Daidzein N,N-dimethylacetamide solvate with large particle size and high fluidity and preparation method thereof

Abstract

The present invention relates to a daidzein N,N-dimethylacetamide solvate with large particle size and high fluidity and a preparation method thereof. The infrared spectrum of the daidzein N,N-dimethylacetamide solvate prepared by cooling crystallization or constant temperature suspension crystallization is as follows: 3550, 3475, 3412, 3238, 2829, 1822, 1589, 1529, 1483, 1408, 1363, 1323, 1303, 1203, 1110, 1056, 1028, 968, 904, 860, 808, 621, 559, 410 cm ‑1 The characteristic peak is located at 1.47°. Daidzein N,N-dimethylacetamide solvate not only effectively replaces the poor fluidity and agglomeration problems inherent in daidzein itself, but also fills a gap in research on daidzein's particle size and fluidity. It is suitable for new drug development and industrial production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a daidzein N,N-dimethylacetamide solvate with large particle size and high fluidity and a preparation method thereof. Background Art

[0002] Polymorphism refers to the phenomenon in which a solid substance forms two or more distinct spatial arrangements, resulting in solid states with different physicochemical properties. In pharmaceutical research, polymorphism includes multi-component crystal forms such as organic solvates and hydrates. Different crystal forms exhibit distinct colors, melting points, reactivity, chemical stability, fluidity, and mechanical stability. These physicochemical properties and processability can sometimes directly impact a drug's safety and efficacy. Therefore, the study and control of crystal forms have become crucial research areas in drug development. Solvation alters the chemical properties of a drug, converting it into a solvate. The phenomenon of drug solvates is already widespread in drug development. Solvates can promote absorption and effectively enhance drug bioavailability. They can also improve drug stability, enhance fluidity, and, to a certain extent, enhance drug storage.

[0003] Daidzein, also known as soybean flavonoid, 4',7-dihydroxy-isosulfone, soybean flavonoid, 4,7-dihydroxyisoflavone, 4',7-dihydroxyisoflavone; CAS number: 486-66-8; molecular formula: C 15 H 10 O4, its chemical structure is as follows:

[0004]

[0005] Daidzein, a member of the isoflavone family of phytoestrogens, is one of the most commonly consumed and extensively studied isoflavones. It is widely found in kudzu root, soybeans, fruits, nuts, and soy products. Its anticancer potential has been reported in various cancer types. In leukemia, daidzein can induce cell cycle arrest, apoptosis, and phagocytosis in K562 and Jurkat cells by reducing annexin A1 levels. In human ovarian cancer, 20 μM daidzein induces 50% cell death in SKOV-3 cells within 24 hours, exerting its effects through the PAF / MEK / ERK and PI3K / AKT / GSK signaling pathways. Daidzein has been shown to treat a wide range of hormonal disorders and exert anticancer properties by binding to estrogen receptors and exerting both estrogenic and anti-estrogenic effects. Furthermore, daidzein has shown significant efficacy in treating osteoporosis, diabetes, and other conditions.

[0006] The X-ray powder diffraction of the daidzein raw material measured using Cu-Kα radiation showed that the diffraction angles expressed in 2θ were 6.628±0.20°, 8.169±0.20°, 10.060±0.20°, 12.620±0.20°, 13.489±0.20°, 15.220±0.20°, 15.570±0.20°, 16.690±0.20°, 18.730±0.20°, 21.921±0.20°, 24. There are characteristic peaks at .300±0.20°, 25.030±0.20°, 26.230±0.20°, 27.001±0.20°, 27.820±0.20°, 28.500±0.20°, 29.530±0.20°, 30.980±0.20°, 31.929±0.20°, and 32.830±0.20°. Its DSC curve has a melting peak in the range of about 335-338°C, the crystal particle size is small, and the water solubility is poor.

[0007] Daidzein has a spatially flat structure, with tightly packed molecules. The presence of two phenolic hydroxyl groups at the 7 and 4' positions facilitates the formation of intermolecular hydrogen bonds, resulting in strong intermolecular forces and poor water solubility. Due to its poor water solubility, poor fat solubility, and poor permeability, and a strong first-pass effect, daidzein has a very low oral bioavailability, limiting its widespread clinical use.

