A hydrated compound and a method for preparing the same

Abstract

The application provides a hydrated compound and a preparation method thereof, and relates to the technical field of compound preparation. The hydrated compound is fumaric acid rupatadine monohydrate, which has a crystal structure. The preparation method of the hydrated compound is as follows: fumaric acid rupatadine is added into a reaction solvent containing at least a first organic solvent, heated, stirred and refluxed until the fumaric acid rupatadine is completely dissolved, the concentration of the fumaric acid rupatadine in the reaction system is not less than 70% of the saturated solution concentration of the fumaric acid rupatadine in the reaction system, the refluxing is continued for 1 min to 24 h, the temperature is lowered to not more than 8 DEG C and crystallization is performed, the crystals are collected, washed and dried, and the hydrated compound is obtained.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of compound preparation and relates to a hydrated compound and a preparation method thereof. BACKGROUND

[0002] Fumic acid rupatadine, the chemical name of which is 4-[1-[(5-methylpyridin-3-yl)methyl]piperidyl-4-yl]-4,9-dihydro-10H-benzo[4,5]cyclohepta[1,2-b]thiophen-10-ketone fumarate, is a new type of multi-channel antiallergic drug. According to the published technology, fumic acid rupatadine 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, the yield, solvent residue and moisture content of fumic acid rupatadine crystal form A, crystal form B and mixed crystal are worse than those of fumic acid rupatadine crystal form C. Therefore, in the process of drug research and development, screening the most suitable and best crystal form is an important work that cannot be ignored. The currently published fumic acid rupatadine with different crystal structures has the disadvantages of insufficient stability, high residual moisture, low melting point, sensitivity to pressure and poor flowability, and has more residual organic solvents in the preparation process, which affects the safety of use and is not conducive to commercial production. Crystal form C has the advantages of low solvent residue, less moisture and higher purity, and the preparation method is simple and easy to realize industrialization, which is an advantageous crystal form suitable for preparation of preparations. However, crystal form C still has the disadvantage of sensitivity to pressure, and the long-term stability of the oral tablet prepared therefrom is poor. Therefore, further improvement is still needed. SUMMARY

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

[0004] Another object of the present application is to provide a preparation method of the hydrated compound.

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

[0006] A hydrated compound, which is fumic acid rupatadine monohydrate, has the structure shown in the following formula (1),

[0007]

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

[0009] More preferably, the crystalline compound has characteristic peaks in X-ray powder diffraction, using Cu-Ka radiation, expressed in 2-theta, 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°, 24.0°±0.2°.

[0010] More preferably, the crystalline compound belongs to 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°, and the unit cell volume is

[0012] Preferably, the melting point of the hydrate compound is 171±2℃.

[0013] A method for preparing the hydrate compound according to any one of the preceding embodiments, wherein fumaric acid of rubipafant is added into a reaction solvent comprising at least a first organic solvent, heated and stirred to reflux until the fumaric acid of rubipafant is completely dissolved, the concentration of the fumaric acid of rubipafant in the reaction system is not less than 70% of the saturated solution concentration of the fumaric acid of rubipafant in the reaction system, the refluxing is continued for 1 min-24 h, the temperature is lowered to not more than 8℃ and the crystals are precipitated, the crystals are collected, washed and dried, thereby obtaining the hydrate compound.

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

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

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

[0017] More preferably, the pH of the aqueous inorganic base is not more than 9.0, and preferably the pH is 7.5-8.5.

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

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

[0020] Preferably, the washing is washing with the reaction solvent.

[0021] The fumarate lupatifin monohydrate provided by the present application is a crystalline compound, has better stability, water solubility and flowability than the fumarate lupatifin crystal form A, the fumarate lupatifin crystal form B, the fumarate lupatifin mixed crystal, the fumarate lupatifin crystal form C and the like which have been reported, is less sensitive to the pressing pressure, thereby reducing the requirement for the preparation technology process, the preparation prepared therefrom has better dissolution performance and bioavailability, and the preparation dosage form has higher selectivity. BRIEF DESCRIPTION OF DRAWINGS

[0022] Figure 1 The XRD pattern of the fumarate lupatifin monohydrate obtained in Example 1.

[0023] Figure 2 The differential scanning calorimetric pattern of the fumarate lupatifin monohydrate obtained in Example 1.

[0024] Figure 3 The thermogravimetric analysis pattern of the fumarate lupatifin monohydrate obtained in Example 1.

