Rupatadine fumarate crystal form C, and its preparation method and use

Abstract

The present invention provides ruptifene fumarate crystalline form C, and its preparation method and use. The characteristic peaks of the powder X-ray diffraction pattern of crystalline form C of the present invention represented by 2θ (±0.2°) by using Cu-Kα rays are located at 12.3° ± 0.2°, 14.4° ± 0.2°, 17.6° ± 0.2°, and 22.4° ± 0.2°. Crystalline form C has characteristics such as a high melting point, a low residual moisture content, a low residual ethanol content, a stable crystal form, a small number of types of residual solvents and high safety, using a single solvent, a small amount of solvent, being able to effectively save material costs, having less environmental pollution, a high yield, mild conditions, simple operation, and being advantageous for subsequent commercial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to crystalline form C of rupatifene fumarate, a method for its preparation, and its use.

Background Art

[0002] Patent Document 1 discloses rupatifene fumarate, a multi-channel drug for comprehensively suppressing allergies, that is, 4-[1-[(5-methylpyridin-3-yl)methyl]piperidyl-4-ylidene]-4,9-dihydro-10H-benzo[4,5]cycloheptyl[1,2-b]thiophen-10-one fumarate, and its structural formula is as follows:

Chemical Formula

[0003] Polymorphism of a drug refers to the existence of two or more different crystalline forms of the drug. Polymorphism widely exists in drugs. Different crystalline forms of the same drug have significantly different solubility, melting point, density, stability, etc., and therefore affect the stability, uniformity, bioavailability, therapeutic effect, and safety of the drug to varying degrees. Therefore, it is one of the important contents that cannot be ignored to conduct comprehensive and systematic polymorphism screening in drug research and development and select the most appropriate crystalline form.

[0004] Rupatadine fumarate is polymorphic. Patent Document 2 discloses Crystal Form A of rupatadine fumarate, and its powder X-ray diffraction pattern has characteristic peaks at the following 2θ (±0.2°) angles: 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°, 29.1°. Patent Document 3 discloses Crystal Form B of rupatadine fumarate, and its powder X-ray diffraction pattern has characteristic peaks at the following 2θ (±0.2°) angles: 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°. Organic solvents such as dichloromethane are used in the preparation of these two crystal forms, which causes a certain degree of environmental pollution. At the same time, the yield is relatively low due to a certain temperature drop.

[0005] Patent Document 4 discloses a mixed crystal of rupatadine fumarate.

[0006] However, the above crystal forms have low stability, low purity, high residual moisture content, low melting point, and low safety and high cost as a result of a large amount of residual solvent during the preparation process. Therefore, these cannot be commercialized.

Prior Art Documents

Patent Documents

[0007]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Summary of the Invention

Problems to be Solved by the Invention

[0008] In order to overcome the drawbacks of the prior art, the present invention provides a crystalline form C of rupatadine fumarate and a method for preparing the same. The crystalline form C of rupatadine fumarate is more stable, has a low solvent residue amount, low moisture content, and high purity. The preparation method of this crystalline form is simple, easy to industrialize, and can ensure the quality and dosing safety of the novel rupatadine fumarate drug.

[0009] In order to achieve the above object of the present invention, the following technical solutions are adopted.

Means for Solving the Problems

[0010] In one aspect, the present invention provides a crystalline form C of rupatadine fumarate having characteristic peaks represented by 2θ degrees (±0.2°) of 12.3° ± 0.2°, 14.4° ± 0.2°, 17.6° ± 0.2°, and 22.4° ± 0.2° in a powder X-ray diffraction pattern using Cu-Kα radiation.

[0011] Preferably, the powder X-ray diffraction pattern of crystalline form C using Cu-Kα radiation has characteristic peaks represented by 2θ degrees (±0.2°) of 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, the powder X-ray diffraction pattern of crystalline form C using Cu-Kα radiation has characteristic peaks represented by 2θ degrees (±0.2°) of 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 powder X-ray diffraction pattern of crystalline form C represented by 2θ degrees (±0.2°) using Cu-Kα radiation is as shown in FIG. 1.

[0014] Preferably, the melting point of crystalline form C is 204.0 °C to 212.0 °C.

[0015] Preferably, crystalline form C is spherical under microscopic conditions.

[0016] In another aspect, the present invention provides a method for preparing crystalline form C of rupatufen fumarate, comprising: dissolving rupatifen free base and fumaric acid in solvent A, and reacting by stirring, heating, and refluxing until the solution becomes transparent, or dissolving crude rupatifen fumarate in solvent A, preparing a saturated solution by heating, stirring, and refluxing, then cooling to 2 °C to 8 °C, crystallizing by stirring, filtering, washing with solvent A, and drying under reduced pressure to obtain crystalline form C of rupatufen fumarate.