[0008] In the pharmaceutical field, pharmaceutical powders include solid APIs, additives, pharmaceutical excipients, powders, granules, capsules, tablets, and sterile powders for injection. The flowability of pharmaceutical powders is a crucial factor that must be considered during the preparation of solid dosage forms, impacting not only the normal production process but also the quality of the final product. Powders with good free-flowing properties flow smoothly from the feed hopper to the tableting equipment, facilitating consistent tablet weight and drug content. However, powders with poor flowability can easily lead to tablet breakage and overlapping during high-speed tableting. Taking the production of solid traditional Chinese medicine preparations as an example, powders with poor flowability often make it difficult to mix and fill the ingredients evenly, affecting the precise drug content and resulting in varying fill volumes during tablet and capsule molding or filling. Powders with poor flowability often have a rough surface or easily clump together, making drug dispersion difficult and inconvenient for patients to take. During storage and transportation, preparations made with materials with poor flowability are susceptible to factors such as ambient temperature, humidity, and mechanical forces, which can reduce drug stability and effectiveness.

[0009] Up to now, there are few studies on the polymorphic forms of daidzein. CN107739358A discloses daidzein anhydrous crystal form II, which has deficiencies in terms of particle size, stability and fluidity. However, there is almost no research on the particle size, stability and fluidity of daidzein. Therefore, the present invention adopts a solvated form of daidzein to improve its physicochemical properties. Summary of the Invention

[0010] In response to the challenges of the prior art, the present invention proposes a novel daidzein N,N-dimethylacetamide solvate. The prepared daidzein N,N-dimethylacetamide solvate exhibits large crystal size, regular crystal shape, strong stability, and excellent fluidity, making it suitable for new drug development and industrial production. This approach will also provide insights into the development of other poorly soluble active ingredients in traditional Chinese medicine. Furthermore, the daidzein N,N-dimethylacetamide solvate is dried at 90°C to 130°C and 0.08MPa to 0.1MPa to obtain a solvent-free daidzein compound, which retains the advantages of the original daidzein N,N-dimethylacetamide solvate, such as its rod-shaped crystal morphology and large crystal size.

[0011] The present invention is the first to prepare daidzein with large particle size and high fluidity. A daidzein solvate is also proposed for the first time. Previously, there were no reports on daidzein solvates. This provides new ideas for pharmaceutical production, lays a foundation for expanding the application of daidzein in various fields, and provides practical reference value for the further development of other drugs that have the above-mentioned problems. The present invention also provides a novel method for preparing daidzein N,N-dimethylacetamide solvate with simple process, diverse preparation methods, good reproducibility, high stability, high fluidity, and large particle size, which is suitable for new drug development and industrial production.

[0012] The technical solutions of the present invention are as follows:

[0013] A daidzein N,N-dimethylacetamide solvate with large particle size and high fluidity, wherein the X-ray powder diffraction obtained by Cu-Kα ray measurement of the crystal form is 7.700±0.20°, 13.540±0.20°, 15.270±0.20°, 16.360±0.20°, 17.840±0.20°, 20.550±0.20°, 22.040±0 There are characteristic peaks at 0.20°, 23.049±0.20°, 23.670±0.20°, 25.200±0.20°, 25.800±0.20°, 26.951±0.20°, 27.830±0.20°, 28.440±0.20°, 30.340±0.20°, 31.769±0.20°, 32.620±0.20°, and 33.982±0.20°.

[0014] The daidzein N,N-dimethylacetamide solvate is a monoclinic crystal with a space group of P21 / n and a unit cell parameter of a=90.00°;β=92.468(2)°;γ=90°,the unit cell volume is The minimum number of asymmetric units in the unit cell is Z = 4, and its minimum asymmetric unit contains 1 daidzein molecule and 1 N,N-dimethylacetamide molecule.

[0015] The daidzein N, N-dimethylacetamide solvate, wherein the molar ratio of daidzein and N, N-dimethylacetamide molecules is 1:1, and the molecular formula is C 19 H 19 NO5, before heating to 130℃, will have a weight loss of 23.8%±0.5%.

[0016] The daidzein N,N-dimethylacetamide solvate has an endothermic peak at 119.7±5°C and a characteristic melting peak at 337.8±5°C in a differential scanning calorimetry (DSC) analysis of the daidzein N,N-dimethylacetamide solvate.

[0017] The daidzein N, N-dimethylacetamide solvate, the infrared spectrum of the daidzein N, N-dimethylacetamide solvate is at 3550, 3475, 3412, 3238, 2829, 1822, 1589, 1529, 1483, 1408, 1363, 1323, 1303, 1203, 1110, 1056, 1028, 968, 904, 860, 808, 621, 559, 410cm -1 There is a characteristic peak.

