A crystalline form c of rupatadine fumarate and a process for its preparation

Abstract

The application provides a crystal form C of rupatadine fumarate and a preparation method thereof. Using Cu-Ka radiation, the crystal form C of the application has characteristic peaks at 12.3°±0.2°, 14.4°±0.2°, 17.6°±0.2° and 22.4°±0.2° in an X-ray powder diffraction pattern expressed by 2θ (±0.2°). The crystal form C has the characteristics of high melting point, small water residue, small ethanol residue, more stable crystal form, less residual solvent type, higher safety, single solvent and small solvent dosage, effective saving of material cost, small environmental pollution, high yield and more favorable for commercial production in the later period.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry technology, specifically relating to a rupatifine fumarate crystal form C and its preparation method. Background Technology

[0002] WO2013000406 discloses a multi-pathway comprehensive anti-allergy drug—rupatifine fumarate, namely 4-[1-[(5-methylpyridin-3-yl)methyl]piperidinyl-4-ylidene]-4,9-dihydro-10H-benzo[4,5]cyclohepta[1,2-b]thiophene-10-one fumarate, with the following structural formula:

[0003]

[0004] Drug polymorphism refers to the existence of a drug in two or more different crystalline forms. Polymorphism is widespread in pharmaceuticals. Different crystalline forms of the same drug exhibit significant differences in solubility, melting point, density, and stability, thus affecting the drug's stability, homogeneity, bioavailability, efficacy, and safety to varying degrees. Therefore, comprehensive and systematic polymorph screening in drug development to select the most suitable crystalline form for development is an essential and indispensable aspect.

[0005] Rupatifine fumarate exhibits polymorphism. CN104045633B discloses a polymorph A of rupatifine fumarate, whose characteristic peaks in its X-ray powder diffraction pattern are represented by 2θ (±0.2°) and located at 6.9°, 9.1°, 11.4°, 12.2°, 13.6°, 15.1°, 16.9°, 18.1°, 18.6°, 20.3°, 21.3°, 23.2°, 24.0°, 24.9°, 25.8°, 27.1°, 28.2°, and 29.1°. CN 104059056 B discloses a crystalline form B of rupatifine fumarate, whose characteristic peaks in its X-ray powder diffraction pattern, represented by 2θ (±0.2°), are located at 5.9°, 6.7°, 8.0°, 11.7°, 12.0°, 12.9°, 14.5°, 16.7°, 17.2°, 18.9°, 19.7°, 20.2°, 22.3°, 24.4°, 25.9°, 27.0°, 28.8°, and 30.7°. The preparation of these two crystalline forms uses organic solvents such as dichloromethane, which will cause a certain degree of environmental pollution. Furthermore, the use of a constant-rate cooling method results in a relatively low yield.

[0006] CN 104031035 B discloses a mixed crystal of rupatifine fumarate.

[0007] However, the above-mentioned crystal forms have low stability, low purity, high residual moisture, low melting point, and a lot of residual solvent during the preparation process, resulting in low safety and high cost, making them unsuitable for commercial production. Summary of the Invention

[0008] To overcome the shortcomings of existing technologies, this invention provides a rupatifen fumarate crystal form C and its preparation method. The rupatifen fumarate crystal form C of this invention is more stable, has lower solvent residue, less moisture, and higher purity. The preparation method of this crystal form is simple, easy to industrialize, and can ensure the quality and safety of the new drug rupatifen fumarate.

[0009] To achieve the above-mentioned objectives of the present invention, the following technical solution is adopted.

[0010] On one hand, the present invention provides a rupatifine fumarate crystal form C, which, when irradiated with Cu-Ka, has characteristic peaks in its X-ray powder diffraction pattern, expressed in 2θ (±0.2°), located at 12.3°±0.2°, 14.4°±0.2°, 17.6°±0.2°, and 22.4°±0.2°.

[0011] Preferably, Cu-Ka radiation is used, and the characteristic peaks of the X-ray powder diffraction pattern of the crystal form C, expressed in 2θ (±0.2°), are located at 8.7°±0.2°, 10.0°±0.2°, 12.3°±0.2°, 14.4°±0.2°, 17.6°±0.2°, and 22.4°±0.2°.