[0017] Preferably, solvent A is selected from ethanol aqueous solutions with an ethanol concentration of 95% or more (mass ratio), absolute ethanol solutions, ethyl acetate - acetone solutions, dichloromethane - acetone solutions, ether - methanol solutions, cyclohexane - ethyl acetate solutions, and other crystallization solvents, and is preferably an absolute ethanol solution.

[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 ether to methanol in the 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 mass ratio of rupatadine free base to fumaric acid is 4:1 to 1:2.

[0023] Preferably, the temperature for stirring, heating, and refluxing until the solution becomes transparent is 30°C to 90°C, preferably 70°C.

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

[0025] When the temperature at which the solution becomes transparent is higher than 40°C, the gradient cooling procedure is to 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 at that temperature for 2 hours; cool to 5 ± 3°C at a rate of 7.5 ± 2.5°C / h and hold at that temperature for 2 hours.

[0026] When the temperature at which the solution becomes transparent is lower than 40°C, the gradient cooling procedure is to cool to 15°C at a rate of 7.5 ± 2.5°C / h and hold at that temperature for 2 hours; cool to 5 ± 3°C at a rate of 7.5 ± 2.5°C / h and hold at that temperature for 2 hours.

[0027] Preferably, the stirring speed for crystallization is 50 rpm to 200 rpm, preferably 90 rpm to 110 rpm.

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

[0029] In yet another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline form C and an optional pharmaceutically acceptable carrier or excipient.

[0030] In yet another aspect, the present invention provides the use of crystalline form C in the preparation of a medicament for the treatment of allergic diseases or disorders.

[0031] Preferably, allergic diseases or disorders include allergy, drug hypersensitivity, skin allergy, eczema, allergic rhinitis, urticaria, atopic dermatitis, dry eye, allergic contact allergy, food allergy, allergic conjunctivitis, insect sting allergy, bronchial asthma, allergic asthma, intrinsic asthma, occupational asthma, ectopic asthma, acute respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD).

[0032] In yet another aspect, the present invention provides a method for treating an allergic disease or disorder, comprising administering crystalline form C or a pharmaceutical composition thereof to a patient in need thereof.

[0033] Preferably, allergic diseases or disorders include allergy, drug hypersensitivity, skin allergy, eczema, allergic rhinitis, urticaria, atopic dermatitis, dry eye, allergic contact allergy, food allergy, allergic conjunctivitis, insect sting allergy, bronchial asthma, allergic asthma, intrinsic asthma, occupational asthma, ectopic asthma, acute respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD).

[0034] Compared with the prior art, the present invention has at least the following beneficial effects:

[0035] The present invention provides crystalline form C of rupatadine fumarate. Crystalline form C has high purity, is more stable, has a high melting point (reaching 204.0 °C to 212.0 °C), and has less moisture and residual solvents. The preparation method of crystalline form C has the advantages of high product yield, mild conditions, environmentally friendly reagents, simple operation, and easy industrialization.

[0036] Compared with the disclosed crystal forms (including crystal form A, crystal form B, and mixed crystals), crystal form C has advantages such as a higher melting point, a lower residual moisture content, a more stable crystal form, higher solubility, lower hygroscopicity, and excellent fat solubility. However, it has less residual ethanol, fewer types of residual solvents, and high safety. From the analysis of process feasibility, both crystal form A and crystal form B employ mixed solvents, while crystal form C uses a single solvent with a lower solvent consumption, which can effectively save material costs. The use of organic solvents such as dichloromethane in crystal form A and crystal form B causes a certain degree of environmental pollution, but the use of absolute ethanol in crystal form C causes little environmental pollution. The yield of the preparation method of crystal form C is significantly higher than that of other crystal forms, which is more advantageous for subsequent commercial production.

[0037] The present invention will be further described with reference to the accompanying drawings.

Brief Description of the Drawings

[0038]

Figure 1

Figure 2

Figure 3

Figure 4

Modes for Carrying Out the Invention

[0039] The present invention will be described below with reference to specific examples. Those skilled in the art will understand that these examples are merely illustrative of the present invention and do not limit the scope of the present invention in any way.