[0025] Figure 4 The microscope image of the fumarate lupatifin monohydrate obtained in Example 1. DETAILED DESCRIPTION

[0026] The technical solutions of the present application are further described and explained in detail through the specific embodiments.

[0027] In order to improve the stability, water solubility and flowability of the fumarate lupatifin, reduce the sensitivity to the pressing pressure and the content of the organic solvent and the like, on the one hand, the present application proposes a hydrate compound, which is fumarate lupatifin monohydrate, has the structure shown in the following formula (1),

[0028]

[0029]

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

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

[0032] More preferably, the crystalline compound has characteristic peaks in X-ray powder diffraction, using Cu-Ka radiation, expressed in 2θ 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°, 24.0°±0.2°.

[0033] More preferably, the crystalline compound belongs to 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°, and the unit cell volume is For example, the unit cell parameters can be α=90°, β=96°, γ=90°, and the unit cell volume can be

[0035] In some embodiments, the melting point of the hydrated compound of the present application is 171±2℃.

[0036] In another aspect, the present application provides a preparation method of the hydrated compound described in any of the above embodiments, wherein fumaric acid lupatutidine is added to a reaction solvent comprising at least a first organic solvent, heated and stirred to reflux until the fumaric acid lupatutidine is completely dissolved, the concentration of fumaric acid lupatutidine in the reaction system is not less than 70% of the saturation solution concentration of fumaric acid lupatutidine in the reaction system, the reflux is continued for 1 min-24 h, the temperature is lowered to not more than 8℃ and the crystals are precipitated, the crystals are collected, washed and dried to obtain the hydrated compound of the present application.

[0037] The application adopts fumaric acid rupatadine for recrystallization, by adjusting the concentration of fumaric acid rupatadine in the reaction system, the fumaric acid rupatadine in the reaction system is in a supersaturated state after cooling and gradually crystallizes, and the fumaric acid rupatadine monohydrate crystal can be directly obtained, and the operation process is simple. For the concentration of fumaric acid rupatadine in the reaction system under heating, stirring and reflux, for example, it can be any value in 70%, 72%, 75%, 78%, 80%, 82%, 84%, 85%, 87%, 88%, 90%, 92%, 95%, 96%, 98%, 99%, 100% of the saturated solution concentration of fumaric acid rupatadine at this temperature and this reaction system, and there is no special limitation. The concentration of fumaric acid rupatadine in the reaction system under heating, stirring and reflux has no effect on obtaining fumaric acid rupatadine monohydrate crystal, but affects the yield of fumaric acid rupatadine monohydrate crystal. Generally, the higher the concentration of fumaric acid rupatadine in the reaction system under heating, stirring and reflux, the higher the yield of fumaric acid rupatadine monohydrate crystal.

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

[0039] In the above preparation method of fumaric acid rupatadine monohydrate, the heating temperature of heating and stirring can be 70-90℃, or further, the heating temperature can be 85-90℃.

[0040] In the above preparation method, the cooling has no particular limitation, and can be natural cooling, gradient cooling or rapid cooling, etc., and is preferably gradient cooling, the cooling rate is faster at a higher temperature, and the cooling rate is slower at a lower temperature, for example, first reduced to 40℃ at a rate of 15±5℃ / h, then reduced to 20℃ at a rate of 7.5±2.5℃ / h and kept for 0.5-5h, and finally reduced to not more than 8℃ (such as 4℃, 5℃, 7℃, etc.) at a rate of 7.5±2.5℃ / h and kept until spherical crystals are precipitated.

[0041] In some embodiments, the first organic solvent comprises at least a second organic solvent that is soluble in water. For example, the second organic solvent can be selected from one or more of isopropanol, ethanol, acetone, methanol, tetrahydrofuran, DMF, DMAc, and DMSO, and combinations of two or more thereof. 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 or slightly soluble in water. The presence of the second organic solvent that is soluble in water and the third organic solvent that is insoluble or slightly soluble in water in the reaction solvent can further improve the recrystallization effect of the lupatkin fumarate monohydrate, and facilitate the precipitation and crystallization of the lupatkin fumarate monohydrate. For example, the third organic solvent can be selected from one or more of 1,2-dichloroethane, dichloromethane, trichloromethane, carbon tetrachloride, 1,1-dichloroethane, cyclohexane, n-hexane, and petroleum ether, and combinations of two or more thereof. The weight ratio of the second organic solvent and the third organic solvent is not particularly limited, and for example, can be 10-1:1.

