Hydrated compound and preparation method thereof

Abstract

The invention provides a hydrated compound and a preparation method thereof, and relates to the technical field of compound preparation. The hydrated compound is rupatinifen fumarate monohydrate and has a crystal structure. The preparation method of the hydrated compound comprises the following steps: adding rupatinifen fumarate into a reaction solvent at least containing a first organic solvent, heating, stirring and refluxing until the rupatinifen fumarate is completely dissolved, the concentration of the rupatinifen fumarate in a reaction system is not lower than 70% of the concentration of a saturated solution of the rupatinifen fumarate in the reaction system, and carrying out solid-liquid separation to obtain the hydrated compound. And continuously refluxing for 1 min to 24 h, cooling to the temperature not exceeding 8 DEG C, crystallizing, collecting crystals, washing and drying to obtain the product.

Description

Technical Field

[0001] The invention belongs to the technical field of compound preparation and relates to a hydrate compound and a preparation method thereof. Background Art

[0002] Rupatifene fumarate, chemically named 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, is a new type of multi-pathway antiallergic drug. According to the disclosed technology, rupatifene fumarate has multiple crystal structures such as crystal form A, crystal form B, mixed crystal, and crystal form C. Different crystal forms of the same drug may have significant differences in physical and chemical properties such as melting point, density, stability, and solubility, and further affect the stability, bioavailability, efficacy, and product quality of the drug. For example, rupatifene fumarate crystal form A, crystal form B, and mixed crystal are inferior to rupatifene fumarate crystal form C in terms of yield, residual solvent, and moisture content. Therefore, in the process of drug development, screening the most suitable and most effective crystal form is an important task that cannot be ignored. The currently disclosed different crystal structures of rupatifene fumarate have deficiencies such as insufficient stability, high residual moisture, low melting point, pressure sensitivity, and fluidity deviation, and the residual organic solvent in the preparation process is too much, which affects the safety of use and is not conducive to commercial production. Crystal form C has the advantages of low residual solvent, less moisture, and higher purity, and the preparation method is simple and easy to industrialize. It is an advantageous crystal form suitable for preparation. However, crystal form C still has the deficiency of being sensitive to pressure, and the long-term stability after being prepared into oral tablets is poor. Therefore, further improvement is still needed. Summary of the invention

[0003] An object of the present invention is to provide a hydrated compound.

[0004] Another object of the present invention is to provide a method for preparing the hydrated compound.

[0005] The technical solution of the present invention is as follows:

[0006] A hydrated compound, wherein the hydrated compound is rupatifene fumarate monohydrate, having a structure as shown in the following formula (1):

[0007]

[0008] Preferably, the hydrated compound is a crystalline compound.

[0009] More preferably, the crystalline compound is irradiated with Cu-Kα rays, and X-ray powder diffraction is represented by 2θ, and there are characteristic peaks at 5.5°±0.2°, 7.0°±0.2°, 8.5°±0.2°, 9.8°±0.2°, 10.5°±0.2°, 12.1°±0.2°, 14.2°±0.2°, 16.0°±0.2°, 17.4°±0.2°, 19.5°±0.2°, 21.0°±0.2°, 22.2°±0.2°, 23.0°±0.2°, and 24.0°±0.2°.

[0010] More preferably, the crystalline compound belongs to the monoclinic system, P2(1) / c space group.

[0011] Further preferably, the unit cell parameters of the crystalline compound are α=90°,β=96°,γ=90°,the unit cell volume is

[0012] Preferably, the melting point of the hydrated compound is 171±2°C.

[0013] A method for preparing a hydrated compound according to any of the above embodiments, comprising adding rupatifen fumarate to a reaction solvent comprising at least a first organic solvent, heating, stirring and refluxing until the rupatifen fumarate is completely dissolved, the concentration of the rupatifen fumarate in the reaction system is not less than 70% of the concentration of a saturated solution of the rupatifen fumarate in the reaction system, continuing to reflux for 1 min-24 h, cooling to no more than 8° C. and crystallizing, collecting the crystals, washing, and drying to obtain the hydrated compound.