[0040] Unless otherwise specified, all experimental procedures in the following examples are conventional. Unless otherwise specified, all raw materials, reagent materials, etc. used in the following examples are commercially available. The conditions of some devices are as follows: Apparatus: Constant temperature magnetic stirrer (HWCL-5, Great Wall Science and Industry), rotary evaporator (IKA), forced air drying box (DHG-9070, Shanghai Sanfa Scientific Instrument), spherical condenser, and several eggplant-shaped flasks (500 ml).

Example

[0041] Example 1 1.0 g of rupatadine free base and 0.29 g of fumaric acid were dissolved in 15 ml of absolute ethanol, heated to 70 °C to 80 °C, stirred and refluxed until the sample was completely dissolved to prepare a saturated solution, reacted at a rotation speed of 100 rpm for 1 hour, cooled to 40 °C at a rate of 15 ± 5 °C / h, then cooled to 15 °C at a rate of 7.5 ± 2.5 °C / h, held at that temperature for 2 hours, cooled to 5 ± 3 °C at a rate of 7.5 ± 2.5 °C / h, and held at that temperature for 2 hours. Spherical crystals precipitated, which were washed with absolute ethanol at 2 °C to 8 °C and dried under reduced pressure at 60 °C to obtain the product.

[0042] Example 2 1.0 g of rupatadine free base and 0.29 g of fumaric acid were dissolved in 15 ml of absolute ethanol, heated, stirred, and refluxed at 70 °C until the sample was completely dissolved to prepare a saturated solution, reacted for 1 hour, allowed to cool to 50 °C to 60 °C, seeded, and then continuously stirred to crystallize to room temperature, and then held at a temperature of 2 °C to 8 °C for 2 hours. Spherical crystals precipitated, which were washed with absolute ethanol at 2 °C to 8 °C and dried under reduced pressure at 60 °C to obtain the product.

[0043] Example 3 1.0 g of crude loperamide fumarate was dissolved in 15 ml of absolute ethanol, heated to 70 °C - 80 °C, and stirred and refluxed until the sample was completely dissolved to prepare a saturated solution. The reaction was carried out at a rotation speed of 100 rpm for 1 hour, cooled to 40 °C at a rate of 15 ± 5 °C / h, then cooled to 15 °C at a rate of 7.5 ± 2.5 °C / h, held at that temperature for 2 hours, cooled to 5 ± 3 °C at a rate of 7.5 ± 2.5 °C / h, and held at that temperature for 2 hours. Spherical crystals precipitated, which were washed with absolute ethanol at 2 °C - 8 °C and dried under reduced pressure at 60 °C to obtain the product.

[0044] Example 4 2.0 g of crude loperamide fumarate was dissolved in 35 ml of absolute ethanol solution, heated, stirred, and refluxed until the sample was completely dissolved to prepare a saturated solution, allowed to cool to room temperature, then cooled to 2 °C - 8 °C for crystallization, stirred to precipitate spherical crystals, which were washed with absolute ethanol solution at 2 °C - 8 °C and dried under reduced pressure at 60 °C to obtain the product.

[0045] Example 5 1.0 g of loperamide free base and 0.29 g of fumaric acid were dissolved in 18 ml of 95% ethanol (by mass), heated, stirred, and refluxed at 70 °C - 80 °C until the sample was completely dissolved to prepare a saturated solution, reacted for 1 hour, cooled to 40 °C at a rate of 15 ± 5 °C / h, then cooled to 15 °C at a rate of 7.5 ± 2.5 °C / h, held at that temperature for 2 hours, cooled to 5 ± 3 °C at a rate of 7.5 ± 2.5 °C / h, held at that temperature for 2 hours, stirred to precipitate spherical crystals, which were washed with 95% ethanol solution at 2 °C - 8 °C and dried under reduced pressure at 60 °C to obtain the product.

[0046] Example 6 2.0 g of crude loperamide fumarate was dissolved in 40 ml of 95% ethanol (by mass), heated, stirred, and refluxed until the sample was completely dissolved to prepare a saturated solution, allowed to cool to room temperature, cooled to 2 °C - 8 °C for crystallization, stirred to precipitate spherical crystals, which were washed with 95% ethanol solution at 2 °C - 8 °C and dried under reduced pressure at 60 °C to obtain the product.

[0047] Example 7 1.0 g of rupatadine free base and 0.29 g of fumaric acid were dissolved in 30 ml of ethyl acetate - acetone (1:1, w / w). Heating, stirring, and refluxing were carried out until the sample was completely dissolved to prepare a saturated solution. The reaction was carried out for 0.5 hour, and the saturated solution was cooled to 5°C at a rate of 20°C - 30°C / h to precipitate spherical crystals. These were washed with ethyl acetate - acetone (1:1, w / w) at 2°C - 8°C and dried under reduced pressure at 60°C to obtain the product.