[0012] Preferably, Cu-Ka radiation is used, and the characteristic peaks of the X-ray powder diffraction pattern of the crystal form C, expressed in 2θ (±0.2°), are located at 8.7°±0.2°, 10.0°±0.2°, 12.3°±0.2°, 14.4°±0.2°, 17.6°±0.2°, 21.2°±0.2°, 22.4°±0.2°, and 24.1°±0.2°.

[0013] Preferably, the melting point of crystal form C is 204.0℃-212.0℃.

[0014] Preferably, the crystal form C is a spheroidal crystal under microscopic conditions.

[0015] On the other hand, the present invention provides a method for preparing the above-mentioned rupatifine fumarate crystal form C, the method comprising the following steps:

[0016] The reaction is carried out by dissolving rupatifine free base and fumaric acid in solvent A, stirring and heating under reflux until the solution is clear, or by dissolving crude rupatifine fumarate in solvent A, heating and stirring under reflux to prepare a saturated solution, then cooling to 2-8℃, stirring to induce crystallization, filtering, washing with solvent A, and drying under reduced pressure.

[0017] Preferably, solvent A is selected from solvents such as an aqueous ethanol solution (mass ratio) with an ethanol concentration of not less than 95%, anhydrous ethanol solution, ethyl acetate-acetone solution, dichloromethane-acetone solution, diethyl ether-methanol solution, and cyclohexane-ethyl acetate solution for crystallization, and preferably anhydrous ethanol.

[0018] Preferably, the mass ratio of ethyl acetate to acetone in the ethyl acetate-acetone solution is 2:1 to 1:4 (w / w).

[0019] Preferably, the mass ratio of dichloromethane to acetone in the dichloromethane-acetone solution is 1:1 to 1:10 (w / w).

[0020] Preferably, the mass ratio of diethyl ether to methanol in the diethyl ether-methanol solution is 1:1 to 1:5 (w / w).

[0021] Preferably, the mass ratio of cyclohexane to ethyl acetate in the cyclohexane-ethyl acetate solution is 1:1 to 1:10 (w / w).

[0022] Preferably, the weight ratio between the rupatifen free base and the fumaric acid is 4:1 to 1:2.

[0023] Preferably, the temperature at which the solution is stirred, heated, and refluxed to clear is 30°C to 90°C, and more preferably 70°C.

[0024] Preferably, the cooling is natural cooling, gradient cooling, or rapid cooling.

[0025] When the temperature of the solution is higher than 40℃, the gradient cooling program is as follows: cool down to 40℃ at a rate of 15±5℃ / h; cool down to 15℃ at a rate of 7.5±2.5℃ / h and hold for 2h; cool down to 5±3℃ at a rate of 7.5±2.5℃ / h and hold for 2h.

[0026] When the temperature of the solution is below 40℃, the gradient cooling program is as follows: cool down to 15℃ at a rate of 7.5±2.5℃ / h and hold for 2h; cool down to 5±3℃ at a rate of 7.5±2.5℃ / h and hold for 2h.

[0027] Preferably, the stirring speed during crystallization is 50-200 rpm, more preferably 90-110 rpm.

[0028] Preferably, the mass-to-volume ratio of the rupatifen free base to solvent A or the crude rupatifen fumarate to solvent A is 2:1 to 1:30, more preferably 1:15-17.5.

[0029] Compared with the prior art, the present invention has at least the following beneficial effects:

[0030] This invention provides a crystalline form C of rupatifine fumarate, which has high purity, greater stability, a higher melting point (reaching 204.0℃~212.0℃), and less water and residual solvent. The preparation method of crystalline form C of this invention features high product yield, mild conditions, environmentally friendly reagents, simple operation, and ease of industrialization.