[0014] Preferably, the first organic solvent contains at least a second organic solvent soluble in water, and preferably, the second organic solvent is selected from one or a combination of two or more of isopropanol, ethanol, acetone, methanol, tetrahydrofuran, DMF, DMAc and DMSO.

[0015] More preferably, the first organic solvent further comprises a third organic solvent that is insoluble or slightly soluble in water. Preferably, the third organic solvent is selected from one or a combination of two or more of 1,2-dichloroethane, dichloromethane, chloroform, carbon tetrachloride, 1,1-dichloroethane, cyclohexane, n-hexane and petroleum ether.

[0016] Preferably, the reaction solvent further comprises an inorganic alkali aqueous solution, and preferably, the inorganic alkali aqueous solution is a NaOH aqueous solution.

[0017] More preferably, the pH of the inorganic base aqueous solution does not exceed 9.0, preferably, the pH is 7.5-8.5.

[0018] More preferably, the weight ratio of the first organic solvent to the inorganic alkali aqueous solution is 1:0.5-3.

[0019] Preferably, the weight ratio of the rupatifene fumarate to the reaction solvent is 1:10-30.

[0020] Preferably, the washing is performed using the reaction solvent.

[0021] The beneficial effects of the present invention are as follows: the rupatifene fumarate monohydrate provided by the present invention is a crystalline compound, which has better stability, water solubility and fluidity than the publicly reported rupatifene fumarate crystal form A, rupatifene fumarate crystal form B, rupatifene fumarate mixed crystal, rupatifene fumarate crystal form C, etc., and has low sensitivity to pressing pressure, thereby reducing the requirements for the preparation technology process, and the preparation prepared therefrom has better dissolution performance and bioavailability, and the selectivity of the preparation dosage form is higher. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 This is the XRD pattern of rupatifene fumarate monohydrate obtained in Example 1.

[0023] Figure 2 The differential scanning calorimetry diagram of rupatifene fumarate monohydrate obtained in Example 1 is shown in FIG.

[0024] Figure 3 This is the thermogravimetric analysis chart of rupatifene fumarate monohydrate obtained in Example 1.

[0025] Figure 4 This is a microscope image of rupatifene fumarate monohydrate obtained in Example 1. DETAILED DESCRIPTION

[0026] The technical solution of the present invention is further illustrated and described below through specific implementation methods.

[0027] In order to improve the stability, water solubility and fluidity of rupatifen fumarate, reduce the sensitivity to pressing pressure and the content of organic solvents, etc., the present invention provides a hydrated compound, which is rupatifen fumarate monohydrate, having a structure shown in the following formula (1):

[0028]

[0030] The present invention finds that, compared with existing rupatifen fumarate crystal form A, crystal form B, mixed crystal, crystal form C and other structures, rupatifen fumarate monohydrate has better stability, water solubility and fluidity, lower pressure sensitivity, lower organic solvent content, suitable melting point, etc., is more conducive to various formulations and processing techniques, and has better dissolution performance and bioavailability.

[0031] In some embodiments, the hydrated compound is a crystalline compound.

[0032] More preferably, the crystalline compound is irradiated with Cu-Kα rays, and X-ray powder diffraction is represented by 2θ, with characteristic peaks at 5.5°±0.2°, 7.0°±0.2°, 8.5°±0.2°, 9.8°±0.2°, 10.5°±0.2°, 12.1°±0.2°, 14.2°±0.2°, 16.0°±0.2°, 17.4°±0.2°, 19.5°±0.2°, 21.0°±0.2°, 22.2°±0.2°, 23.0°±0.2°, and 24.0°±0.2°.

[0033] More preferably, the crystalline compound belongs to the monoclinic system, P2(1) / c space group.

[0034] Further preferably, the unit cell parameters of the crystalline compound are α=90°,β=96°,γ=90°,the unit cell volume is For example, the unit cell parameters can be α=90°,β=96°,γ=90°,the unit cell volume can be

[0035] In some embodiments, the melting point of the hydrated compounds of the present invention is 171 ± 2 °C.