[0048] Example 8 1.0 g of crude rupatadine fumarate was dissolved in 25 ml of ethyl acetate - acetone (1:1, w / w). Heating, stirring, and refluxing were carried out until the sample was completely dissolved to prepare a saturated solution. The reaction was carried out for 0.5 hour, and the saturated solution was cooled to 5°C at a rate of 20°C - 30°C / h to precipitate spherical crystals. These were washed with ethyl acetate - acetone (1:1, w / w) at 2°C - 8°C and dried under reduced pressure at 60°C to obtain the product.

[0049] Example 9 1.0 g of rupatadine free base and 0.32 g of fumaric acid were dissolved in 20 ml of dichloromethane - acetone solution (1:1, w / w). Stirring, heating, and refluxing were carried out until the sample was completely dissolved to prepare a saturated solution. The reaction was carried out for 1 hour, allowed to cool to room temperature, cooled to 2°C - 8°C for crystallization, stirred to precipitate spherical crystals, which were washed with dichloromethane - acetone solution (1:1, w / w) at 2°C - 8°C and dried under reduced pressure at 60°C to obtain the product.

[0050] Example 10 1.0 g of crude rupatadine fumarate was dissolved in 20 ml of dichloromethane - acetone solution (1:1, w / w). Stirring, heating, and refluxing were carried out until the sample was completely dissolved to prepare a saturated solution. The reaction was carried out for 1 hour, allowed to cool to room temperature, cooled to 2°C - 8°C for crystallization, stirred to precipitate spherical crystals, which were washed with dichloromethane - acetone solution (1:1, w / w) at 2°C - 8°C and dried under reduced pressure at 60°C to obtain the product.

[0051] Example 11 3.5 g of rupatadine free base and 1 g of fumaric acid were dissolved in 70 ml of a diethyl ether - methanol solution (1:1, w / w). Heating, stirring, and refluxing were carried out until the sample was completely dissolved to prepare a saturated solution. The solution was reacted for 1 hour, allowed to cool to room temperature, cooled to 2°C - 8°C for crystallization, stirred to precipitate spherical crystals, which were washed with a diethyl ether - methanol solution (1:1, w / w) at 2°C - 8°C, and dried under reduced pressure at 60°C to obtain the product.

[0052] Example 12 2.0 g of crude rupatadine fumarate was dissolved in 40 ml of a diethyl ether - methanol solution (1:1, w / w). Heating, stirring, and refluxing were carried out until the sample was completely dissolved to prepare a saturated solution. The solution was reacted for 1 hour, allowed to cool to room temperature, cooled to 2°C - 8°C for crystallization, stirred to precipitate spherical crystals, which were washed with a diethyl ether - methanol solution (1:1, w / w) at 2°C - 8°C, and dried under reduced pressure at 60°C to obtain the product.

[0053] Example 13 1.0 g of rupatadine free base and 0.32 g of fumaric acid were dissolved in 30 ml of a cyclohexane - ethyl acetate solution (1:1, w / w). Heating, stirring, and refluxing were carried out until the sample was completely dissolved to prepare a saturated solution. The solution was allowed to cool to room temperature, cooled to 2°C - 8°C for crystallization, stirred to precipitate spherical crystals, which were washed with a cyclohexane - ethyl acetate solution (1:1, w / w) at 2°C - 8°C, and dried under reduced pressure at 60°C to obtain the product.

[0054] Example 14 2.0 g of crude rupatadine fumarate was dissolved in 60 ml of a cyclohexane - ethyl acetate solution (1:1, w / w). Heating, stirring, and refluxing were carried out until the sample was completely dissolved to prepare a saturated solution. The solution was allowed to cool to room temperature, cooled to 2°C - 8°C for crystallization, stirred to precipitate spherical crystals, which were washed with a cyclohexane - ethyl acetate solution (1:1, w / w) at 2°C - 8°C, and dried under reduced pressure at 60°C to obtain the product.

[0055] Example 15 In this example, crystalline form C was compared with crystalline form A, crystalline form B, and mixed crystals. Crystalline form C was prepared from Example 1, crystalline form A was prepared from Example 1 of Patent Document 2, crystalline form B was prepared from Example 1 of Patent Document 3, and the mixed crystals were obtained from Example 1 of Patent Document 4. The main process parameters, yields, physical and chemical properties, residual solvents, and other data for preparing these crystalline forms are shown in Table 1.