[0018] The preparation method of daidzein N,N-dimethylacetamide solvate of the present invention adopts cooling crystallization or constant temperature suspension crystallization method, and is specifically described as follows:

[0019] The method adopts cooling crystallization as the preparation method. A daidzein raw material is added to N,N-dimethylacetamide and heated to 50-55°C to form a clear solution. The mass ratio of the solvent N,N-dimethylacetamide to the daidzein raw material is 4.1-5.3:1. The clear solution is cooled to 5-15°C at a rate of 0.2-1°C / min and maintained for 1-2 hours. After the cooling crystallization is completed, the solution is filtered and dried to obtain the daidzein N,N-dimethylacetamide solvate.

[0020] The preparation is carried out by constant temperature suspension crystallization, wherein daidzein is added to N,N-dimethylacetamide, the daidzein is added once or in batches, the mass ratio of daidzein to the solvent N,N-dimethylacetamide is 3.5-6.9:1, the constant temperature suspension crystallization temperature is 25°C-55°C, stirring is carried out for 0.5-1h, a white solid is generated, and the daidzein N,N-dimethylacetamide solvate is obtained by filtration and drying.

[0021] The daidzein N,N-dimethylacetamide solvate of the present invention is used to prepare a daidzein solvent-free compound.

[0022] The method for preparing a daidzein solvent-free compound from daidzein N,N-dimethylacetamide solvate is characterized in that the daidzein N,N-dimethylacetamide solvate is dried under the conditions of 90° C. to 130° C. and 0.08 MPa to 0.1 MPa to obtain a daidzein solvent-free compound with a rod-like crystal morphology and a large crystal size.

[0023] The specific instructions are as follows:

[0024] A daidzein N,N-dimethylacetamide solvate with large particle size and high fluidity, characterized in that the X-ray powder diffraction obtained by measuring the crystal form using Cu-Kα ray and the diffraction angle expressed in 2θ is 7.700±0.20°, 13.540±0.20°, 15.270±0.20°, 16.360±0.20°, 17.840±0.20°, 20.550±0.20°, 22.04 There are characteristic peaks at 0±0.20°, 23.049±0.20°, 23.670±0.20°, 25.200±0.20°, 25.800±0.20°, 26.951±0.20°, 27.830±0.20°, 28.440±0.20°, 30.340±0.20°, 31.769±0.20°, 32.620±0.20°, and 33.982±0.20°.

[0025] The X-ray powder diffraction of the daidzein N-methylpyrrolidone solvate of the present invention measured using Cu-Kα radiation has a diffraction angle expressed in 2θ as shown in Table 1 below.

[0026] Table 1 X-ray powder diffraction list of daidzein N,N-dimethylacetamide solvate

[0027]

[0028] The daidzein N,N-dimethylacetamide solvate of the present invention has the d-value (A) shown in the above table. Preferably, the solvate has the characteristic peak intensity shown in the above table.

[0029] The daidzein N,N-dimethylacetamide solvate of the present invention is a monoclinic crystal with a space group of P21 / n and a unit cell parameter of a=90.00°;β=92.468(2)°;γ=90°,the unit cell volume is The minimum number of asymmetric units in the unit cell, Z, is 4, containing one daidzein molecule and one N,N-dimethylacetamide molecule. See Table 2 for information on the crystal structure of daidzein N,N-dimethylacetamide solvate (DAID-NMP).

[0030] Table 2 Crystal structure information of daidzein N,N-dimethylacetamide solvate (DAID-NMP)

[0031]

[0032] In the daidzein N,N-dimethylacetamide solvate of the present invention, the molar ratio of daidzein and N,N-dimethylacetamide molecules is 1:1, and the molecular formula is C 19 H 19 NO5, before heating to 130℃, will have a weight loss of 23.8% ± 0.5%, see Figure 4 This is a thermogravimetric analysis TG diagram of the daidzein N,N-dimethylacetamide solvate provided by the present invention.

[0033] The differential scanning calorimetry DSC spectrum of the daidzein N,N-dimethylacetamide solvate of the present invention has an endothermic peak at 119.7±5°C and a characteristic melting peak at 337.8±5°C. Figure 7 The present invention provides a differential scanning calorimetry (DSC) diagram of the daidzein N,N-dimethylacetamide solvate.