[0036] On the other hand, the present invention provides a method for preparing the hydrated compound described in any of the above embodiments, comprising adding rupatifene fumarate to a reaction solvent comprising at least a first organic solvent, heating, stirring and refluxing until the rupatifene fumarate is completely dissolved, the concentration of rupatifene fumarate in the reaction system is not less than 70% of the concentration of a saturated solution of rupatifene fumarate in the reaction system, continuing to reflux for 1 min-24 h, cooling to no more than 8° C. and crystallizing, collecting the crystals, washing, and drying to obtain the hydrated compound of the present invention.

[0037] The present invention adopts rupatifen fumarate for recrystallization, and by adjusting the concentration of rupatifen fumarate in the reaction system, the rupatifen fumarate in the reaction system is in a supersaturated state after cooling and gradually crystallizes and precipitates, and rupatifen fumarate monohydrate crystals can be directly obtained, and the operation process is simple. For example, the concentration of rupatifen fumarate in the reaction system under heating, stirring and reflux can be any value of 70%, 72%, 75%, 78%, 80%, 82%, 84%, 85%, 87%, 88%, 90%, 92%, 95%, 96%, 98%, 99%, 100% of the saturated solution concentration of rupatifen fumarate in the reaction system at the temperature and in the reaction system, without special restrictions. The concentration of rupatifene fumarate in the reaction system under heating, stirring and reflux has no effect on obtaining rupatifene fumarate monohydrate crystals, but will affect the yield of rupatifene fumarate monohydrate crystals. Generally, the higher the concentration of rupatifene fumarate in the reaction system under heating, stirring and reflux, the higher the yield of rupatifene fumarate monohydrate crystals.

[0038] In the present invention, the source of rupatifen fumarate is not particularly limited, and it can be prepared according to the prior art or according to the following method: 1.0 g of rupatifen free base and 0.29 g of fumaric acid are dissolved in 15 ml of anhydrous ethanol, heated to 70-80° C. and refluxed under stirring, anhydrous ethanol is continuously added dropwise until the sample is completely dissolved and a saturated solution is prepared, the reaction is carried out for 1 hour, the temperature is reduced to 40° C. at a rate of 15±5° C. / h, the temperature is then reduced to 15° C. at a rate of 7.5±2.5° C. / h and kept warm for 2 hours, and finally the temperature is reduced to 5±3° C. at a rate of 7.5±2.5° C. / h and kept warm for 2 hours, spherical crystals are precipitated, and then washed with an anhydrous ethanol solution of 2° C.-8° C., and dried under reduced pressure at 60° C. to obtain rupatifen fumarate.

[0039] In the above-mentioned method for preparing rupatifene fumarate monohydrate, the heating temperature for heating and stirring may be 70-90°C, or further, the heating temperature may be 85-90°C.

[0040] In the above preparation method, there is no particular limitation on cooling, and it can be natural cooling, gradient cooling or rapid cooling, etc., preferably gradient cooling. When the temperature is high, the cooling rate is faster, and when the temperature is low, the cooling rate is slower. For example, first cool to 40°C at a cooling rate of 15±5°C / h, then cool to 20°C at a cooling rate of 7.5±2.5°C / h and keep warm for 0.5-5h, and finally cool to no more than 8°C (such as 4°C, 5°C, 7°C, etc.) at a cooling rate of 7.5±2.5°C / h and keep warm until spherical crystals precipitate.

[0041] In some embodiments, the first organic solvent comprises at least a second organic solvent soluble in water. For example, the second organic solvent can be selected from one or a combination of two or more of isopropanol, ethanol, acetone, methanol, tetrahydrofuran, DMF, DMAc and DMSO. More preferably, the second organic solvent is isopropanol or ethanol.

[0042] More preferably, the first organic solvent further comprises a third organic solvent that is insoluble in water or slightly soluble in water. The reaction solvent contains a second organic solvent that is soluble in water and a third organic solvent that is insoluble in water or slightly soluble in water, which can further improve the recrystallization effect of rupatifen fumarate monohydrate and is beneficial to the precipitation and crystallization of rupatifen fumarate monohydrate. For example, the third organic solvent can be selected from one or a combination of two or more of 1,2-dichloroethane, dichloromethane, chloroform, carbon tetrachloride, 1,1-dichloroethane, cyclohexane, n-hexane and petroleum ether. There is no particular limitation on the weight ratio of the second organic solvent to the third organic solvent, and for example, it can be 10-1:1.