[0056] 1. Main processing conditions

[0057] [Table 1]

[0058] All of crystalline form A, crystalline form B, and the mixed crystals employ a mixed solvent, while crystalline form C employs a single solvent using a small amount of solvent, so that the material cost can be effectively saved. On the other hand, the use of organic solvents such as dichloromethane in crystalline form A and crystalline form B causes a certain degree of environmental pollution, while the use of absolute ethanol in crystalline form C hardly causes environmental pollution. The yield of the preparation method of crystalline form C is clearly higher than that of other crystalline forms, which is more advantageous for subsequent commercial production.

[0059] 2. Physical and chemical properties The following analytical methods were used to test samples of different crystalline forms. The data are shown in Tables 2 to 5.

[0060] 2.1 Melting point determination method: A sample was taken and placed in a capillary for melting point measurement. The powder was concentrated densely at the sealed end of 3 mm of the capillary. The set temperature was 190 °C and the heating rate was 3 °C / min. The temperature from the initial melting to the complete melting of the test sample was recorded, and the measurement was repeated 3 times, and the average value was taken as the result.

[0061] 2.2 Moisture determination method: An 0.8 g sample was collected and measured according to the moisture determination method (Chinese Pharmacopoeia, 2020 Edition, General Rule 0832, Method 1). The specific operations are as follows: 1) Blank calibration: The moisture meter was calibrated in an anhydrous state; 2) Calibration: 10 mg of purified water was accurately weighed into the analyzer in an anhydrous state for measurement, and the titer was calculated. The measurement was performed 3 times. The calculated RSD should not exceed 2.0%; 3) Determination of test sample: A test sample of more than 0.8 g (based on the sample weight calculated from the actually measured F value of the commercially available Fisher test solution) was put into the analyzer in an anhydrous state for measurement. The measurement was performed continuously 3 times, and the average value was taken as the result.

[0062] 2.3 Crystal habit detection method An appropriate amount of the sample was collected, dispersed in cyclohexane and observed under a microscope.

[0063] 2.4 Fluidity detection method: Measurement of the angle of repose: The fixed cone bottom method was used. The funnel was fixed at an appropriate height on the horizontal coordinate paper so that the distance from the lower opening of the funnel to the coordinate paper was H, and the powder was carefully poured into the funnel until the tip of the cone formed under the funnel touched the outlet of the funnel. The radius r of the cone can be measured by the coordinate paper. The measurement was performed continuously 3 times, and the average value was taken as the result. The angle of repose α was calculated as follows: α = tan-1(H / r).

[0064] Judgment criteria: When the angle of repose is less than 30°, the fluidity is good. When the angle of repose exceeds 40°, the fluidity is poor.

[0065] 2.5 Hygroscopicity analysis method: 1) A dried glass weighing bottle with a stopper (outer diameter 50 mm, height 15 mm) was prepared, placed in an appropriate constant temperature dryer at 25°C ± 1°C (with an ammonium chloride or ammonium sulfate saturated solution placed at the bottom) the day before the test, and the weight of the weighing bottle was accurately measured (m1). 2) An appropriate amount of the test sample was collected and spread out in a weighing bottle. The thickness of the test sample was approximately 1 mm, and the weight of the test sample was accurately measured (m2). 3) The weighing bottle was opened and placed under constant temperature and humidity conditions together with the bottle cap for 24 hours. 4) The bottle was tightly capped, and the weight of the capped bottle was accurately measured (m3). Weight increase rate = (m3 - m2) / (m2 - m1) × 100%

[0066] According to the guidelines of the drug hygroscopicity test in Part 4 of the Chinese Pharmacopoeia 2020 Edition, the description of hygroscopicity and the definition of weight increase due to moisture absorption are as follows: Deliquescence: Absorbing sufficient water to form a liquid. Highly hygroscopic: The weight increase rate due to moisture absorption is 15% or more. Hygroscopic: The weight increase rate due to moisture absorption is less than 15% and 2% or more. Slightly hygroscopic: The weight increase rate due to moisture absorption is less than 2% and 0.2% or more. Non - hygroscopic or almost non - hygroscopic: The weight increase rate due to moisture absorption is less than 0.2%.

[0067] 2.6 Analytical method for solubility: An excess amount of the test sample was placed in the cup of the dissolution apparatus, and water and appropriate amounts of water - soluble media with different pH values (pH = 1.2, 2.2, 4.0, 4.5, 5.5, 6.8) were added. It was stirred at 37°C ± 1°C (rotation speed: 100 r / min) until dissolved (for more than 6 hours) to form a supersaturated solution. The saturated solution was filtered, the filtrate was diluted to the corresponding multiple with the mobile phase, and the concentration was measured by HPLC method to calculate the solubility.