[0034] The infrared spectrum of the daidzein N, N-dimethylacetamide solvate is at 3550, 3475, 3412, 3238, 2829, 1822, 1589, 1529, 1483, 1408, 1363, 1323, 1303, 1203, 1110, 1056, 1028, 968, 904, 860, 808, 621, 559, 410 cm -1 There is a characteristic peak at Figure 8 The infrared spectrum IR graph of the daidzein N,N-dimethylacetamide solvate provided by the present invention.

[0035] The large-particle, high-fluidity daidzein N,N-dimethylacetamide solvate of the present invention is prepared by cooling crystallization or constant-temperature suspension crystallization, as specifically described below:

[0036] Method 1 is to prepare by cooling crystallization: add daidzein raw material to N,N-dimethylacetamide and heat to 50-55°C to form a clear solution, the mass ratio of solvent N,N-dimethylacetamide to daidzein raw material is 4.1-5.3:1, cool the clear solution to 5-15°C at a rate of 0.2-1°C / min and maintain for 1-2 hours. After the cooling crystallization is completed, filter and dry to obtain daidzein N,N-dimethylacetamide solvate. Figure 1 Is the X-ray powder diffraction XRPD pattern of the daidzein raw material used in the present invention, see Figure 2 This is the X-ray powder diffraction XRPD pattern of daidzein N,N-dimethylacetamide solvate prepared by cooling crystallization method.

[0037] Method 2 is to prepare by constant temperature suspension crystallization, add daidzein to N,N-dimethylacetamide, daidzein is added once or in batches, the mass ratio of daidzein to solvent N,N-dimethylacetamide is 3.5-6.9:1, the constant temperature suspension crystallization temperature is 25℃-55℃, stir for 0.5-1h, generate a white solid, filter and dry to obtain daidzein N,N-dimethylacetamide solvate, see Figure 3 This is the X-ray powder diffraction XRPD pattern of daidzein N,N-dimethylacetamide solvate prepared by constant temperature suspension crystallization method.

[0038] In the pharmaceutical production process, many steps involve the flow of powders, such as mixing and discharging in the mixing barrel, capsule filling, and die filling during tableting. Powder flow is the result of unbalanced forces acting on particles within the powder. For formulation production, the quality of powder flowability significantly affects the mixing efficiency, production rate, and uniformity of the powder. The above two methods can quickly, conveniently, and simply prepare large-particle, highly fluid N,N-dimethylacetamide solvate of daidzein. This not only effectively replaces the poor fluidity of daidzein itself (angle of repose of 46°) that can lead to problems such as compaction, but also fills a gap in the research of daidzein's particle size and flowability.

[0039] In addition, the daidzein N,N-dimethylacetamide solvate with large particle size and high fluidity prepared by the above method is characterized in that a daidzein solvent-free compound with good fluidity and large particle size can be prepared by desolvating the daidzein N,N-dimethylacetamide solvate. The specific operation method is to dry the daidzein N,N-dimethylacetamide solvate at 90°C to 130°C and 0.08MPa to 0.1MPa to obtain a solvent-free daidzein compound. It can be clearly seen from X-ray powder diffraction that the solvent-free daidzein compound after desolvation has the same X-ray powder diffraction spectrum as the commercially available daidzein, as shown in Figures 1 and 2. Figure 1 X-ray powder diffraction XRPD pattern of the daidzein raw material used in the present invention and Figure 9 This is the XRPD pattern of the daidzein solvent-free compound prepared by desolvating the daidzein N,N-dimethylacetamide solvate. The daidzein solvent-free compound obtained by this method can also maintain the advantages of the original daidzein N,N-dimethylacetamide solvate such as rod-shaped crystal morphology and large crystal size, and the particle size can be controlled during the preparation process. This method is also the first time that daidzein has been proposed. Among them, the average particle size of the daidzein solvent-free compound can reach 535 microns. The average particle size of commercially available daidzein is only 65.5 microns, which can be seen. Figure 12 This is a SEM image of commercially available daidzein. Currently, the commercially available daidzein crystals are mainly needle-shaped crystals, which are the most undesirable crystals. They are easy to clog the filter cloth, making filtration difficult and difficult to wash. Figure 10 SEM images of daidzein solvent-free compound prepared by desolvation of daidzein N,N-dimethylacetamide solvate and Figure 11 Scanning electron microscope (SEM) image of the prepared daidzein N,N-dimethylacetamide solvate.