[0043] In some embodiments, the reaction solvent further comprises an aqueous solution of an inorganic base. Under alkaline conditions, the solubility of rupatifen fumarate in the reaction system will decrease, which can increase the yield of rupatifen fumarate monohydrate during cooling and crystallization. For example, the aqueous solution of an inorganic base can be an aqueous solution of sodium carbonate, an aqueous solution of KaOH, an aqueous solution of NaOH, etc., preferably an aqueous solution of NaOH.

[0044] Too high a pH of the aqueous solution of an inorganic base may cause the decomposition of rupatifen fumarate and affect the yield of rupatifen fumarate monohydrate. More preferably, the pH of the aqueous solution of an inorganic base does not exceed 9.0, for example, the pH value may be 7.2, 7.5, 7.8, 8.0, 8.2, 8.5, 8.8, 9.0, etc. Further, the pH is 7.5-8.5.

[0045] More preferably, the weight ratio of the first organic solvent to the inorganic alkali aqueous solution is 1:0.5-3. For example, the weight ratio can be any value of 1:0.5, 1:0.8, 1:1, 1:1.2, 1:1.5, 1:1.8, 1:2, 1:2.2, 1:2.3, 1:2.5, 1:2.7, 1:2.8, 1:3, etc., without special restrictions. Further, the weight ratio of the first organic solvent to the inorganic alkali aqueous solution can be 1:0.8-1.5.

[0046] In some embodiments, the weight ratio of rupatifene fumarate to the reaction solvent is 1:10-30. For example, the weight ratio can be any value of 1:10, 1:12, 1:15, 1:17, 1:18, 1:20, 1:22, 1:23, 1:25, 1:27, 1:28, 1:30, etc., without particular limitation. Preferably, the weight ratio of crude rupatifene fumarate to the reaction solvent can be 1:15-25.

[0047] In some embodiments, washing is performed using a reaction solvent, or an organic solvent such as isopropanol, ethanol, or dichloroethane. In order to avoid the effect of the temperature of the reaction solvent or other detergent on crystallization, the temperature of the reaction solvent or other detergent used in washing can be the temperature of crystallization (e.g., 4° C., 5° C., 7° C., etc.). Drying can be performed at 45-65° C. and negative pressure.

[0048] The technical solution of the present invention is further described and illustrated according to various embodiments below.

[0049] Example 1

[0050] 1.5 g of rupatifen fumarate was added to a reaction solvent composed of isopropanol and a sodium hydroxide aqueous solution with a weight ratio of 1:1, heated to 85-88°C, stirred and refluxed to dissolve and prepare a saturated solution of rupatifen fumarate, and continued to reflux for 1 hour. A gradient cooling method was used, first cooling to 40°C at a cooling rate of 15°C / h, then cooling to 20°C at a cooling rate of 7.5°C / h and keeping warm for 2 hours, and finally cooling to 5°C at a cooling rate of 7.5°C / h and keeping warm until spherical crystals were precipitated. The crystals were collected, washed with the above reaction solvent at 5°C, and dried in a vacuum oven at 55°C for 12 hours to obtain crystalline rupatifen fumarate monohydrate, with a yield of 91%.

[0051] X-ray diffraction, using Cu-Kα rays as the X-ray source for testing, set the ω / 2θ scanning mode, the results are shown in the attached Figure 1 As shown, the characteristic peaks of rupatifene fumarate monohydrate include 5.5°±0.2°, 7.0°±0.2°, 8.5°±0.2°, 9.8°±0.2°, 10.5°±0.2°, 12.1°±0.2°, 14.2°±0.2°, 16.0°±0.2°, 17.4°±0.2°, 19.5°±0.2°, 21.0°±0.2°, 22.2°±0.2°, 23.0°±0.2°, and 24.0°±0.2°. The product rupatifene fumarate monohydrate belongs to the monoclinic system, P2(1) / c space group, and the unit cell parameters are α=90°,β=96°,γ=90°,the unit cell volume is

[0052] The differential scanning calorimetry (DSC) analysis results of rupatifene fumarate monohydrate are shown in the attached figure. Figure 2 The results of thermogravimetric analysis (TGA) are shown in the attached Figure 3 As shown. Figure 2 and attached Figure 3 It can be seen that the product contains only one crystal water in its structure, so the crystalline product obtained in the present invention is rupatifene fumarate monohydrate.