[0068] 2.7 Analytical method for oil - water partition coefficient: The logP (n-octanol-water) of the test substance was detected by HPLC using a standard substance with a known logP. This principle is based on the fact that the retention time of a chemical substance in a long-chain hydrocarbon chromatography column such as a C18 column is related to the hydrocarbon-water partition coefficient. Hydrophilic substances are eluted first, and lipophilic substances are eluted later. There is a linear relationship between the oil-water partition coefficient and the retention time, and the formula is as follows: logP = alogK + b K=(T n -T0) / T0. logP: The oil-water partition coefficient (n-octanol-water) of the sample; T0: Dead time (measured with uracil here); T n : Retention time of the sample by HPLC; According to the above formula, by detecting the retention time of the standard substance and the known logP (n-octanol-water), a linear relationship formula can be established. Using the theoretical value of logP as the vertical axis and the logK value as the horizontal axis to draw a line, the values of a and b are obtained by calculation, and then the retention time of the detected sample (i.e., the logK value in the table) is substituted into the formula to calculate the logP (n-octanol-water) value of the sample.

[0069] 2.8 Results The results of the above analysis method are shown in Tables 2 to 5. Table 2 shows the physical and chemical properties of different crystal forms, Table 3 shows the results of hygroscopicity, Table 4 shows the solubility data, and Table 5 shows the results of the oil-water partition coefficient.

[0070]

Table 2

[0071] As shown in Table 2, crystalline form C has a higher melting point and less moisture than other crystalline forms. Therefore, it is inferred that the possibility of crystalline form C containing crystal water is low, and the raw material of crystalline form C tends to become a more stable crystalline form. On the other hand, the crystal form of crystalline form C is spherical, while other crystalline forms are rod-shaped. The angle of repose of crystalline form C is less than 30°, and the fluidity of crystalline form C is better. Therefore, crystalline form C is more useful for the development of rupatadine fumarate capsule formulations with a uniform content.

[0072]

Table 3

[0073] As shown in Table 3, crystalline form C is slightly more hygroscopic than other crystalline forms, and there is less influence by water molecules during the storage and use of the active ingredient. This is more advantageous for ensuring the stability of the active ingredient during storage and use.

[0074]

Table 4

[0075] As shown in Table 4, according to the classification system of biopharmaceuticals, under the conditions of pH = 1.2, pH = 2.2, pH = 4.0, pH = 4.5, pH = 5.5, and an aqueous medium, various crystalline forms have high solubility according to the requirements of formulation development. However, in a medium with pH = 6.8, various crystalline forms do not have high solubility, and the solubility of crystalline form C is slightly better than that of other crystalline forms. Therefore, crystalline form C is considered to have slightly better dissolution characteristics compared to other crystalline forms.

[0076]

Table 5

[0077] As shown in Table 5, the oil-water partition coefficient of crystalline form C is slightly better than that of other crystalline forms, and crystalline form C has excellent liposolubility. This suggests that crystalline form C is easily absorbed by the human body and has a therapeutic effect.

[0078] 3. Residual Solvent An appropriate amount of the sample was taken, accurately weighed, and dissolved by adding N,N-dimethylformamide to prepare a solution containing about 50 mg of N,N-dimethylformamide per 1 ml. Appropriate amounts of methanol, n-pentane, ethanol, dichloromethane, and ethyl acetate were taken, accurately weighed, and quantitatively diluted by adding N,N-dimethylformamide to prepare a mixed solution containing 150 μg of methanol, 250 μg of n-pentane, 500 μg of ethanol, 30 μg of dichloromethane, and 250 μg of ethyl acetate per 1 ml. A capillary column with 6% cyanopropylphenyl-94% dimethylpolysiloxane (or similar polarity) as the stationary phase was used as the chromatography column. The initial temperature was 30 °C, which was maintained for 4 minutes, and then the temperature was raised to 130 °C at a rate of 20 °C per minute and maintained for 3.5 minutes. The inlet temperature was 200 °C, and the detector temperature was 250 °C. The sample volume was 1 μl. In the chromatogram of the standard solution, the resolution between the peaks of each component should be greater than 1.5. The test solution and the standard solution were precisely measured and injected into the gas chromatograph respectively to record the chromatograms.