[0040] The method of the present invention adopts cooling crystallization or constant temperature suspension crystallization. The crystallization process is simple and easy, with good reproducibility and easy control. It avoids high temperature operation, is safer and has lower energy consumption. The solvent N,N-dimethylacetamide used has a high boiling point (116.10°C) and is not easy to remove at room temperature. Therefore, the stability of the daidzein N,N-dimethylacetamide solvate is strong and the storage conditions are simple. The crystal product obtained by the method of the present invention has high crystallinity and is a short rod-shaped crystal habit. Figure 11 The SEM image of the prepared daidzein N,N-dimethylacetamide solvate, the commercial product is shown in Figure 12SEM image of commercially available daidzein. Not only that, daidzein N, N-dimethylacetamide solvate also has substantial improvements in particle size distribution and fluidity. The average particle size of the product of the present invention is about 839 microns, while the average particle size of the commercial product is about 65.5 microns, which is about 13 times the original. The angle of repose of the product of the present invention is 22°, Figure 13 The repose angle of daidzein N,N-dimethylacetamide solvate powder is 46°, while the repose angle of the commercial product is 46°. Figure 14 Figure 2 shows the angle of repose of commercially available daidzein powder, demonstrating significantly enhanced fluidity. Another advantage is that, due to the small particle size and poor crystallinity of commercially available daidzein, the daidzein N,N-dimethylacetamide solvate obtained by the present invention can be desolvated to produce a solvent-free daidzein compound. This compound is superior to commercially available daidzein and retains the advantages of the original daidzein N,N-dimethylacetamide solvate, such as its rod-shaped crystal morphology and large particle size. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 is the X-ray powder diffraction (XRPD) pattern of the daidzein raw material used in the present invention;

[0042] Figure 2 This is an X-ray powder diffraction (XRPD) pattern of daidzein N,N-dimethylacetamide solvate prepared by cooling crystallization;

[0043] Figure 3 This is an X-ray powder diffraction (XRPD) pattern of daidzein N,N-dimethylacetamide solvate prepared by isothermal suspension crystallization;

[0044] Figure 4 This is a thermogravimetric analysis (TG) diagram of the daidzein N,N-dimethylacetamide solvate provided by the present invention;

[0045] Figure 5 is the asymmetric unit ellipsoid diagram of daidzein N,N-dimethylacetamide solvate;

[0046] Figure 6 This is the unit cell packing diagram of daidzein N,N-dimethylacetamide solvate;

[0047] Figure 7 This is a differential scanning calorimetry (DSC) diagram of the daidzein N,N-dimethylacetamide solvate provided by the present invention;

[0048] Figure 8 This is an infrared spectrum (IR) of the daidzein N,N-dimethylacetamide solvate provided by the present invention;

[0049] Figure 9 is an XRPD pattern of a daidzein solvent-free compound prepared by desolvation of daidzein N,N-dimethylacetamide solvate;

[0050] Figure 10 This is a scanning electron microscope (SEM) image of a daidzein solvent-free compound prepared by desolvation of daidzein N,N-dimethylacetamide solvate;

[0051] Figure 11 This is a scanning electron microscope (SEM) image of the daidzein N,N-dimethylacetamide solvate provided by the present invention;

[0052] Figure 12 This is a scanning electron microscope (SEM) image of commercially available daidzein;

[0053] Figure 13 This is a graph of the angle of repose of powder of daidzein N,N-dimethylacetamide solvate;

[0054] Figure 14 This is a graph showing the angle of repose of commercially available daidzein powder.

[0055] Note: The coordinate Two-Theta represents the scanning angle of the diffractometer, and Intensity represents the intensity. DETAILED DESCRIPTION

[0056] The present invention will be described in detail below with reference to the figures and embodiments. It should be understood that the specific embodiments described herein are intended only to illustrate the present invention and are not intended to limit the present invention. Any improvements and variations based on the present invention are still within the scope of protection of the present invention.

[0057] Example 1: 37.48 g of solvent N, N-dimethylacetamide was added to a crystallizer and stirred at 50°C. 7.07 g of daidzein raw material was added to the crystallizer. After the raw materials were added, stirring was continued until the solution was clear. After the solution was clear, stirring was stopped and the temperature was lowered to 15°C at a rate of 1°C / min and maintained for 2 hours. After cooling and crystallization, filtration and drying were performed to obtain daidzein N, N-dimethylacetamide solvate. The prepared product was at 7.700±0.20°, 13.540±0.20°, 15.270±0.20°, 16.360±0.20°, 17.840±0.20°, 20.550±0.20°, 22.040±0.20°, 23.049±0.20°, 23.670±0.20°, 25.200±0.20°, 25. Characteristic peaks are found at 800±0.20°, 26.951±0.20°, 27.830±0.20°, 28.440±0.20°, 30.340±0.20°, 31.769±0.20°, 32.620±0.20°, and 33.982±0.20°. TGA results show a 23.8%±0.5% weight loss before heating to 130°C. DSC results reveal an endothermic peak at 119.7±5°C and a characteristic melting peak at 337.8±5°C. The crystals are rod-shaped, with an average particle size of approximately 839 microns and a repose angle of 22°, demonstrating good stability and fluidity.