[0031] Compared with the disclosed crystal forms (including crystal form A, crystal form B, and mixed crystals), crystal form C of the present invention has a higher melting point, less residual moisture, and more stable crystal form; at the same time, it has less residual ethanol, fewer types of residual solvents, and higher safety; from the perspective of process feasibility, crystal form A and crystal form B both use mixed solvents, while crystal form C uses a single solvent and a small amount of solvent, which can effectively save material costs; crystal form A and crystal form B use organic solvents such as dichloromethane, which will cause a certain degree of environmental pollution, while crystal form C uses anhydrous ethanol, which has less environmental pollution; the preparation method of crystal form C has a significantly higher yield than other crystal forms, which is more conducive to subsequent commercial production. Attached Figure Description

[0032] The invention will now be further described with reference to the accompanying drawings.

[0033] Figure 1 Powder diffraction pattern of rupatifen fumarate crystal form C;

[0034] Figure 2 DSC spectrum of rupatifine fumarate crystal form C;

[0035] Figure 3 TGA spectrum of rupatifine fumarate crystal form C;

[0036] Figure 4 A 100x magnified image of rupatifine fumarate crystal form C. Detailed Implementation

[0037] The present invention will be described below with reference to specific embodiments. Those skilled in the art will understand that these embodiments are for illustrative purposes only and do not limit the scope of the invention in any way.

[0038] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, all raw materials, reagents, and other materials used in the following examples are commercially available products. The details of some instruments and equipment are as follows:

[0039] Instruments: Thermostatic magnetic stirrer (Changcheng Science & Industry Trade HWCL-5), rotary evaporator (IKA), forced-air drying oven (Shanghai Sanfa Scientific Instruments DHG-9070), spherical condenser, and several 500ml flasks.

[0040] Example 1

[0041] Dissolve 1.0 g of rupatifen free base and 0.29 g of fumaric acid in 15 ml of anhydrous ethanol, heat to 70–80 °C, stir and reflux, add the above solution dropwise until the sample is completely dissolved to prepare a saturated solution, react for 1 h at 100 rpm, cool to 40 °C at a rate of 15 ± 5 °C / h; cool to 15 °C at a rate of 7.5 ± 2.5 °C / h and hold for 2 h; cool to 5 ± 3 °C at a rate of 7.5 ± 2.5 °C / h and hold for 2 h. Globular crystals precipitate, wash with anhydrous ethanol solution at 2 °C–8 °C, and dry under reduced pressure at 60 °C to obtain the final product.

[0042] Example 2

[0043] Dissolve 1.0 g of rupatifen free base and 0.29 g of fumaric acid in 15 ml of anhydrous ethanol. Heat and reflux at 70 °C with stirring. Add the above solution dropwise until the sample is completely dissolved to prepare a saturated solution. React for 1 h, then cool naturally to 50–60 °C. Add seed crystals, and continue stirring until crystallization occurs at room temperature. Then keep warm at 2 °C–8 °C for 2 h. Globular crystals precipitate. Wash with anhydrous ethanol solution at 2 °C–8 °C, and dry under reduced pressure at 60 °C to obtain the final product.

[0044] Example 3

[0045] Dissolve 1.0 g of crude rupatifine fumarate in 15 ml of anhydrous ethanol, heat to 70–80 °C, stir and reflux, add the above solution dropwise until the sample is completely dissolved to prepare a saturated solution, react for 1 h at 100 rpm, cool to 40 °C at a rate of 15 ± 5 °C / h; cool to 15 °C at a rate of 7.5 ± 2.5 °C / h and hold for 2 h; cool to 5 ± 3 °C at a rate of 7.5 ± 2.5 °C / h and hold for 2 h. Globular crystals precipitate, wash with anhydrous ethanol solution at 2 °C–8 °C, and dry under reduced pressure at 60 °C to obtain the final product.

[0046] Example 4

[0047] Dissolve 2.0 g of crude rupatifine fumarate in 35 ml of anhydrous ethanol solution, heat and stir under reflux, add the above solution dropwise until the sample is completely dissolved to prepare a saturated solution, cool naturally to room temperature, then lower to 2℃~8℃ to crystallize, stir to precipitate spherical crystals, wash with anhydrous ethanol solution at 2℃~8℃, and dry under reduced pressure at 60℃ to obtain the final product.

