Rupatadine fumarate hemihydrate and a method for its preparation

Abstract

The application provides fumarate lopanfene hemihydrate and a preparation method thereof, and relates to the technical field of drug synthesis. The fumarate lopanfene hemihydrate is a crystalline compound in orthorhombic system, has high purity, low moisture content, low content of related substances, good fluidity and high stability, and the fumarate lopanfene hemihydrate can be obtained by controlling the water activity of an alcohol solvent during recrystallization, and the preparation method is simple.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology and relates to a rupatifine fumarate hemihydrate and its preparation method. Background Technology

[0002] Rupatifine fumarate is a novel multi-pathway anti-allergy drug. According to publicly available technologies, rupatifine fumarate exists in various crystalline forms, including crystal form A, crystal form B, mixed crystals, crystal form C, and monohydrate. These different crystal forms of rupatifine fumarate exhibit significant differences in physical and chemical properties such as melting point, density, stability, and solubility, further affecting the drug's stability, bioavailability, efficacy, and product quality.

[0003] Currently disclosed rupapatefen fumarate compounds exhibit shortcomings such as insufficient stability, low melting point, pressure sensitivity, and poor flowability. Furthermore, the high residual organic solvent content during preparation negatively impacts safety and hinders commercial production. Rupapatefen fumarate monohydrate, compared to other reported rupapatefen fumarate crystal forms (crystal form A, crystal form B, mixed crystal, and crystal form C), demonstrates better stability, water solubility, and flowability, with lower sensitivity to pressure. However, it also suffers from a complex preparation process. Therefore, existing rupapatefen fumarate compounds require further optimization. Summary of the Invention

[0004] To address the aforementioned technical problems, this invention provides a rupatifine fumarate hemihydrate and its preparation method.

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

[0006] A rupatifine fumarate hemihydrate has the structure shown in formula (1). (1); The rupatifine fumarate hemihydrate is a crystalline compound with an orthorhombic crystal system.

[0008] Preferably, the crystalline compound is detected using differential scanning calorimetry and shows absorption peaks at 185±2℃ and 201±2℃.

[0009] Preferably, the space group of the crystalline compound is Iba2.

[0010] Preferably, the cell parameters of the crystalline compound are as follows: a = 19.6654 ± 0.0011 Å; b = 21.7075 ± 0.0011 Å; c = 12.1699 ± 0.0007 Å; α = 90 °; β=90 °; γ=90°.

[0011] A method for preparing rupatifen fumarate hemihydrate according to any of the above embodiments includes: adding rupatifen fumarate with a purity of not less than 99% to an alcoholic organic solvent with a water activity of 0.1-0.7 at 25°C at room temperature, controlling the temperature at 30-50°C to completely dissolve the rupatifen fumarate, obtaining a rupatifen fumarate solution, cooling the rupatifen fumarate solution until it is supersaturated, crystallizing, and obtaining the rupatifen fumarate hemihydrate.

[0012] Preferably, the water activity is 0.3-0.5; The water activity was measured using a water activity meter.

[0013] Preferably, the alcohol solvent is selected from one or more of methanol, ethanol, and isopropanol.

[0014] Preferably, the concentration of the rupatifen fumarate solution is 60-100% of the concentration of a saturated rupatifen fumarate solution at the current temperature.

[0015] More preferably, the concentration of the rupatifine fumarate solution is 70-100% of the concentration of a saturated rupatifine fumarate solution at the current temperature.

[0016] Preferably, the cooling temperature is -10~20℃; The cooling method is selected from natural cooling, gradient cooling, and rapid cooling.

[0017] The beneficial effects of this invention are: (1) The present invention proposes a new crystal structure of rupatifen fumarate hydrate-rupatifen fumarate hemihydrate, which has the characteristics of small particle size, uniform particle size, high dissolution efficiency, high purity and good storage stability, and is suitable for more formulations.

[0018] (2) The present invention prepares rupatifine fumarate hemihydrate by recrystallization and by controlling the water activity of organic solvent in the reaction system, which effectively avoids the formation of monohydrate or anhydrous impurity crystals. The preparation process is simple and suitable for industrial production. Attached Figure Description

[0019] Figure 1 The image shows the DSC chromatogram of the rupatifine fumarate hemihydrate obtained in Example 1.

[0020] Figure 2 The graphs show the changes in blood concentrations of rupatifine fumarate crystal form C, monohydrate, and hemihydrate over time. Detailed Implementation

[0021] The technical solution of the present invention will be further explained and described below through specific embodiments.

