 to 8 to detect rupatadine fumarate and its related impurities, and obtaining a chromatogram; (3) Based on the chromatogram obtained in step (2), the content of each impurity is calculated using the principal component self-comparison method with a correction factor added.

10. The method according to claim 9, characterized in that Before step (1), a solvent is used to prepare a test solution; the solvent is composed of the mobile phase A and acetonitrile in a volume ratio of 70:30.

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