Eutectic crystal form DCTRI of Baloxavir marboxil and tropical acid and preparation method of eutectic crystal form DCTRI

Abstract

The invention discloses a preparation process of a Baloxavir marboxil and tropine acid eutectic crystal form. The X-ray powder diffraction pattern of the Baloxavir marboxil and tropine acid eutectic crystal form under Cu-Ka radiation has diffraction angle 2theta values of 4.7 + / -0.2 degrees, 9.1 + / -0.2 degrees, 10.0 + / -0.2 degrees, 10.8 + / -0.2 degrees, 11.9 + / -0.2 degrees, 13.4 + / -0.2 degrees, 14.1 + / -0.2 degrees, 15.0 + / -0.2 degrees, 16.4 + / -0.2 degrees, 17.5 + / -0.2 degrees, 18.0 + / -0.2 degrees, 19.1 + / -0.2 degrees, 20.5 + / -0.2 degrees, 21.5 + / -0.2 degrees, 22.5 + / -0.2 degrees, 23.8 + / -0.2 degrees, 24.5 + / the angle is 30.7 + / -0.2 degrees, and the angle is 31.6 + / -0.2 degrees. And characteristic peaks exist at all positions. The Baloxavir marboxil and tropine acid eutectic crystal form provided by the invention has stable physicochemical properties, excellent solid stability and mechanical stability, and can be stably stored for a long time, the preparation method is simple and convenient, the repeatability is good, and the Baloxavir marboxil and tropine acid eutectic crystal form has important application value for the development of the medicine in the future.

Description

Technical Field

[0001] The present invention relates to the technical field of drug crystal forms, and in particular to a co-crystal form of baloxavir marboxil and tropic acid and a preparation method thereof. Background Art

[0002] Baloxavir marboxil is an innovative CAP-dependent endonuclease inhibitor and one of the few new drugs worldwide that can treat influenza virus proliferation. It targets a key step in influenza virus replication, inhibiting the CAP structure at the 5' end of host mRNA, which is required for influenza virus acquisition from host cells, thereby inhibiting the transcription of the virus's own mRNA.

[0003] Currently, there are the following reports on the crystal form patents of baloxavir marboxil. Among them, the original pharmaceutical company Shionogi of Japan disclosed three crystal forms in WO2018030463: Form I, Form II, and Form III. However, the article did not collect DSC / TGA data, so the crystal type could not be determined. At the same time, the article also did not report stability data.

[0004] CN111377944 discloses two crystal forms, of which Form A is Form I in WO2018030463. The article also conducted a DSC study on this crystal form, confirming that it is an anhydrous crystal form; Form B is another anhydrous crystal form.

[0005] WO2022100395 discloses two crystalline forms, namely methyl benzoate solvate Form C and anhydrate Form D.

[0006] CN111875619 discloses a new crystal form of Baloxavir marboxil and a preparation method thereof.

[0007] WO2020181025 discloses six crystalline forms of Baloxavir marboxil, including three anhydrate crystalline forms, Form BM1, BM2, and BM3, and three solvate crystalline forms, Form BM4, BM5, and BM6, whose solvents are 1,4-dioxane, N,N-dimethylacetamide, and 2-methyltetrahydrofuran, respectively.

[0008] WO2021057834 discloses the anhydrate crystalline form Form C of baloxavir marboxil.

[0009] Drug crystal form is an important factor affecting drug quality. Different crystal forms of the same drug molecule can have significant differences in appearance, solubility, melting point, dissolution, bioavailability and other properties, which directly affect the stability, bioavailability and efficacy of the drug.

[0010] Based on the above patents, it is not difficult to find that the crystal forms of Baloxavir marboxil have been studied more comprehensively, and most of the anhydrate crystal forms can be used as medicine. existing Baloxavir marboxil crystals have poor stability and solubility; therefore, conducting research on their crystal forms is of great significance. Summary of the Invention

[0011] The present invention is intended to at least partially address one of the technical problems in the related art. To this end, the present invention also provides comprehensive characterization data and a process for preparing the aforementioned baloxavir marboxil and tropic acid cocrystal, which exhibits good solubility and stability.