[0079] [Table 6]

[0080] As shown in Table 6, when comparing crystal forms, Crystal Form A is dissolved by methanol and dichloromethane. Methanol belongs to Class 2 solvents, and residual methanol is not beneficial for pharmaceutical preparation. Crystal Form B is dissolved in a dichloromethane - ethanol solution, and all solvents belong to Class 3 solvents. Since a mixed solvent is used for crystallization in the process, the risk of solvent residue in the final product is high, and it is necessary to control the residues of the two solvents to be less than the limit requirement of 0.5%. Crystal Form C uses absolute ethanol belonging to Class 3 solvents and needs to be below the limit requirement of less than 0.5%. Residual ethanol is clearly less than that of other crystal forms, and the types of residual solvents are fewer than those of other crystal forms (Crystal Form A, Crystal Form B, mixed crystals). From this, it can be inferred that the possibility of the crystallization solvent being contained in the product is low. In conclusion, Crystal Form C of rupatadine fumarate is safer.

[0081] Example 16 1.0 g of rupatadine free base and 0.29 g of fumaric acid were dissolved in 15 ml of absolute ethanol, heated to 70 °C - 80 °C, stirred and refluxed until the sample was completely dissolved to prepare a saturated solution, and reacted at a rotation speed of 100 rpm for 1 hour.

[0082] The cooling methods were as follows: (1) 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, hold at that temperature for 2 hours, cool to 5 ± 3 °C at a rate of 7.5 ± 2.5 °C / h, and hold at that temperature for 2 hours; (2) Cool to 40 °C at a rate of 20 °C - 30 °C / h, cool to 15 °C at a rate of 10 °C - 20 °C / h, hold at that temperature for 2 hours, and cool to 2 °C - 8 °C at a rate of 10 °C - 20 °C / h; (3) Cool to room temperature and then cool to 2 °C - 8 °C; (4) Cool to 2 °C - 8 °C at a rate of 20 °C - 30 °C / h. Spherical crystals precipitated, which were washed with an absolute ethanol solution at 2 °C - 8 °C and dried under reduced pressure at 60 °C to obtain Crystal Form C. Residual solvents and water were detected respectively.

[0083] [Table 7]

[0084] From the experimental investigation, it has been shown that the cooling rate should not be too fast. When accelerated cooling is carried out, crystallization proceeds rapidly and a stable state cannot be achieved. In the rapidly cooled group, there is more residual solvent and water than in the gradient-cooled group, suggesting that the phenomenon of solvent and water uptake has occurred.

[0085] Example 17 The crystalline form C of rupatadine fumarate obtained in Example 1 was collected, pulverized, and sampled for powder X-ray diffraction. The radiation source was Cu-Kα. The results are shown in Figure 1.

[0086] The crystalline form C of rupatadine fumarate obtained in Examples 2 to 14 was collected, pulverized, and sampled for powder X-ray diffraction. The radiation source was Cu-Kα. The results are the same as those in Figure 1.

[0087] Example 18 When the crystalline form C of rupatadine fumarate obtained in Example 1 was detected by differential scanning calorimetry (DSC), as shown in Figure 2, the melting point was about 200°C to 220°C, and it decomposed at this point.

[0088] When the crystalline form C of rupatadine fumarate obtained in Examples 2 to 14 was detected by differential scanning calorimetry (DSC), the melting point was about 200°C to 220°C, and it decomposed at this point. The results are the same as those in Figure 2.

[0089] Example 19 When the crystalline form C of rupatadine fumarate obtained in Example 1 was detected by thermogravimetric analysis (TGA), as shown in Figure 3, the melting point was about 200°C to 220°C, and it decomposed at this point.

[0090] When the crystalline form C of the ruptifene fumarate obtained in Examples 2 to 14 was detected by thermogravimetric analysis (TGA), the melting point was about 200°C to 220°C, and decomposition occurred at this point. The results were the same as those in Figure 3.

[0091] Example 20 When the crystalline form C of the ruptifene fumarate obtained in Example 1 was observed with a 100-fold microscope, its shape was spherical as shown in Figure 4.

[0092] When the crystalline form C of the ruptifene fumarate obtained in Examples 2 to 14 was observed with a 100-fold microscope, its shape was spherical, and the results were the same as those in Figure 4.

Claims

1. Crystal form C of rupatadine fumarate having characteristic peaks represented by 2θ degrees (±0.2°) of 12.3° ± 0.2°, 14.4° ± 0.2°, 17.6° ± 0.2°, and 22.4° ± 0.2° in a powder X-ray diffraction pattern using Cu-Kα line.