[0048] Example 5

[0049] Dissolve 1.0 g of rupatifine free base and 0.29 g of fumaric acid in 18 ml of 95% ethanol (mass ratio). Heat and reflux at 70–80 °C with stirring. Add the above solution dropwise until the sample is completely dissolved to prepare a saturated solution. React for 1 h, then cool to 40 °C at a rate of 15 ± 5 °C / h; cool to 15 °C at a rate of 7.5 ± 2.5 °C / h and hold for 2 h; then cool to 5 ± 3 °C at a rate of 7.5 ± 2.5 °C / h and hold for 2 h. Stirring will precipitate spherical crystals, which are then washed with 95% ethanol solution at 2 °C–8 °C and dried under reduced pressure at 60 °C to obtain the final product.

[0050] Example 6

[0051] Dissolve 2.0 g of crude rupatifine fumarate in 40 ml of 95% ethanol (mass ratio), heat and stir under reflux, add the above solution dropwise until the sample is completely dissolved to prepare a saturated solution, cool naturally to room temperature, then lower to 2℃~8℃ to crystallize, stir to precipitate spherical crystals, wash with 95% ethanol solution at 2℃~8℃, and dry under reduced pressure at 60℃ to obtain the final product.

[0052] Example 7

[0053] Dissolve 1.0 g of rupatifen free base and 0.29 g of fumaric acid in 30 ml of ethyl acetate-acetone (1:1, w / w), heat and stir under reflux, and add the above solution dropwise until the sample is completely dissolved to prepare a saturated solution. React for 0.5 h, and then cool the saturated solution to 5 °C at a rate of 20-30 °C / h to precipitate spherical crystals. Wash with ethyl acetate-acetone (1:1, w / w) at 2-8 °C, and dry under reduced pressure at 60 °C to obtain the final product.

[0054] Example 8

[0055] 1.0 g of crude rupatifine fumarate was dissolved in 25 ml of ethyl acetate-acetone (1:1, w / w), heated and stirred under reflux, and the above solution was added dropwise until the sample was completely dissolved to prepare a saturated solution. The reaction was carried out for 0.5 h, and the saturated solution was cooled to 5 °C at a rate of 20-30 °C / h to precipitate spherical crystals. The crystals were then washed with ethyl acetate-acetone (1:1, w / w) at 2-8 °C and dried under reduced pressure at 60 °C to obtain the final product.

[0056] Example 9

[0057] Dissolve 1.0 g of rupatifen free base and 0.32 g of fumaric acid in 20 ml of dichloromethane-acetone solution (1:1, w / w), stir and heat to reflux, add the above solution dropwise until the sample is completely dissolved to prepare a saturated solution, react for 1 h, cool naturally to room temperature, and then lower to 2℃~8℃ to crystallize. Stir to precipitate spherical crystals, wash with dichloromethane-acetone solution (1:1, w / w) at 2℃~8℃, and dry under reduced pressure at 60℃ to obtain the final product.

[0058] Example 10

[0059] Dissolve 1.0 g of crude rupatifine fumarate in 20 ml of dichloromethane-acetone solution (1:1, w / w), stir and heat to reflux, add the above solution dropwise until the sample is completely dissolved to prepare a saturated solution, react for 1 h, cool naturally to room temperature, and then lower to 2℃~8℃ to crystallize. Stir to precipitate spherical crystals, wash with dichloromethane-acetone solution (1:1, w / w) at 2℃~8℃, and dry under reduced pressure at 60℃ to obtain the final product.

[0060] Example 11

[0061] Dissolve 3.5g of rupatifen free base and 1g of fumaric acid in 70ml of ether-methanol solution (1:1, w / w), heat and stir under reflux, add the above solution dropwise until the sample is completely dissolved to prepare a saturated solution, react for 1h, cool naturally to room temperature, then lower to 2℃~8℃ to crystallize, stir to precipitate spherical crystals, wash with ether-methanol solution (1:1, w / w) at 2℃~8℃, and dry under reduced pressure at 60℃ to obtain the final product.