[0053] The microscopic image of the crystalline structure of the product rupatifen fumarate monohydrate is shown in the attached figure. Figure 4 shown.

[0054] Example 2

[0055] The difference between this example and Example 1 is that in Example 1, the isopropanol in the reaction solvent is replaced by an equal weight of anhydrous ethanol, and the other steps remain unchanged. The yield of the crystallized rupatifen fumarate monohydrate was measured to be 72%.

[0056] Example 3

[0057] The difference between this example and Example 2 is that in Example 2, the anhydrous ethanol in the reaction solvent is replaced by an equal weight of an organic solvent consisting of anhydrous ethanol and chloroform in a weight ratio of 5:1, and the other steps remain unchanged. The yield of the crystallized rupatifen fumarate monohydrate was measured to be 77%.

[0058] Example 4

[0059] 1.5 g of rupatifen fumarate was added to a reaction solvent consisting of isopropanol and a pH 8.0 sodium hydroxide aqueous solution in a weight ratio of 2:1, heated to 85-88° C., stirred and refluxed to dissolve and make the concentration of rupatifen fumarate 80% of the concentration of the saturated solution of rupatifen fumarate, continued to reflux for 1 hour, naturally cooled to 20° C. and kept warm for 2 hours, and finally cooled to 5° C. at a cooling rate of 5° C. / h and kept warm until spherical crystals precipitated. The crystals were collected, washed with 5° C. anhydrous ethanol, and dried in a vacuum oven at 55° C. for 12 hours to obtain crystalline rupatifen fumarate monohydrate, with a yield of 84%.

[0060] Example 5

[0061] The difference between this embodiment and embodiment 4 is that the reaction solvent in embodiment 3 is adjusted to be composed of isopropanol and pH 8.0 sodium hydroxide aqueous solution in a weight ratio of 1:2. The remaining steps remain unchanged. The yield of rupatifen fumarate monohydrate is measured to be 79%.

[0062] Example 6

[0063] The difference between this embodiment and embodiment 4 is that the concentration of rupatifene fumarate in embodiment 3 is adjusted to 92% of the concentration of rupatifene fumarate saturated solution. The other steps remain unchanged. The yield of rupatifene fumarate monohydrate is measured to be 88%.

[0064] Example 7

[0065] The difference between this embodiment and embodiment 4 is that the concentration of rupatifene fumarate in embodiment 3 is adjusted to 70% of the concentration of rupatifene fumarate saturated solution. The other steps remain unchanged. The yield of rupatifene fumarate monohydrate is measured to be 73%.

[0066] Performance Testing

[0067] 1. Comparison of organic solvent residues

[0068] The rupatifene fumarate monohydrate obtained in Example 1 was compared with rupatifene fumarate crystal form A, crystal form B, crystal form C, and mixed crystal. Among them, crystal form A was prepared according to Example 1 of Chinese patent CN104045633A, crystal form B was prepared according to Example 1 of Chinese patent CN104059056A, crystal form C was prepared according to Example 1 of CN117263923A, and mixed crystal was prepared according to Example 1 of Chinese patent CN104031035A. The drying of the crystals was carried out as follows: 2 g of the crystals after crystallization were placed in an oven at 55°C and dried under vacuum (-0.099MPa) for 12 hours.

[0069] Organic solvent residue test method:

[0070] Test solution: Accurately weigh the sample powder to be tested, add appropriate amount of DMF to dissolve and dilute to make a solution with a concentration of 50 mg / mL.

[0071] Reference solution: Accurately weigh appropriate amounts of methanol, n-pentane, isopropanol, ethanol, dichloromethane and ethyl acetate, add DMF to quantitatively dilute to make a mixed solution containing 150μg methanol, 250μg n-pentane, 300μg isopropanol, 500μg ethanol, 30μg dichloromethane and 250μg ethyl acetate per 1ml. Use a capillary column with 6% cyanopropylphenyl-94% dimethylpolysiloxane as the stationary liquid as the chromatographic column, the starting temperature is 30℃, maintained for 4 minutes, and the temperature is increased to 130℃ at a rate of 20℃ per minute, and maintained for 3.5 minutes; the injection port temperature is 200℃, the detector temperature is 250℃; the injection volume is 1μl; in the chromatogram of the reference solution, the separation between the peaks of each component should be greater than 1.5. Accurately measure the test solution and the reference solution, inject them into the gas chromatograph respectively, and record the chromatogram. According to the peak area, calculate the residual amount of different solvents, and the results are shown in Table 1 below.