[0022] On the one hand, the present invention proposes a rupatifine fumarate hemihydrate having the structure shown in formula (1). (1); Lupatifine fumarate hemihydrate is a crystalline compound with an orthorhombic crystal system.

[0024] This invention proposes rupatifine fumarate hemihydrate, in which one rupatifine fumarate molecule binds 0.5 water molecules of crystallization. It is an orthorhombic crystalline compound with high purity (≥99%), low water content (≤0.3%), low content of related substances (≤0.3%), good storage stability, and good flowability.

[0025] In some embodiments, the crystalline compound was detected using differential scanning calorimetry (DSC) and showed absorption peaks at 185±2 °C and 201±2 °C.

[0026] In some embodiments, the space group of the crystalline compound is Iba2.

[0027] In some embodiments, the unit cell parameters of the orthorhombic crystalline compounds are as follows: a = 19.6654 ± 0.0011 Å; b = 21.7075 ± 0.0011 Å; c = 12.1699 ± 0.0007 Å; α = 90 °; β=90 °; γ=90°.

[0028] On the other hand, the present invention also proposes a method for preparing rupatifen fumarate hemihydrate as described in any of the above embodiments, comprising: adding rupatifen fumarate with a purity of not less than 99% to an alcoholic organic solvent with a water activity of 0.1-0.7 at 25°C at room temperature, controlling the temperature at 30-50°C to completely dissolve rupatifen fumarate, obtaining a rupatifen fumarate solution, cooling the rupatifen fumarate solution to supersaturation, crystallizing, and obtaining rupatifen fumarate hemihydrate.

[0029] This invention uses a method that controls the water activity of organic solvents to prepare rupatifine fumarate hemihydrate, effectively avoiding the formation of monohydrate or anhydrous impurity crystals. It can be prepared by simple dissolution and cooling crystallization, making it simple to operate and suitable for industrial production.

[0030] For example, the water activity can be 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, etc. If the water activity is too high, more rupapatefumarate monohydrate will be obtained; if the water activity is too low, more anhydrous rupapatefumarate will be obtained. Therefore, both excessively high and low water activity will affect the yield of rupapatefumarate hemihydrate.

[0031] In some embodiments, the water activity is 0.3-0.5; Water activity was tested using a water activity meter.

[0032] There are no particular limitations on the method for controlling the water activity of the reaction solution; either the saturated salt solution method or the inert gas method can be used. Taking the saturated salt solution method as an example, different salts have different water activities in their saturated solutions. Therefore, by equilibrating the alcohol organic solvent with different salt saturated solutions in a closed system, alcohol organic solvents with different water activities can be obtained. For example, the water activity of a saturated aqueous solution of magnesium chloride at 25°C is 0.328, that of a saturated aqueous solution of potassium carbonate at 25°C is 0.432, that of a saturated aqueous solution of magnesium nitrate at 25°C is 0.529, that of a saturated aqueous solution of lithium chloride at 25°C is 0.113, and that of a saturated aqueous solution of sodium nitrate at 25°C is 0.635. Different water activities can be obtained by using saturated aqueous solutions with different combinations and weight ratios of salts. For example, the water activity of a saturated aqueous solution of sodium chloride at 25°C is 0.753, and the saturated aqueous solution of a combination of lithium chloride and sodium chloride at 25°C falls between 0.113 and 0.753.

[0033] In some embodiments, the alcohol solvent is selected from one or more of methanol, ethanol, and isopropanol. Further, ethanol is used as the alcohol solvent because it has high dissolution efficiency, low toxicity, a moderate boiling point, and is easy to remove.

[0034] In some embodiments, the concentration of the rupatifine fumarate solution is 60-100% of the concentration of a saturated rupatifine fumarate solution at the current temperature. For example, the concentration of the rupatifine fumarate solution is 60%, 70%, 80%, 90%, 100%, etc., of the concentration of a saturated rupatifine fumarate solution at the current temperature.

[0035] In some embodiments, the concentration of the rupatifen fumarate solution is 70-100% of the concentration of a saturated rupatifen fumarate solution at the current temperature.

[0036] In some embodiments, the cooling temperature is -10~20℃; Cooling is selected from natural cooling, gradient cooling, and rapid cooling.

[0037] Furthermore, the cooling temperature can be 0-5℃, using a gradient cooling method. For gradient cooling, for example, if the melting temperature is 40℃, the temperature can be lowered to 30℃ at a rate of 10-20℃ / h, then lowered to 15℃ at a rate of 5-10℃ / h and held for 2 hours, and finally lowered to 5℃ at a rate of 5-10℃ / h and held for crystallization. The crystals can be washed with anhydrous ethanol at 5℃ and then dried at 50-60℃.