[0062] Example 12

[0063] 2.0 g of crude rupatifine fumarate was dissolved in 40 ml of diethyl ether-methanol solution (1:1, w / w), heated and stirred under reflux, and the above solution was added dropwise until the sample was completely dissolved to prepare a saturated solution. The reaction was carried out for 1 h, and then naturally cooled to room temperature, and then lowered to 2℃~8℃ to crystallize. Spherical crystals were precipitated by stirring, and then washed with diethyl ether-methanol solution (1:1, w / w) at 2℃~8℃, and dried under reduced pressure at 60℃ to obtain the final product.

[0064] Example 13

[0065] Dissolve 1.0 g of rupatifen free base and 0.32 g of fumaric acid in 30 ml of cyclohexane-ethyl acetate solution (1:1, w / w), heat and stir under reflux, add the above solution dropwise until the sample is completely dissolved to prepare a saturated solution, cool naturally to room temperature, then lower to 2℃~8℃ to crystallize, stir to precipitate spherical crystals, wash with cyclohexane-ethyl acetate solution (1:1, w / w) at 2℃~8℃, and dry under reduced pressure at 60℃ to obtain the final product.

[0066] Example 14

[0067] 2.0 g of crude rupatifine fumarate was dissolved in 60 ml of cyclohexane-ethyl acetate solution (1:1, w / w), heated and stirred under reflux, and the above solution was added dropwise until the sample was completely dissolved to prepare a saturated solution. The solution was allowed to cool naturally to room temperature, and then cooled to 2℃~8℃ to crystallize. Spherical crystals were precipitated by stirring, and then washed with cyclohexane-ethyl acetate solution (1:1, w / w) at 2℃~8℃. The solution was dried under reduced pressure at 60℃ to obtain the final product.

[0068] Example 15

[0069] This embodiment compares crystal form C with crystal forms A, B, and mixed crystals. Crystal form C was prepared in Example 1; crystal form A was prepared in Example 1 of Chinese Patent CN 104045633 B; crystal form B was prepared in Example 1 of Chinese Patent CN 104059056 B; and mixed crystals were prepared in Example 1 of Chinese Patent CN104031035 B. Table 1 lists the key preparation process parameters, yields, physicochemical properties, moisture content, flowability, and solvent residue for preparing these crystal forms.

[0070] 1. Key preparation process conditions

[0071] Table 1. Preparation process conditions for different crystal forms of rupapatefen fumarate

[0072]

[0073]

[0074] Crystal forms A, B, and mixed crystals all use mixed solvents, while crystal form C uses a single solvent in small quantities, effectively saving material costs. Furthermore, crystal forms A and B use organic solvents such as dichloromethane, which can cause some environmental pollution, while crystal form C uses anhydrous ethanol, resulting in less environmental pollution. The preparation method for crystal form C has a significantly higher yield than other crystal forms, making it more suitable for subsequent commercial production.

[0075] 2. Physicochemical properties

[0076] The following analytical methods were used to examine samples of different crystal forms, and the data are shown in Table 2.

[0077] 2.1 Melting point determination method:

[0078] Take a sample and place it in a capillary tube for melting point determination, ensuring the powder is tightly packed within 3 mm of the fused end of the capillary. Set the temperature to 190℃ and the heating rate to 3℃ / min. Record the temperature of the sample from initial melting to complete melting. Repeat the measurement three times and take the average value as the result.

[0079] 2.2 Moisture determination method:

[0080] Take 0.8g of sample and determine the moisture content according to the method for moisture determination (General Chapter 0832, Method 1, Chinese Pharmacopoeia 2020 Edition). The specific operation is as follows:

[0081] 1) Blank calibration: Calibrate the moisture analyzer to an anhydrous state;

[0082] 2) Accurately weigh 10 mg of purified water until it is anhydrous, and measure the water content using a moisture analyzer. Calculate the titer. Perform three consecutive measurements, and calculate the RSD, which should not exceed 2.0%.

[0083] 3) For the determination of the test sample, take no less than 0.8g of this product (the specific amount should be calculated based on the actual measured F value of commercially available Fischer test solution) and measure the moisture content in an anhydrous state using a moisture analyzer. Measure 3 times consecutively and take the average value as the result.

[0084] 2.3 Crystal detection method

[0085] Take an appropriate amount of sample, disperse it with cyclohexane, and observe it under a microscope.