[0058] Example 2: 18.74 g of solvent N, N-dimethylacetamide was added to a crystallizer and stirred at 55°C. 4.57 g of daidzein raw material was added to the crystallizer. After the raw materials were added, stirring was continued until the solution was clear. After the solution was clear, stirring was stopped and the temperature was lowered to 5°C at a rate of 0.2°C / min and maintained for 1 hour. After cooling and crystallization, filtration and drying were performed to obtain daidzein N, N-dimethylacetamide solvate. The prepared product was at 7.700±0.20°, 13.540±0.20°, 15.270±0.20°, 16.360±0.20°, 17.840±0.20°, 20.550±0.20°, 22.040±0.20°, 23.049±0.20°, 23.670±0.20°, 25.200±0.20°, 25. Characteristic peaks are found at 800±0.20°, 26.951±0.20°, 27.830±0.20°, 28.440±0.20°, 30.340±0.20°, 31.769±0.20°, 32.620±0.20°, and 33.982±0.20°. TGA results show a 23.8%±0.5% weight loss before heating to 130°C. DSC results reveal an endothermic peak at 119.7±5°C and a characteristic melting peak at 337.8±5°C. The crystals are rod-shaped, with an average particle size of approximately 839 microns and a repose angle of 22°, demonstrating good stability and fluidity.

[0059] Example 3: 28.11 g of solvent N,N-dimethylacetamide was added to a crystallizer and stirred at 53°C. 5.76 g of daidzein raw material was added to the crystallizer. After the raw materials were added, stirring was continued until the solution was clear. After the solution was clear, stirring was stopped and the temperature was lowered to 7°C at a rate of 0.5°C / min and maintained for 1.5 hours. After cooling and crystallization, filtration and drying were performed to obtain daidzein N-methylpyrrolidone solvate. The prepared product was at 7.700±0.20°, 13.540±0.20°, 15.270±0.20°, 16.360±0.20°, 17.840±0.20°, 20.550±0.20°, 22.040±0.20°, 23.049±0.20°, 23.670±0.20°, 25.200±0.20°, 25. Characteristic peaks are found at 800±0.20°, 26.951±0.20°, 27.830±0.20°, 28.440±0.20°, 30.340±0.20°, 31.769±0.20°, 32.620±0.20°, and 33.982±0.20°. TGA results show a 23.8%±0.5% weight loss before heating to 130°C. DSC results reveal an endothermic peak at 119.7±5°C and a characteristic melting peak at 337.8±5°C. The crystals are rod-shaped, with an average particle size of approximately 839 microns and a repose angle of 22°, demonstrating good stability and fluidity.

[0060] Example 4: 18.74 g of solvent N, N-dimethylacetamide was added to a crystallizer and stirred at 25°C. 2.72 g of daidzein raw material was weighed and added to the crystallizer for constant temperature suspension crystallization. After the raw materials were added, the solution was stirred for 1 hour, the solid was filtered, and the product was dried to obtain the product. The prepared product was at 7.700 ± 0.20°, 13.540 ± 0.20°, 15.270 ± 0.20°, 16.360 ± 0.20°, 17.840 ± 0.20°, 20.550 ± 0.20°, 22.040 ± 0.20°, 23.049 ± 0.20°, 23.670 ± 0.20°, 25.200 ± 0.20°, 25. Characteristic peaks are found at 800±0.20°, 26.951±0.20°, 27.830±0.20°, 28.440±0.20°, 30.340±0.20°, 31.769±0.20°, 32.620±0.20°, and 33.982±0.20°. TGA results show a 23.8%±0.5% weight loss before heating to 130°C. DSC results reveal an endothermic peak at 119.7±5°C and a characteristic melting peak at 337.8±5°C. The crystals are rod-shaped, with an average particle size of approximately 839 microns and a repose angle of 22°, demonstrating good stability and fluidity.