[0072] Table 1 Residual organic solvents of different crystal forms

[0073]

[0074] From the data results in Table 1 above, it can be seen that the rupatifene fumarate monohydrate of the present invention has lower organic solvent residues than rupatifene fumarate crystal form A, crystal form B, crystal form C, and mixed crystal, which can improve the safety of the drug. Among them, the acetone detected in the crystal form B originates from the preparation process of rupatifene free base and is a residue of the previous step.

[0075] 2. Comparison of physical and chemical properties

[0076] 1. Melting point determination: The melting point of each sample to be tested is determined by the capillary method. The specific steps are as follows: Grind the different samples to be tested into fine powders, put the powders into the capillary, tap the tube wall to make the powders gather tightly, and the sample height is about 3mm. Set the temperature to 150℃, first increase the temperature by 3℃ per minute, and change the temperature to 1℃ per minute when the temperature reaches 164℃. Record the temperature from the initial melting to the complete melting of the sample, repeat three times, and take the average value. The results are shown in Table 2.

[0077] 2. Determination of moisture content: The Fischer method is used to determine the moisture content of the crystal form. The specific steps are as follows: Grind different samples to be tested into fine powders for later use. Blank calibration calibrates the moisture meter to anhydrous state. Accurately weigh 10 mg of purified water, calibrate with the moisture meter, and calculate the titer. Then accurately weigh an appropriate amount of test sample powder (consume about 1 ml of commercially available Fischer test solution), directly measure with the moisture meter, calculate the moisture content in the test sample powder, repeat three times, and take the average value. The results are shown in Table 2.

[0078] 3. Angle of repose measurement: The angle of repose is determined by the fixed cone bottom method. The specific steps are as follows: Fix the funnel on the horizontal coordinate paper, adjust the height of the funnel so that the distance between the bottom of the funnel and the coordinate paper is H. Let the powder flow down the funnel to form a cone until the tip of the cone just touches the funnel outlet. According to the formula tan(θ) = cone height H / bottom radius, calculate the angle of repose θ. The results are shown in Table 2. Flowability judgment standard: When the angle of repose <30°, the flowability is good; when the angle of repose >40°, the flowability is poor.

[0079] Table 2 Physicochemical properties of different crystal forms

[0080] Crystal form Melting point Moisture content Angle of repose Liquidity Crystalline Form A 152-156℃ 3.12％ 47° Difference Crystalline Form B 184-188℃ 2.57％ 50° Difference Crystalline Form C 204-212℃ 0.54％ 28° good mixed crystal 152-156℃ 2.68％ 49° Difference Example 1 169-173℃ 0.36% (excluding crystal water) 22° good

[0081] 3. Stability comparison

[0082] Since the rupatifen fumarate crystal form A, crystal form B and mixed crystal are inferior to the rupatifen fumarate crystal form C in terms of yield, residual solvent, moisture content and other indicators, the following comparison uses crystal form C as a comparison.

[0083] The stability of rupatifene fumarate monohydrate and rupatifene fumarate crystal form C of test example 1 under high temperature, high humidity, strong light and pressure conditions is compared. The specific test method is as follows: appropriate amounts of rupatifene fumarate monohydrate powder and crystal form C powder are placed in a closed container and dispersed in a loose state with a paving thickness not exceeding 3 mm. Separately take 100 mg of rupatifene fumarate monohydrate powder and crystal form C powder, place them on a tablet press and use a force of 3 kg to directly press them into tablets, and place them in a closed container. The loose and tablet samples of rupatifene fumarate monohydrate and rupatifene fumarate crystal form C are placed in high temperature (60°C), high humidity (25°C, RH90%±5%) and strong light (total illumination 1.2×10 6 Lux / hr, near ultraviolet energy 200w·hr / m 2 ) conditions, sampled at specific time points, observed the properties of rupatifen fumarate monohydrate and crystal form C, and further determined the content of related substances. The content of related substances is the total impurity content, which can be detected according to the detection method described in CN107021954A. The results are shown in Table 3.