[0086] 2.4 Method for determining fluidity:

[0087] Determination of the angle of repose: Using the fixed cone base method, fix the funnel at a suitable height on a horizontally placed graph paper, ensuring the distance H between the bottom of the funnel and the graph paper. Carefully pour the powder into the funnel until the tip of the cone formed at the bottom of the funnel touches the outlet of the funnel. The radius r of the cone can be measured from the graph paper. Perform three consecutive measurements and take the average value as the result. The calculation method for the angle of repose α is as follows:

[0088] α = tan⁻¹(H / r).

[0089] Judgment criterion: Angle of repose < 30° 0 At that time, the fluidity is relatively good. Angle of repose > 40° 0 At that time, liquidity was poor.

[0090] Table 2 Physicochemical properties of different crystal forms of rupapatefen fumarate

[0091]

[0092] Crystal form C has a higher melting point than other crystal forms and contains less moisture in its product, suggesting that crystal form C is less likely to contain water of crystallization, and that raw materials of crystal form C tend to be in a more stable crystal state. Furthermore, since crystal form C is predominantly globular while other crystal forms are rod-shaped, and the angle of repose of crystal form C is less than 30°... 0 It has good fluidity, which is more conducive to the development of uniformity of content in rupatifen fumarate capsule formulations.

[0093] 3. Solvent residue

[0094] Accurately weigh an appropriate amount of sample, dissolve and dilute with N,N-dimethylformamide to prepare a solution containing approximately 50 mg per ml; accurately weigh appropriate amounts of methanol, n-pentane, ethanol, dichloromethane, and ethyl acetate, quantitatively dilute with N,N-dimethylformamide to prepare a mixed solution containing approximately 150 μg methanol, 250 μg n-pentane, 500 μg ethanol, 30 μg dichloromethane, and 250 μg ethyl acetate per ml; use 6% cyanopropylphenyl-94% dimethylformamide... A capillary column with methyl polysiloxane (or similar polarity) as the stationary phase was used as the chromatographic column. The initial temperature was 30℃, maintained for 4 minutes, and then increased to 130℃ at a rate of 20℃ per minute, maintained for 3.5 minutes. The injection port temperature was 200℃, and the detector temperature was 250℃. The injection volume was 1 μl. In the chromatogram of the reference solution, the resolution between each component peak should be greater than 1.5. The test solution and the reference solution were accurately measured and injected separately into the gas chromatograph, and the chromatograms were recorded.

[0095] Table 3 Residual solvents for different crystal forms of rupapatefen fumarate

[0096]

[0097]

[0098] Note: N / A means "not applicable".

[0099] Comparative analysis of crystal forms: Crystal form A is dissolved in methanol and dichloromethane. Methanol is a Class II solvent, and methanol residue is detrimental to the drug formulation. Crystal form C is dissolved in anhydrous ethanol, which is a Class III solvent and is less than the 0.5% limit requirement. The ethanol residue is significantly less than other crystal forms, and the types of residual solvents are fewer than other crystal forms (crystal form A, crystal form B, and mixed crystals). It can be inferred that the product is less likely to contain crystallization solvents. In conclusion, crystal form C of rupatifine fumarate is more likely to be safer.

[0100] Example 16

[0101] Dissolve 1.0 g of rupatifen free base and 0.29 g of fumaric acid in 15 ml of anhydrous ethanol, heat to 70-80 °C, stir and reflux, add the above solution dropwise until the sample is completely dissolved to prepare a saturated solution, react for 1 h at 100 rpm.

[0102] The cooling methods were as follows: 1. Cooling to 40℃ at a rate of 15±5℃ / h; cooling to 15℃ at a rate of 7.5±2.5℃ / h and holding for 2 hours; cooling to 5±3℃ at a rate of 7.5±2.5℃ / h and holding for 2 hours; 2. Cooling to 40℃ at a rate of 20-30℃ / h; cooling to 15℃ at a rate of 10-20℃ / h and holding for 2 hours; cooling to 2-8℃ at a rate of 10-20℃ / h; 3. Natural cooling to room temperature, then cooling to 2℃~8℃; 4. Cooling to 2-8℃ at a rate of 20-30℃ / h. Spherical crystals precipitated, which were then washed with anhydrous ethanol solution at 2℃~8℃ and dried under reduced pressure at 60℃ to obtain crystal form C. Solvent residue and moisture content were then tested.