2. The powder X-ray diffraction pattern of the crystal form C using Cu-Kα line has characteristic peaks represented by 2θ degrees (±0.2°) of 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°, Preferably, the powder X-ray diffraction pattern of the crystal form C using Cu-Kα line has characteristic peaks represented by 2θ degrees (±0.2°) of 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°, Preferably, the powder X-ray diffraction pattern of the crystal form C represented by 2θ degrees (±0.2°) using Cu-Kα line is as shown in FIG. 1, Crystal form C according to claim 1.

3. Having a melting point of 204.0°C to 212.0°C, Preferably spherical under microscopic conditions, Crystal form C according to claim 1 or 2.

4. A method for preparing crystal form C of rupatadine fumarate according to any one of claims 1 to 3, Dissolving rupatadine free base and fumaric acid in solvent A, and reacting by stirring, heating, and refluxing until the solution becomes transparent, or dissolving crude rupatadine fumarate in solvent A, heating, stirring, and refluxing to prepare a saturated solution, then cooling to 2°C to 8°C, stirring to crystallize, filtering, washing with solvent A, and drying under reduced pressure to obtain crystal form C of rupatadine fumarate.

5. The method according to claim 4, wherein the solvent A is selected from an aqueous ethanol solution (mass ratio) having an ethanol concentration of 95% or more, absolute ethanol solution, ethyl acetate - acetone solution, dichloromethane - acetone solution, ether - methanol solution, cyclohexane - ethyl acetate solution, and other solvents for crystallization, and preferably an absolute ethanol solution.

6. The mass ratio of ethyl acetate to acetone in the ethyl acetate - acetone solution is 2:1 to 1:4 (w / w), Preferably, the mass ratio of dichloromethane to acetone in the dichloromethane - acetone solution is 1:1 to 1:10 (w / w), Preferably, the mass ratio of ether to methanol in the ether - methanol solution is 1:1 to 1:5 (w / w), Preferably, the mass ratio of cyclohexane to ethyl acetate in the cyclohexane - ethyl acetate solution is 1:1 to 1:10 (w / w). The method according to claim 5.

7. The mass ratio of the rupatadine free base to the fumaric acid is 4:1 to 1:2, Preferably, the temperature at which stirring, heating, and refluxing are performed until the solution becomes transparent is 30°C to 90°C, preferably 70°C. The method according to any one of claims 4 to 6.

8. The cooling is natural cooling, gradient cooling, or rapid cooling, When the temperature at which the solution becomes transparent is higher than 40°C, the procedure for gradient cooling is to 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 at that temperature for 2 hours; cool to 5 ± 3°C at a rate of 7.5 ± 2.5°C / h and hold at that temperature for 2 hours, When the temperature at which the solution becomes transparent is lower than 40°C, the procedure for gradient cooling is to cool to 15°C at a rate of 7.5 ± 2.5°C / h and hold at that temperature for 2 hours; cool to 5 ± 3°C at a rate of 7.5 ± 2.5°C / h and hold at that temperature for 2 hours. The method according to any one of claims 4 to 7.

9. The method according to any one of claims 4 to 8, wherein the speed of the stirring for crystallization is 50 rpm to 200 rpm, preferably 90 rpm to 110 rpm.

10. The method according to any one of claims 4 to 9, wherein the mass-to-volume ratio of the rupatadine free base to the solvent A or the crude rupatadine fumarate to the solvent A is 2:1 to 1:30, preferably 1:15 to 17.

5.

11. A pharmaceutical composition comprising a therapeutically effective amount of crystalline form C according to any one of claims 1 to 3 and an optional pharmaceutically acceptable carrier or excipient.

12. Use of crystalline form C according to any one of claims 1 to 3 in the preparation of a medicament for the treatment of allergic diseases or disorders, preferably, the allergic diseases or disorders include allergy, drug hypersensitivity, skin allergy, eczema, allergic rhinitis, urticaria, atopic dermatitis, dry eye, allergic contact allergy, food allergy, allergic conjunctivitis, insect venom allergy, bronchial asthma, allergic asthma, intrinsic asthma, occupational asthma, ectopic asthma, acute respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD).

13. A method for treating allergic diseases or disorders, comprising administering the crystalline form C according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 11 to a patient in need thereof, preferably, the allergic diseases or disorders include allergy, drug hypersensitivity, skin allergy, eczema, allergic rhinitis, urticaria, atopic dermatitis, dry eye, allergic contact allergy, food allergy, allergic conjunctivitis, insect venom allergy, bronchial asthma, allergic asthma, intrinsic asthma, occupational asthma, ectopic asthma, acute respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD).

Images