[0061] Example 5: 18.74 g of solvent N, N-dimethylacetamide was added to the crystallizer and stirred at 45°C. 4.41 g of daidzein raw material was weighed and added to the crystallizer for constant temperature suspension crystallization. After the raw materials were added, the solution was stirred for 0.6 h, the solid was filtered, and the product was dried to obtain the product. The prepared product was at 7.700 ± 0.20°, 13.540 ± 0.20°, 15.270 ± 0.20°, 16.360 ± 0.20°, 17.840 ± 0.20°, 20.550 ± 0.20°, 22.040 ± 0.20°, 23.049 ± 0.20°, 23.670 ± 0.20°, 25.200 ± 0.20°, 25. Characteristic peaks are found at 800±0.20°, 26.951±0.20°, 27.830±0.20°, 28.440±0.20°, 30.340±0.20°, 31.769±0.20°, 32.620±0.20°, and 33.982±0.20°. TGA results show a 23.8%±0.5% weight loss before heating to 130°C. DSC results reveal an endothermic peak at 119.7±5°C and a characteristic melting peak at 337.8±5°C. The crystals are rod-shaped, with an average particle size of approximately 839 microns and a repose angle of 22°, demonstrating good stability and fluidity.

[0062] Example 6: 18.74 g of solvent N, N-dimethylacetamide was added to the crystallizer and stirred at 55°C. 5.35 g of daidzein raw material was weighed and added to the crystallizer for constant temperature suspension crystallization. After the raw materials were added, the solution was stirred for 0.5 h, the solid was filtered, and the product was dried to obtain the product. The prepared product was at 7.700 ± 0.20°, 13.540 ± 0.20°, 15.270 ± 0.20°, 16.360 ± 0.20°, 17.840 ± 0.20°, 20.550 ± 0.20°, 22.040 ± 0.20°, 23.049 ± 0.20°, 23.670 ± 0.20°, 25.200 ± 0.20°, 25. Characteristic peaks are found at 800±0.20°, 26.951±0.20°, 27.830±0.20°, 28.440±0.20°, 30.340±0.20°, 31.769±0.20°, 32.620±0.20°, and 33.982±0.20°. TGA results show a 23.8%±0.5% weight loss before heating to 130°C. DSC results reveal an endothermic peak at 119.7±5°C and a characteristic melting peak at 337.8±5°C. The crystals are rod-shaped, with an average particle size of approximately 839 microns and a repose angle of 22°, demonstrating good stability and fluidity.

[0063] Example 7: Take 2.5 g of the product in Example 1 and place it in a drying oven at 90 ° C. The vacuum degree is maintained at about 0.1 MPa and dried for 12 h. The solid product is characterized and Figure 1 X-ray powder diffraction (XRPD) of the daidzein raw material used Figure 1 The results were consistent, with identical peak positions and shapes. TGA thermogravimetric analysis revealed no weight loss before the decomposition temperature of the dried sample, indicating that the daidzein N,N-dimethylacetamide solvate was converted into a solvent-free compound. The resulting daidzein N,N-dimethylacetamide solvate retained the rod-shaped crystal morphology and crystal size of the original daidzein N,N-dimethylacetamide solvate, and exhibited significantly improved fluidity compared to commercially available products.

[0064] Example 8: 5.5 g of the product in Example 1 was placed in a drying oven at 130 ° C. The vacuum degree was maintained at about 0.08 MPa and dried for 12 h. The solid product was characterized and Figure 1 X-ray powder diffraction (XRPD) of the daidzein raw material used Figure 1 The results were consistent, with identical peak positions and shapes. TGA thermogravimetric analysis revealed no weight loss before the decomposition temperature of the dried sample, indicating that the daidzein N,N-dimethylacetamide solvate was converted into a solvent-free compound. The resulting daidzein N,N-dimethylacetamide solvate retained the rod-shaped crystal morphology and crystal size of the original daidzein N,N-dimethylacetamide solvate, and exhibited significantly improved fluidity compared to commercially available products.

[0065] Example 9: 4 g of the product in Example 1 was placed in a drying oven at 110°C with a vacuum degree of about 0.09 MPa and dried for 12 h. The solid product was characterized and Figure 1 X-ray powder diffraction (XRPD) of the daidzein raw material used Figure 1 The results were consistent, with identical peak positions and shapes. TGA thermogravimetric analysis revealed no weight loss before the decomposition temperature of the dried sample, indicating that the daidzein N,N-dimethylacetamide solvate was converted into a solvent-free compound. The resulting daidzein N,N-dimethylacetamide solvate retained the rod-shaped crystal morphology and crystal size of the original daidzein N,N-dimethylacetamide solvate, and exhibited significantly improved fluidity compared to commercially available products.