[0103] Table 4. Comparison of experimental data results for different cooling crystallization methods.

[0104]

[0105]

[0106] Experimental studies have shown that the cooling rate should not be too fast. Accelerated cooling leads to excessively rapid crystallization, which prevents the crystals from reaching a stable state. The residual solvent and moisture content in the rapid cooling group is higher than that in the gradient cooling group, indicating that solvent and moisture encapsulation has occurred.

[0107] Example 17

[0108] The rupatifine fumarate crystal form C obtained in Example 1 was ground, and a sample was subjected to X-ray powder diffraction using a Cu-Ka radiation source. The results are shown in [Figure 1]. Figure 1 .

[0109] The rupatifine fumarate crystal form C obtained in Examples 2-14 was ground, and samples were taken for X-ray powder diffraction using Cu-Ka as the radiation source. The results were consistent with... Figure 1 resemblance.

[0110] Example 18

[0111] Differential scanning calorimetry (DSC) was used to detect the crystal form C of rupatifine fumarate from Example 1. Its melting point was found to be around 200-220°C, at which point it decomposed. Figure 2 .

[0112] Differential scanning calorimetry (DSC) was used to detect the melting point of rupatifine fumarate crystal form C in Examples 2-14. It also showed decomposition at around 200-220℃, and the results were consistent with... Figure 2 resemblance.

[0113] Example 19

[0114] Thermogravimetric analysis (TGA) was used to detect the crystal form C of rupatifine fumarate from Example 1. It decomposed at approximately 200-220°C. Figure 3 .

[0115] Thermogravimetric analysis (TGA) was used to detect the crystal form C of rupatifine fumarate in Examples 2-14, which also decomposed at around 200-220℃. The results were consistent with... Figure 3 resemblance.

[0116] Example 20

[0117] The rupatifine fumarate crystal form C obtained in Example 1 was observed under a 100x microscope to be a spherical crystal. Figure 4 .

[0118] The rupatifine fumarate crystal form C obtained in Examples 2-14, observed under a 100x microscope, also exhibited a spherical crystal shape, consistent with... Figure 4 resemblance.

Claims

1. A crystalline Form C of rupatadine fumarate, wherein, X-ray powder diffraction pattern of the crystalline Form C is characterized by peaks at 8.7°±0.2°, 10.0°±0.2°, 12.3°±0.2°, 14.4°±0.2°, 17.6°±0.2°, 22.4°±0.2° in terms of 2θ using Cu-Ka radiation.

2. The crystalline Form C of claim 1, wherein, X-ray powder diffraction pattern of the crystalline Form C is characterized by peaks at 8.7°±0.2°, 10.0°±0.2°, 12.3°±0.2°, 14.4°±0.2°, 17.6°±0.2°, 21.2°±0.2°, 22.4°±0.2°, 24.1°±0.2° in terms of 2θ using Cu-Ka radiation.

3. The crystalline Form C of claim 1 or 2, wherein, The melting point of the crystalline Form C is 204.0-212.0°C.

4. The crystalline Form C of claim 1 or 2, wherein, The crystalline Form C is spheroid-like crystal under microscopic condition.

5. A preparation method of the crystalline Form C of any one of claims 1 to 4, comprising the following steps: dissolving the free base of Rupatadine and fumaric acid in solvent A, stirring and heating to reflux until clear, then cooling to 2-8°C, stirring to crystallize, filtering, washing with solvent A, and drying under reduced pressure to obtain the crystalline Form C of Rupatadine fumarate; wherein the solvent A is selected from 95% ethanol aqueous solution or anhydrous ethanol, the weight ratio between the free base of Rupatadine and fumaric acid is 1.0:0.29; the temperature for stirring and heating to reflux until clear is 70-80°C.