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

[0044] A pH of the aqueous inorganic base that is too high can cause decomposition of the lupatkin fumarate and affect the yield of the lupatkin fumarate monohydrate. More preferably, the pH of the aqueous inorganic base is not more than 9.0, and for example, the pH can 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 and the aqueous inorganic base is 1:0.5-3, and for example, the weight ratio can be any value in 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 particular limitation. Further, the weight ratio of the first organic solvent and the aqueous inorganic base can be 1:0.8-1.5.

[0046] In some embodiments, the weight ratio of fumic acid lupatifin and reaction solvent is 1:10-30, for example, the weight ratio can be any value selected from 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 fumic acid lupatifin crude product and reaction solvent can be 1:15-25.

[0047] In some embodiments, the washing is performed with reaction solvent, or organic solvents such as isopropyl alcohol, ethanol, dichloroethane, etc. In order to avoid the influence of the temperature of reaction solvent or other washing agents on crystallization, the temperature of reaction solvent or other washing agents used in washing can be the temperature in crystallization (such as 4°C, 5°C, 7°C, etc.). The drying can be performed at 45-65°C and under negative pressure.

[0048] The technical solutions of the present application are further described and explained according to various embodiments as follows.

[0049] Example 1

[0050] Take 1.5g fumic acid lupatifin and add it to reaction solvent composed of isopropyl alcohol and pH 8.0 sodium hydroxide aqueous solution with a weight ratio of 1:1, heat to 85-88°C, stir to dissolve and prepare a saturated solution of fumic acid lupatifin, continue to reflux for 1h. Use gradient cooling method, first cool to 40°C at a cooling rate of 15°C / h, then cool to 20°C at a cooling rate of 7.5°C / h and keep for 2h, finally cool to 5°C at a cooling rate of 7.5°C / h and keep until spherical crystals are precipitated. Collect the crystals, wash the crystals with 5°C reaction solvent as described above, and dry in a vacuum oven at 55°C for 12h, to obtain crystalline fumic acid lupatifin monohydrate, with a yield of 91%.

[0051] X-ray diffraction, use Cu-Kα ray as X-ray source for testing, set ω / 2θ scanning mode, the results are shown in FIG. 1, the characteristic peaks of fumic acid lupatifin 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°, 24.0°±0.2°. Figure 1 The product fumic acid lupatifin monohydrate belongs to monoclinic system, P2(1) / c space group, with cell parameters of α=90°, β=96°, γ=90°, and cell volume of

[0052] The differential scanning calorimetry (DSC) analysis result of the fumarate lupatiquin monohydrate is shown in Figure 1, and the thermogravimetric analysis (TGA) result is shown in Figure 2. It can be seen from Figures 1 and 2 that the product only contains one crystal water in the structure, and thus the crystalline product obtained in the present application is fumarate lupatiquin monohydrate. Figure 2 Figure 3 Figure 2 Figure 3

[0053] The microscope image of the crystalline structure of the product fumarate lupatiquin monohydrate is shown in Figure 3. Figure 4

[0054] Example 2

[0055] The difference between the present example and Example 1 is that in Example 1, the isopropyl alcohol in the reaction solvent is replaced with anhydrous ethanol of the same weight, and the remaining steps remain unchanged. The yield of the crystalline fumarate lupatiquin monohydrate is measured to be 72%.

[0056] Example 3

[0057] The difference between the present example and Example 2 is that in Example 2, the anhydrous ethanol in the reaction solvent is replaced with an organic solvent composed of anhydrous ethanol and chloroform in a weight ratio of 5:1, and the remaining steps remain unchanged. The yield of the crystalline fumarate lupatiquin monohydrate is measured to be 77%.

[0058] Example 4

[0059] Take 1.5 g of fumarate lupatiquin and add it to a reaction solvent composed of isopropyl alcohol and pH 8.0 sodium hydroxide aqueous solution in a weight ratio of 2:1, heat to 85-88°C, stir to dissolve under reflux and make the concentration of fumarate lupatiquin 80% of the saturated solution concentration of fumarate lupatiquin, continue to reflux for 1 h, naturally cool to 20°C and incubate for 2 h, and finally cool to 5°C at a cooling rate of 5°C / h and incubate until spherical crystals are precipitated. Collect the crystals, wash the crystals with 5°C anhydrous ethanol, and dry in a vacuum oven at 55°C for 12 h to obtain crystalline fumarate lupatiquin monohydrate, with a yield of 84%.