[0038] The technical solution of the present invention will be further described and illustrated below with reference to various embodiments. Unless otherwise specified, the parts mentioned in the following embodiments are parts by weight.

[0039] Example 1 The entire reaction system was placed in a sealed glove box, along with one 1L cup of saturated sodium bromide solution and one 27g cup of anhydrous ethanol. The mixture was left to stand for 3 hours, and the water activity of the ethanol was measured to be 0.46. 1g of rupatifine fumarate was weighed and added to the 27g ethanol solution with the water activity of 0.46. The solution was heated to 40°C, stirred to dissolve, and a saturated solution of rupatifine fumarate was prepared. A gradient cooling method was used: first, the temperature was lowered to 30°C at a rate of 15°C / h; then, it was lowered to 20°C at a rate of 7.5°C / h and held for 2 hours; finally, it was lowered to 5°C at a rate of 7.5°C / h and held until powdery crystals precipitated. The crystals were collected, washed with anhydrous ethanol at 5°C, and dried in a vacuum oven at 55°C for 12 hours to obtain crystalline rupatifine fumarate hemihydrate.

[0040] Example 2 The difference between this embodiment and Embodiment 1 is that in Embodiment 1, the saturated sodium bromide solution was replaced with a saturated aqueous solution of sodium nitrate and sodium chloride in a 1:1 weight ratio, and the ethanol water activity was 0.68. The remaining steps remained unchanged.

[0041] Example 3 The difference between this embodiment and Embodiment 1 is that in Embodiment 1, the saturated sodium bromide solution was replaced with a saturated aqueous solution of magnesium chloride, and the water activity of the ethanol was 0.30. The remaining steps remain unchanged.

[0042] Example 4 The difference between this embodiment and Embodiment 1 is that in Embodiment 1, the saturated sodium bromide solution was replaced with a saturated aqueous solution of potassium carbonate, and the water activity of the ethanol was 0.42. The remaining steps remain unchanged.

[0043] Example 5 The difference between this embodiment and Embodiment 1 is that in Embodiment 1, the saturated sodium bromide solution was replaced with a saturated aqueous solution of lithium chloride, and the water activity of the ethanol was 0.11. The remaining steps remain unchanged.

[0044] Comparative Example 1 The difference between this embodiment and Embodiment 1 is that in Embodiment 1, anhydrous ethanol was used directly, and the anhydrous ethanol was not subjected to water activation equilibrium; the water activity of the anhydrous ethanol was 0.07. The remaining steps remained unchanged.

[0045] Comparative Example 2 The difference between this embodiment and Embodiment 1 is that in Embodiment 1, the saturated sodium bromide solution was replaced with a saturated potassium chloride aqueous solution, and the water activity of the ethanol was 0.82. The remaining steps remain unchanged.

[0046] The results of rupatifine fumarate obtained in Examples 1-5 and Comparative Examples 1-2 are shown in Table 1 below.

[0047] Table 1

[0048] As can be seen from the data in Table 1 above, the method of the present invention can obtain rupatifine fumarate hemihydrate with high purity and high yield, and the preparation process is simple.

[0049] The DSC chromatogram of the rupatifine fumarate hemihydrate obtained in Example 1 is attached. Figure 1 As shown, absorption peaks are observed at 185±2℃ and 201±2℃, where 185±2℃ is the melting absorption peak (melting point temperature) and 201±2℃ is the decomposition absorption peak (decomposition temperature). For comparison, the melting point and decomposition temperature of rupatifine fumarate crystal form A are 154±2℃ and 180±2℃, respectively; the decomposition temperature of crystal form B is 186±2℃; the melting point and decomposition temperature of the mixed crystal are 154±2℃ and 186±2℃; the decomposition temperature of crystal form C is 200-220℃; and the melting point of the monohydrate is 171±2℃.

[0050] DSC results show that the space group of the rupatifine fumarate hemihydrate in this embodiment is Iba2, and the cell parameters are a=19.6654±0.0011Å, b=21.7075±0.0011Å, c=12.1699±0.0007Å, α=90°, β=90°, γ=90°.

[0051] 1. Comparison of storage stability The storage stability of rupatifen fumarate hemihydrate obtained in Example 1 was compared with that of rupatifen fumarate crystal form A, rupatifen fumarate crystal form B, rupatifen fumarate mixed crystal, rupatifen fumarate crystal form C, and rupatifen fumarate monohydrate. Crystal form A was prepared according to Example 1 of Chinese Patent CN104045633A, crystal form B according to Example 1 of Chinese Patent CN104059056A, crystal form C according to Example 1 of CN117263923A, mixed crystal according to Example 1 of Chinese Patent CN104031035A, and monohydrate according to Example 1 of Chinese Patent CN 119707944A.