6. A preparation method of the crystalline Form C of any one of claims 1 to 4, comprising the following steps: dissolving the free base of Rupatadine and fumaric acid in solvent A, stirring and heating to reflux until clear, then cooling to 2-8°C, stirring to crystallize, filtering, washing with solvent A, and drying under reduced pressure to obtain the crystalline Form C of Rupatadine fumarate; wherein the solvent A is selected from ethyl acetate-acetone solution, dichloromethane-acetone solution, diethyl ether-methanol solution or cyclohexane-ethyl acetate solution; the mass ratio between ethyl acetate and acetone in the ethyl acetate-acetone solution is 1:1; the mass ratio between dichloromethane and acetone in the dichloromethane-acetone solution is 1:1; the mass ratio between diethyl ether and methanol in the diethyl ether-methanol solution is 1:1; the mass ratio between cyclohexane and ethyl acetate in the cyclohexane-ethyl acetate solution is 1:1; the weight ratio between the free base of Rupatadine and fumaric acid is 1.0:0.29, 1.0:0.32 or 3.5:1.

0.

7. A preparation method of the crystalline Form C of any one of claims 1 to 4, comprising the following steps: dissolving the crude fumaric acid Rupatadine in solvent A, stirring and heating to reflux to prepare a saturated solution, then cooling to 2-8°C, stirring to crystallize, filtering, washing with solvent A, and drying under reduced pressure to obtain the crystalline Form C of Rupatadine fumarate; wherein, the solvent A is selected from 95% ethanol aqueous solution or anhydrous ethanol; the temperature for stirring and heating to reflux is 70-80°C.

8. A preparation method of the crystalline Form C of any one of claims 1 to 4, comprising the following steps: The fumarate of crude lufuberidol is dissolved in solvent A, and a saturated solution is prepared by stirring and heating under reflux, then the temperature is decreased to 2-8℃, and the lufuberidol is crystallized by stirring, filtered, washed with solvent A, and dried under reduced pressure to obtain the product; wherein The solvent A is selected from ethyl acetate-acetone solution, dichloromethane-acetone solution, diethyl ether-methanol solution or cyclohexane-ethyl acetate solution; the mass ratio of ethyl acetate to acetone in the ethyl acetate-acetone solution is 1:1; the mass ratio of dichloromethane to acetone in the dichloromethane-acetone solution is 1:1; the mass ratio of diethyl ether to methanol in the diethyl ether-methanol solution is 1:1; and the mass ratio of cyclohexane to ethyl acetate in the cyclohexane-ethyl acetate solution is 1:

1.

9. The production method according to claim 5 or 7, wherein The temperature for stirring and heating under reflux is 70℃.

10. The method of any one of claims 5 to 8, wherein, The temperature decreasing is natural cooling, gradient temperature decreasing or rapid temperature decreasing.

11. The method of claim 10, wherein, When the temperature of the solution is higher than 40℃, the gradient temperature decreasing procedure is: decreasing the temperature to 40℃ at a rate of 15±5℃ / h; decreasing the temperature to 15℃ at a rate of 7.5±2.5℃ / h and keeping the temperature for 2h; decreasing the temperature to 5±3℃ at a rate of 7.5±2.5℃ / h and keeping the temperature for 2h. When the temperature of the solution is lower than 40℃, the gradient temperature decreasing procedure is: decreasing the temperature to 15℃ at a rate of 7.5±2.5℃ / h and keeping the temperature for 2h; decreasing the temperature to 5±3℃ at a rate of 7.5±2.5℃ / h and keeping the temperature for 2h.

12. The method of any one of claims 5 to 8, wherein, The stirring speed for crystallization is 50-200rpm.

13. The method of claim 12, wherein, The stirring speed for crystallization is 90-110rpm.

14. The method of claim 5 or 6, wherein, The mass-volume ratio of the lufuberidol free base to the solvent A is 1:15 to 1:

30.

15. The method of claim 14, wherein, The mass-volume ratio of the lufuberidol free base to the solvent A is 1:15 to 1:17.

5.

16. The method of claim 7 or 8, wherein, The mass-volume ratio of the fumarate of crude lufuberidol to the solvent A is 1:15 to 1:

30.

17. The method of claim 16, wherein, The mass-volume ratio of the fumarate of crude lufuberidol to the solvent A is 1:15 to 1:17.5.

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