[0060] Example 5

[0061] The difference between the present example and Example 4 is that in Example 3, the reaction solvent is adjusted to be composed of isopropyl alcohol and pH 8.0 sodium hydroxide aqueous solution in a weight ratio of 1:2. The remaining steps remain unchanged. The yield of fumarate lupatiquin monohydrate is measured to be 79%.

[0062] Example 6

[0063] ​​​​​The difference between this example and Example 4 is that the concentration of fumic acid lupatitifin in Example 3 is adjusted to 92% of the saturated solution concentration of fumic acid lupatitifin. The remaining steps remain unchanged. The yield of fumic acid lupatitifin monohydrate is measured to be 88%.

[0064] Example 7

[0065] The difference between this example and Example 4 is that the concentration of fumic acid lupatitifin in Example 3 is adjusted to 70% of the saturated solution concentration of fumic acid lupatitifin. The remaining steps remain unchanged. The yield of fumic acid lupatitifin monohydrate is measured to be 73%.

[0066] Performance test

[0067] I. Comparison of organic solvent residues

[0068] The fumic acid lupatitifin monohydrate obtained in Example 1 is compared with fumic acid lupatitifin crystal form A, crystal form B, crystal form C, and mixed crystal. Among them, crystal form A is prepared according to Example 1 of Chinese patent CN104045633A, crystal form B is prepared according to Example 1 of Chinese patent CN104059056A, crystal form C is prepared according to Example 1 of CN117263923A, and mixed crystal is prepared according to Example 1 of Chinese patent CN104031035A. The drying of the crystals is as follows: take 2g of the crystallized crystals and place them in an oven at 55℃ and dry them under vacuum (-0.099MPa) for 12h.

[0069] Organic solvent residue test method:

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

[0071] Control solution: accurately weigh methanol, n-pentane, isopropyl alcohol, ethanol, dichloromethane and ethyl acetate, add DMF to dilute to a mixed solution containing 150μg of methanol, 250μg of n-pentane, 300μg of isopropyl alcohol, 500μg of ethanol, 30μg of dichloromethane and 250μg of ethyl acetate per 1ml. The capillary column with 6% cyanopropylphenyl-94% dimethyl polysiloxane as stationary phase is used as the chromatographic column, the initial temperature is 30℃, maintained for 4 minutes, the temperature is raised at a rate of 20℃ per minute to 130℃, maintained for 3.5 minutes; the injection port temperature is 200℃, the detector temperature is 250℃; the injection volume is 1μl; the separation degree between each component peak in the control solution chromatogram should be greater than 1.5. Accurately measure the test sample solution and the control solution, and inject them into the gas chromatograph respectively, and record the chromatogram. According to the peak area, calculate the residual amount of different solvents, the results are shown in Table 1 below.

[0072] Table 1 Organic solvent residues of different crystal forms

[0073]

[0074] From the data results of Table 1 above, it can be seen that the fumaric acid rupatadine monohydrate of the present application has lower organic solvent residues than fumaric acid rupatadine 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 crystal form B comes from the preparation process of rupatadine free base, which is the residue of the previous step.

[0075] II. Comparison of physicochemical properties

[0076] 1. Melting point determination: The melting points of each sample were determined by capillary method. The specific steps are as follows: different samples were ground into fine powder, and the powder was loaded into the capillary, and the powder was tightly packed by tapping the wall of the tube, and the sample height was about 3 mm. Set the temperature to 150℃, first increase the temperature by 3℃ per minute, and then change to 1℃ per minute when the temperature reaches 164℃. Record the temperature from initial melting to complete melting, repeat three times, take the average value, and the results are shown in Table 2.

[0077] 2. Water content determination: The water content of the crystal was determined by Karl Fischer method. The specific steps are as follows: different samples were ground into fine powder for use. The water content tester was calibrated to the anhydrous state. Accurately weigh 10 mg of purified water, and calibrate the water content tester. Calculate the titer. Then accurately weigh an appropriate amount of test sample powder (about 1 ml of commercially available Karl Fischer reagent is consumed), and directly measure the water content in the test sample powder with the water content tester. Calculate the average value of three repeated measurements, and the results are shown in Table 2.