[0052] Take 2 ± 0.01 g of each sample, spread it evenly in a petri dish, and place it in a constant temperature and humidity chamber at 40℃ and 75% relative humidity for testing. Samples were taken at 1, 3, and 6 months. The results are shown in Table 2 below.

[0053] Table 2

[0054] As can be seen from the data in Table 2 above, the rupatifine fumarate hemihydrate of the present invention has high purity and good storage stability. After being placed in a high temperature and high humidity environment for half a year, the purity, moisture content and related substances content are still very stable. The moisture content increased from 0.22% to 0.24%, which is only an increase of 0.02%, and the related substances content increased from 0.31% to 0.35%, which is only an increase of 0.04%. The increase in moisture content and related substances content is much lower than that of crystal form A, crystal form B, mixed crystal, crystal form C and monohydrate.

[0055] 2. Tableting performance test Crystal form particle size distribution determination: Take powder of each crystal form and determine the D90 particle size of the crystal form by laser diffraction. Perform three parallel determinations and take the average value.

[0056] Angle of repose determination: Powders of each crystal form are slowly flowed down through a fixed funnel to form a cone. The height and radius of the base of the cone are measured, and the angle of repose θ is calculated as arctan(height / radius of base). Three parallel measurements are performed, and the average value is taken.

[0057] Compressibility: Take an appropriate amount of each crystal form powder and place it in a graduated cylinder, record the volume V0, and calculate the bulk density ρ0 = / V0; vibrate the graduated cylinder until the volume no longer changes, and record the volume V. f Calculate the tap density ρ f =m / V f Calculate the compression ratio = (ρ) f -ρ0) / ρ f ×100%.

[0058] The results are shown in Table 3 below.

[0059] Table 3

[0060] Therefore, as can be seen from the data in Table 3 above, the rupatifine fumarate hemihydrate of the present invention has a smaller angle of repose and lower compressibility, exhibiting very good flowability, which is more conducive to industrial production such as dispensing, mixing, and tableting.

[0061] 3. Tablet stability test Take 100 mg of each crystal form of the active pharmaceutical ingredient powder and compress it directly into rupatifine fumarate tablets using a tablet compressor. The pressure of the tablet compressor is set to 35 ± 0.5 N.

[0062] Accelerated testing was conducted on rupatifine fumarate tablets of different crystal forms. The samples were exposed to a high temperature and high humidity environment (40℃, RH 75±5%) and samples were taken on day 0 and month 6 to observe the tablet shape, test the moisture content and related substances content. The results are shown in Table 4 below.

[0063] Table 4

[0064] As can be seen from the data in Table 4 above, the tablets made from the hemihydrate of rupatifine fumarate of the present invention have low moisture content and related substance content during tableting. After 6 months of storage, the moisture content increased to 0.04% and the related substance content increased to 0.16%, both of which are much lower than those of crystal form A, crystal form B, mixed crystal, crystal form C and monohydrate, showing good stability.

[0065] 4. Tableting sensitivity test Weigh out 25.8 mg of the rupatifine fumarate crystalline powder to be tested, 96.2 mg of microcrystalline cellulose as an excipient, 0.5 mg of magnesium stearate as a lubricant, and 2.0 mg of talc as a flow aid. Pass the active pharmaceutical ingredient and all excipients through a No. 3 standard sieve separately. Premix the crystalline powder to be tested with the lubricant for 3 minutes, then sieve it again, and add it to a three-dimensional mixer to mix thoroughly, obtaining premixed powder 1. Separately, mix magnesium stearate with 10 times the amount of microcrystalline cellulose to obtain premixed powder 2. Add the remaining microcrystalline cellulose to premixed powder 1 and premixed powder 2 in equal increments. Compress the mixed powder directly into tablets using a tablet press. The tablet press pressure was set to low (10 N), medium (35 N), and high (65 N), with 1000 tablets tested for each crystalline form and each compression pressure.

[0066] The appearance, hardness, tablet weight variation, friability, and 30-minute dissolution rate of rupatifine fumarate tablets with different crystal forms were determined. Specific methods were performed according to Part IV, General Chapters of the Chinese Pharmacopoeia. The results are shown in Table 5 below.

[0067] Table 5

[0068] As can be seen from the data in Table 5 above, the rupatifine fumarate hemihydrate of the present invention has good compressibility. It can produce tablets with good appearance under low, medium and high pressures. It has low tablet weight difference, low friability, and high 30-minute dissolution. Moreover, its friability and 30-minute dissolution performance are significantly better than those of crystal form A, crystal form B, mixed crystal, crystal form C and monohydrate.