[0084] Table 3 Stability comparison

[0085]

[0086]

[0087] Therefore, compared with the crystal form C, the rupatifene fumarate monohydrate of the present invention has better stability, and the powdered and flaky raw materials have good stability under high temperature, high humidity and strong light conditions, the appearance and shape are intact, and there is no obvious growth of impurities, and the sensitivity to pressure is significantly reduced.

[0088] 4. Performance comparison of preparations

[0089] Tablets and capsules of rupatifene fumarate monohydrate and crystal form C were prepared respectively. The specific preparation steps are as follows: weigh 1.29 mg of rupatifene fumarate monohydrate or crystal form C powder, 96.2 mg of microcrystalline cellulose as an excipient, 0.5 mg of magnesium stearate as a lubricant, and 2.0 mg of talcum powder as a glidant. The raw material and various excipients are respectively passed through a No. 3 standard sieve for use. The crystals to be tested are premixed with the lubricant for 3 minutes and then sieved, and then added to a three-dimensional mixer for mixing to obtain premix powder 1. Magnesium stearate and 10 times the amount of microcrystalline cellulose are also mixed to obtain premix powder 2. The remaining microcrystalline cellulose is mixed with premix powder 1 and premix powder 2 by an equal amount stepwise method. The mixed powder is directly pressed into tablets by a tablet press or filled into a gelatin capsule shell to prepare capsules.

[0090] 1. Stability comparison

[0091] Tablets and capsules were tested according to the above stability comparison test method, and the results are shown in Table 4 below.

[0092] Table 4 Comparison of formulation stability

[0093]

[0094]

[0095] Therefore, tablets and capsules made from rupatifen fumarate monohydrate are relatively stable when stored under high temperature, high humidity and strong light for 30 days, and the impurity content changes little; while tablets and capsules made from crystalline form C show an increase in impurity content when stored under high temperature and high humidity conditions for 30 days. This is because rupatifen fumarate monohydrate has a lower sensitivity to pressure and therefore has higher formulation stability.

[0096] 2. Comparison of dissolution performance

[0097] The dissolution performance test method for tablets and capsules is as follows: the sample to be tested is placed in a sinker basket and the dissolution rate is determined by the paddle method. The dissolution medium is a pH = 1.2 phosphate solution with a volume of 900 mL and a speed of 75 rpm. Samples are taken at specific time points, the compound content in the sample solution is determined, and the dissolved content (%) is calculated. The results are shown in Table 5 below.

[0098] Table 5 Dissolution performance comparison / %

[0099]

[0100] Therefore, tablets and capsules made from rupatifene fumarate monohydrate have better dissolution performance and are dissolved faster than tablets and capsules made from crystalline form C.

[0101] 3. Bioavailability

[0102] (1) Test sample: tablets and capsules of the above-mentioned rupatifene fumarate monohydrate or crystal form C.

[0103] (2) Experimental animals and groups: Male beagle dogs, weighing 8-10 kg, were randomly divided into 2 groups, 3 in each group.

[0104] (3) Dosage method: Each group of dogs was fed 1 tablet (grain) of the test article 12 hours after eating.

[0105] (4) Collection and processing of plasma samples: 4 mL of blood was collected from the forelimb vein before administration and 5 min, 10 min, 20 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 10 h, 24 h, and 48 h after administration. The blood was anticoagulated with 1% heparin, centrifuged at 800 × g for 10 min, and the plasma was separated and stored at -80°C for testing.

[0106] (5) Content determination: Plasma samples at different time points were taken into centrifuge tubes, 200 μL of acetonitrile solution was added, vortexed for 60 seconds, centrifuged at 1500×g for 10 minutes at 4°C, and 20 μL of the supernatant was injected. The concentration of rupatifene fumarate was determined and calculated by liquid chromatography, and a time-blood drug concentration curve was drawn. The results are shown in Tables 6 and 7 below.