[0078] 3. Resting angle measurement: The resting angle was measured by fixed conical bottom method. The specific steps are as follows: the funnel was fixed on the coordinate paper placed horizontally, and the height of the funnel was adjusted so that the distance between the lower opening of the funnel and the coordinate paper was H. The powder was poured from the funnel to form a conical body until the tip of the conical body just touched the outlet of the funnel. According to the formula tan(θ) = H / cone height, the resting angle θ was calculated. The results are shown in Table 2. The flowability judgment standard: when the resting angle is <30°, the flowability is good; when the resting angle is >40°, the flowability is poor.

[0079] Table 2 Physicochemical properties of different crystal forms

[0080] Crystal form Melting point Moisture content Repose angle Flowability Crystal form A 152-156℃ 3.12％ 47° Poor Crystal form B 184-188℃ 2.57％ 50° Poor Crystal form C 204-212℃ 0.54％ 28° Good Mixed crystal 152-156℃ 2.68％ 49° Poor Example 1 169-173℃ 0.36% (not including crystallization water) 22° Good

[0081] III. Stability comparison

[0082] Since fumaric acid rupatadine crystal form A, crystal form B and mixed crystal have differences in yield, solvent residue, water content and other indicators compared with fumaric acid rupatadine crystal form C, the following comparison takes crystal form C as the comparison.

[0083] The stability of fumarate rupatadine monohydrate and fumarate rupatadine crystal form C of Example 1 under high temperature, high humidity, strong light and pressure conditions was compared. The specific test method is as follows: the fumarate rupatadine monohydrate powder and the fumarate rupatadine crystal form C powder were respectively taken in a closed container, and were dispersed in a loose state, and the thickness of the laying was not more than 3 mm. Another 100 mg of fumarate rupatadine monohydrate powder and fumarate rupatadine crystal form C powder were respectively taken and directly compressed into tablets on a tablet press with a force of 3 kg, and were placed in a closed container. The loose and tablet forms of fumarate rupatadine monohydrate and fumarate rupatadine crystal form C samples were respectively placed in high temperature (60℃), high humidity (25℃, RH 90%±5%) and strong light (total illumination 1.2×10 6 Lux / hr, near ultraviolet energy 200 w·hr / m 2 ) conditions for storage, and samples were taken at specific time points, the properties of fumarate rupatadine monohydrate and fumarate rupatadine crystal form C were observed, and further determination of the related substance content was carried out. The related substance content 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 crystal form C, the fumarate rupatadine monohydrate of the application has better stability, and the powder and tablet forms of the raw material have good stability under high temperature, high humidity and strong light conditions, the appearance shape is intact, and there is no obvious impurity increase, and the sensitivity to pressure is obviously reduced.

[0088] Four, comparison of the performance of the preparation

[0089] Tablets and capsules of fumarate rupatadine monohydrate and crystal form C were respectively prepared. The specific preparation steps are as follows: 1.29 mg of fumarate rupatadine 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 talc powder as a glidant were weighed. The raw material and various excipients were respectively passed through a No. 3 standard sieve and reserved. The test crystal was pre-mixed with the lubricant for 3 minutes and then sieved, and then added to a three-dimensional mixer for uniform mixing to obtain pre-mixed powder 1. Another magnesium stearate and 10 times the amount of microcrystalline cellulose were mixed to obtain pre-mixed powder 2. The remaining microcrystalline cellulose was mixed with pre-mixed powder 1 and pre-mixed powder 2 by equal amount incremental method. The mixed powder was directly compressed into tablets by a tablet press or was filled into a gelatin capsule shell to prepare a capsule.

[0090] 1. Stability comparison

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

[0092] Table 4 Formulation stability comparison

[0093]

[0094]

[0095] Therefore, the tablets and capsules made of fumarate lupatifin monohydrate are relatively stable under high temperature, high humidity, and strong light for 30 days, and the impurity content changes little; while the tablets and capsules made of crystal form C show an increase in impurity content under high temperature and high humidity for 30 days. This is because the sensitivity of fumarate lupatifin monohydrate to pressure is reduced, thus having higher formulation stability.

[0096] 2. Dissolution performance comparison

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

[0098] Table 5 Dissolution performance comparison / %

[0099]

[0100] Therefore, the tablets and capsules made of fumarate lupatifin monohydrate have better dissolution performance and dissolve faster than the tablets and capsules made of crystal form C.

[0101] 3. Bioavailability

[0102] (1) Test sample: tablets and capsules of fumarate lupatifin monohydrate or crystal form C described above.