[0069] 5. Bioavailability test Rupatifine fumarate tablets of different crystal forms were obtained using the medium pressure (35 N) compression method described above for the tablet sensitivity test.

[0070] Laboratory animals and grouping: Healthy, SPF-grade beagles weighing 8-12 kg. Randomized to three animals per group.

[0071] Administration: Adaptation feeding should be completed 7 days in advance, with free access to water. All animals should be fasted for 12 hours before administration. Each animal should be given one rupatifine fumarate tablet. Feeding should begin 4 hours after administration.

[0072] Plasma sample collection: 4 mL of blood was collected from the forelimb vein before administration (0 min) 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 1000×g for 10 min, and the plasma was separated and stored at -80℃ for analysis.

[0073] Content determination: Plasma samples from different time points were placed in centrifuge tubes, 200 μL of acetonitrile solution was added, vortexed for 60 s, and centrifuged at 1500 × g for 10 min at 4℃. 20 μL of the supernatant was injected. The concentration of rupatifine fumarate (ng / mL) was determined by ultraviolet high performance liquid chromatography-tandem mass spectrometry.

[0074] The results are shown in Table 6 below.

[0075] Table 6. Concentration of rupatifen fumarate / ng / mL

[0076] Appendix Figure 2 The curves were prepared based on the data in Table 6 for comparison. It can be seen that the distribution and metabolism of tablets prepared from crystal form C, monohydrate, and hemihydrate after entering the body circulation are not affected by crystal form or hydration state. The main difference in pharmacokinetics among the three lies in the dissolution and absorption after oral administration. The hemihydrate dissolves rapidly, has the fastest onset of action in the body, the highest peak concentration, and the highest overall bioavailability.

[0077] As described above, the basic principles, main features, and advantages of the present invention have been shown and described. Those skilled in the art should understand that the present invention is not limited to the above embodiments, which are merely preferred embodiments and should not be construed as limiting the scope of the invention. All equivalent changes and modifications made in accordance with the scope of the patent and the description should still fall within the scope of the present invention. The scope of protection of this invention is defined by the appended claims and their equivalents.

Claims

1. A rupatifine fumarate hemihydrate, characterized in that, It has the structure shown in equation (1) below. （1）； The rupatifine fumarate hemihydrate is a crystalline compound with an orthorhombic crystal system.

2. The rupatifine fumarate hemihydrate according to claim 1, characterized in that, The crystalline compound was detected using differential scanning calorimetry and showed absorption peaks at 185±2℃ and 201±2℃.

3. The rupatifine fumarate hemihydrate according to claim 1, characterized in that, The space group of the crystalline compound is Iba2.

4. The rupatifine fumarate hemihydrate according to claim 1, characterized in that, The unit cell parameters of the crystalline compound are as follows: a=19.6654±0.0011Å； b=21.7075±0.0011Å； c=12.1699±0.0007Å； α=90 °； β=90 °； γ=90 °.

5. A method for preparing rupatifine fumarate hemihydrate according to any one of claims 1-4, characterized in that, include: At room temperature, rupatifen fumarate with a purity of not less than 99% is added to an alcoholic organic solvent with a water activity of 0.1-0.7 at 25°C. The temperature is controlled at 30-50°C to ensure complete dissolution of the rupatifen fumarate, thereby obtaining a rupatifen fumarate solution. The solution is then cooled until it becomes supersaturated, and crystallization occurs to obtain the rupatifen fumarate hemihydrate.

6. The method for preparing rupatifine fumarate hemihydrate according to claim 5, characterized in that, The water activity is 0.3-0.5; The water activity was measured using a water activity meter.

7. The method for preparing rupatifine fumarate hemihydrate according to claim 5, characterized in that, The alcohol solvent is selected from one or more of methanol, ethanol and isopropanol.

8. The method for preparing rupatifine fumarate hemihydrate according to claim 5, characterized in that, The concentration of the rupatifine fumarate solution is 60-100% of the concentration of a saturated rupatifine fumarate solution at the current temperature.

9. The method for preparing rupatifine fumarate hemihydrate according to claim 8, characterized in that, The concentration of the rupatifine fumarate solution is 70-100% of the concentration of a saturated rupatifine fumarate solution at the current temperature.

10. The method for preparing rupatifine fumarate hemihydrate according to claim 5, characterized in that, The cooling temperature is -10~20℃; The cooling method is selected from natural cooling, gradient cooling, and rapid cooling.

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