[0066] The present invention provides a daidzein N,N-dimethylacetamide solvate with large particle size and high fluidity and a preparation method thereof. There are many methods and approaches to implement the technical solution. The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be considered as the scope of protection of the present invention. All components not specified in this example can be implemented using existing technologies.

Claims

1. A daidzein N,N-dimethylacetamide solvate having large particle size and high fluidity, characterized in that: The X-ray powder diffraction of the crystal form measured using Cu-Kα ray showed diffraction angles expressed in 2θ of 7.700±0.20°, 13.540±0.20°, 15.270±0.20°, 16.360±0.20°, 17.840±0.20°, 20.550±0.20°, 22.040±0.20°, 23.049±0.20°. There are characteristic peaks at 23.670±0.20°, 25.200±0.20°, 25.800±0.20°, 26.951±0.20°, 27.830±0.20°, 28.440±0.20°, 30.340±0.20°, 31.769±0.20°, 32.620±0.20°, and 33.982±0.20°.

2. The daidzein N,N-dimethylacetamide solvate according to claim 1, wherein Daidzein N,N-dimethylacetamide solvate is monoclinic with space group P21 / n and unit cell parameters of a=90.00°;β=92.468(2)°;γ=90°,the unit cell volume is The minimum number of asymmetric units in the unit cell is Z = 4, and its minimum asymmetric unit contains 1 daidzein molecule and 1 N,N-dimethylacetamide molecule.

3. The daidzein N,N-dimethylacetamide solvate according to claim 1, wherein In the solvate of daidzein N,N-dimethylacetamide, the molar ratio of daidzein and N,N-dimethylacetamide molecules is 1:1, and the molecular formula is C 19 H 19 NO5, before heating to 130℃, will have a weight loss of 23.8%±0.5%.

4. The daidzein N,N-dimethylacetamide solvate according to claim 1, wherein The differential scanning calorimetry (DSC) spectrum of daidzein N,N-dimethylacetamide solvate showed an endothermic peak at 119.7±5°C and a characteristic melting peak at 337.8±5°C.

5. The daidzein N,N-dimethylacetamide solvate according to claim 1, wherein The infrared spectrum of daidzein N,N-dimethylacetamide solvate is at 3550, 3475, 3412, 3238, 2829, 1822, 1589, 1529, 1483, 1408, 1363, 1323, 1303, 1203, 1110, 1056, 1028, 968, 904, 860, 808, 621, 559, 410 cm -1 There is a characteristic peak.

6. The method for preparing daidzein N,N-dimethylacetamide solvate according to claim 1, wherein: The method adopts cooling crystallization as the preparation method. A daidzein raw material is added to N,N-dimethylacetamide and heated to 50-55°C to form a clear solution. The mass ratio of the solvent N,N-dimethylacetamide to the daidzein raw material is 4.1-5.3:

1. The clear solution is cooled to 5-15°C at a rate of 0.2-1°C / min and maintained for 1-2 hours. After the cooling crystallization is completed, the solution is filtered and dried to obtain the daidzein N,N-dimethylacetamide solvate.

7. The method for preparing daidzein N,N-dimethylacetamide solvate according to claim 1, wherein: The preparation is carried out by constant temperature suspension crystallization, wherein daidzein is added to N,N-dimethylacetamide, the daidzein is added once or in batches, the mass ratio of daidzein to the solvent N,N-dimethylacetamide is 3.5-6.9:1, the constant temperature suspension crystallization temperature is 25°C-55°C, stirring is carried out for 0.5-1h, a white solid is generated, and the daidzein N,N-dimethylacetamide solvate is obtained by filtration and drying.

8. Using the daidzein N,N-dimethylacetamide solvate of claim 1 to prepare a daidzein solvent-free compound.

9. The method for preparing a daidzein solvent-free compound from the daidzein N,N-dimethylacetamide solvate according to claim 8, characterized in that: The daidzein N,N-dimethylacetamide solvate is dried under the conditions of 90° C. to 130° C. and 0.08 MPa to 0.1 MPa to obtain a daidzein solvent-free compound with a rod-like crystal morphology and large crystal size.

Images