[0103] (2) Experimental animals and grouping: beagle dogs, male, body weight 8-10 kg. Randomly divided into 2 groups, 3 in each group.

[0104] (3) Administration method: each dog was fed 12 h after feeding, and was fed with 1 piece (particle) of test sample.

[0105] (4) Collection and processing of plasma samples: 4 mL of blood was collected from the forelimb vein before administration and at 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 x g for 10 min, and the plasma was separated and stored at -80°C for testing.

[0106] (5) Assay: The plasma samples at different time points were taken into centrifuge tubes, 200 μL of acetonitrile solution was added, vortexed for 60 s, centrifuged at 1500 x g at 4°C for 10 min, and 20 μL of supernatant was injected. The concentration of fumaric acid lupatiquin was determined by liquid chromatography and the time-concentration curve was plotted. The results are shown in Tables 6 and 7 below.

[0107] Table 6 Plasma concentration of fumaric acid lupatiquin formulation (unit: ng / mL)

[0108]

[0109]

[0110] Table 7 Pharmacokinetic parameters

[0111]

[0112] Therefore, the tablets and capsules made from fumaric acid lupatiquin monohydrate as the raw material, compared with the crystal form C, have higher solubility and dissolution efficiency, faster initial release in animals, and higher bioavailability in animals.

[0113] The basic principles, main features and advantages of the present application are shown and described as above. It should be understood by those skilled in the art that the present application is not limited by the above examples, which are only preferred embodiments of the present application, and the scope of the present application is not limited by the above examples. Equivalent changes and modifications made in accordance with the scope and content of the present patent are still within the scope of the present application. The scope of protection of the present application is defined by the appended claims and their equivalents.

Claims

1. A hydrated compound characterized in that, The hydrate compound is fumaric acid rupatadine monohydrate, having a structure shown in formula (1) below, （1）； The hydrate compound has 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°, 24.0°±0.2° in X-ray powder diffraction using Cu-Kα radiation, expressed in 2θ.

2. The hydrated compound of claim 1, wherein, The hydrate compound belongs to monoclinic system, P2(1) / c space group.

3. The hydrated compound of claim 2, wherein, The unit cell parameters of the hydrated compound are a = 10.5 ± 0.05 A, b = 12.5 ± 0.05 A, c = 14.5 ± 0.05 A, a = 90°, β = 96°, γ = 90°, and the unit cell volume is 1800 ± 100 A 3 .

4. The hydrated compound of claim 1, wherein, The hydrate compound has a melting point of 171±2℃.

5. A process for the preparation of the hydrate compound according to any one of claims 1 to 4, characterized in that, The fumaric acid rupatadine is added to a reaction solvent comprising at least a first organic solvent, heated and stirred to reflux until the fumaric acid rupatadine is completely dissolved, the concentration of the fumaric acid rupatadine in the reaction system is not less than 70% of the saturated solution concentration of the fumaric acid rupatadine in the reaction system, the reflux is continued for 1 min-24 h, the temperature is lowered to not more than 8℃ and the crystals are precipitated, the crystals are collected, washed, dried, and the hydrate compound is obtained; The first organic solvent comprises at least a second organic solvent soluble in water, and the second organic solvent is selected from one or a combination of two or more of isopropyl alcohol, ethanol and methanol; The first organic solvent further comprises a third organic solvent insoluble or slightly soluble in water, and the third organic solvent is selected from one or a combination of two or more of 1,2-dichloroethane, dichloromethane, trichloromethane, carbon tetrachloride and 1,1-dichloroethane; The reaction solvent further comprises an inorganic alkali aqueous solution, and the pH of the inorganic alkali aqueous solution is not more than 9.

0.

6. The method of claim 5, wherein the hydrate compound is prepared by, The inorganic alkali aqueous solution is a NaOH aqueous solution.

7. The method of claim 5, wherein the hydrate compound is prepared by, The pH of the inorganic alkali aqueous solution is 7.5-8.

5.

8. The method of claim 5, wherein the hydrate compound is prepared by, The weight ratio of the first organic solvent to the inorganic alkali aqueous solution is 1:0.5-3.

9. The method of claim 5, wherein the hydrate compound is prepared by, The weight ratio of the fumaric acid rupatadine to the reaction solvent is 1:10-30.

10. The method of claim 5, wherein the hydrate compound is prepared by, The washing is performed using the reaction solvent.

Images