[0107] Table 6 Plasma concentration of rupatifene fumarate preparations (unit: ng / mL)

[0108]

[0109]

[0110] Table 7 Pharmacokinetic parameters

[0111]

[0112] Therefore, compared with the crystalline form C, the tablets and capsules made of rupatifene fumarate monohydrate as the raw material have higher solubility and dissolution efficiency, faster initial release in animals, and higher bioavailability in animals because of the higher solubility and dissolution efficiency of the monohydrate.

[0113] As described above, the basic principles, main features and advantages of the present invention are shown and described. Those skilled in the art should understand that the present invention is not limited by the above embodiments, which are only preferred embodiments of the present invention and cannot be used to limit the scope of the present invention. That is, equivalent changes and modifications made according to the scope of the present invention and the content of the specification should still be within the scope of the present invention. The scope of protection required by the present invention is defined by the attached claims and their equivalents.

Claims

1. A hydrated compound, characterized in that The hydrated compound is rupatifene fumarate monohydrate, having a structure as shown in the following formula (1):

2. The hydrated compound according to claim 1, characterized in that The hydrated compound is a crystalline compound.

3. The hydrated compound according to claim 2, characterized in that The crystalline compound is irradiated with Cu-Kα rays, and X-ray powder diffraction is represented by 2θ, with characteristic peaks at 5.5°±0.2°, 7.0°±0.2°, 8.5°±0.2°, 9.8°±0.2°, 10.5°±0.2°, 12.1°±0.2°, 14.2°±0.2°, 16.0°±0.2°, 17.4°±0.2°, 19.5°±0.2°, 21.0°±0.2°, 22.2°±0.2°, 23.0°±0.2°, and 24.0°±0.2°.

4. The hydrated compound according to claim 2, characterized in that The crystalline compound belongs to the monoclinic system, P2(1) / c space group.

5. The hydrated compound according to claim 4, characterized in that The unit cell parameters of the crystalline compound are α=90°,β=96°,γ=90°,the unit cell volume is 6. The hydrated compound according to claim 1, characterized in that The melting point of the hydrated compound is 171±2°C.

7. A method for preparing a hydrated compound according to any one of claims 1 to 6, characterized in that: Add rupatifene fumarate to a reaction solvent containing at least a first organic solvent, heat, stir and reflux until the rupatifene fumarate is completely dissolved, and the concentration of the rupatifene fumarate in the reaction system is not less than 70% of the concentration of the saturated solution of the rupatifene fumarate in the reaction system, continue to reflux for 1 min-24 h, cool to no more than 8° C. and crystallize, collect the crystals, wash and dry to obtain the hydrated compound.

8. The method for preparing a hydrated compound according to claim 7, characterized in that: The first organic solvent at least comprises a second organic solvent soluble in water. Preferably, the second organic solvent is selected from one or a combination of two or more of isopropanol, ethanol, acetone, methanol, tetrahydrofuran, DMF, DMAc and DMSO.

9. The method for preparing a hydrated compound according to claim 8, characterized in that: The first organic solvent further comprises a third organic solvent that is insoluble or slightly soluble in water. Preferably, the third organic solvent is selected from one or a combination of two or more of 1,2-dichloroethane, dichloromethane, chloroform, carbon tetrachloride, 1,1-dichloroethane, cyclohexane, n-hexane and petroleum ether.

10. The method for preparing a hydrated compound according to claim 7, characterized in that: The reaction solvent further comprises an inorganic alkali aqueous solution, and preferably, the inorganic alkali aqueous solution is a NaOH aqueous solution.

11. The method for preparing a hydrated compound according to claim 10, characterized in that: The pH of the inorganic alkali aqueous solution does not exceed 9.0, preferably, the pH is 7.5-8.

5.

12. The method for preparing a hydrated compound according to claim 10, characterized in that: The weight ratio of the first organic solvent to the inorganic alkali aqueous solution is 1:0.5-3.

13. The method for preparing a hydrated compound according to claim 7, characterized in that: The weight ratio of the rupatifene fumarate to the reaction solvent is 1:10-30.

14. The method for preparing a hydrated compound according to claim 7, characterized in that: The washing is performed by using the reaction solvent.

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