[0012] In order to solve the above technical problems, the first aspect of the present invention provides a baloxavir marboxil and tropic acid cocrystal form DCTRI, wherein the X-ray powder diffraction spectrum of the cocrystal form with tropic acid under Cu-Ka radiation is 4.7±0.2°, 9.1±0.2°, 10.0±0.2°, 10.8±0.2°, 11.9±0.2°, 13.4±0.2°, 14.1±0.2°, 15.0±0.2°, 16.4±0.2°, 17.5±0.2°, 18 .0±0.2°, 19.1±0.2°, 19.9±0.2°, 20.5±0.2°, 21.5±0.2°, 22.5±0.2°, 23.8±0.2°, 24.5±0.2°, 26.2±0.2°, 26.6±0.2°, 27.5±0.2°, 28.1±0.2°, 29.7±0.2°, 30.2±0.2°, 30.7±0.2°, and 31.6±0.2° all have characteristic peaks.

[0013] As a preferred embodiment, the differential scanning calorimetry spectrum of the co-crystal of Baloxavir marboxil and tropic acid shows endothermic peaks near 137°C and 232°C.

[0014] In a second aspect of the present invention, a method for preparing the above-mentioned baloxavir marboxil and tropic acid cocrystal is provided. 1000 mg of baloxavir marboxil and ~203.3 mg of tropic acid are weighed and added to a 40 ml vial. A solvent is then added to obtain a suspension. The suspension is stirred at room temperature for 48 hours, and the solid is separated by centrifugation and dried to obtain the baloxavir marboxil and tropic acid cocrystal.

[0015] Compared with the prior art, the present invention has the following advantages: (1) The preparation process of the baloxavir marboxil and tropic acid cocrystal of the present invention is simple, easy to operate, and easy to scale up. (2) The solvent required for the baloxavir marboxil and tropic acid cocrystal of the present invention is a conventional organic solvent, the production amount is small, and the production cost is low.

[0016] The concept, specific structure and technical effects of the present invention will be further described below in conjunction with the accompanying drawings to fully understand the purpose, characteristics and effects of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 is an XRPD spectrum of the cocrystal of Baloxavir marboxil and tropic acid prepared in Example 1 of the present invention; Figure 2 is a DSC spectrum of the co-crystal of Baloxavir marboxil and tropic acid prepared in Example 1 of the present invention; Figure 3 The baloxavir marboxil and tropic acid cocrystal prepared in Example 1 of the present invention is 1 HNMR spectrum; Figure 4 The XRPD spectra of the cocrystal of Baloxavir marboxil and tropic acid prepared in Example 5 of the present invention before and after grinding for 15 minutes; Figure 5 The XRPD spectra of the cocrystal of Baloxavir marboxil and tropic acid prepared in Example 6 of the present invention after being placed under different temperature and humidity conditions for 4 to 8 weeks; Figure 6 This is the XRPD spectrum of the baloxavir marboxil and tropic acid cocrystal prepared in the embodiment of the present invention before and after being placed under 25°C / 80%RH conditions for 24 hours. DETAILED DESCRIPTION

[0018] In order to make the technical means, creative features, objectives and effects of the invention easier to understand, the invention is further described below with reference to specific diagrams. However, the invention is not limited to the following implementation cases.

[0019] It should be noted that the structures, proportions, sizes, etc. illustrated in the drawings in this specification are only used to match the contents disclosed in the specification so that people familiar with this technology can understand and read them. They are not used to limit the conditions under which the present invention can be implemented. Therefore, they have no substantive technical significance. Any modification of the structure, change in the proportion relationship or adjustment of the size should still fall within the scope of the technical content disclosed in the present invention without affecting the efficacy and purpose that can be achieved by the present invention.

[0020] Among the various crystal forms of Baloxavir marboxil reported in existing literature, low solubility is a common problem, resulting in poor efficacy and low bioavailability.

[0021] The present application is based on the perspective of changing the preparation method of baloxavir marboxil to obtain a new cocrystal form of baloxavir marboxil and tropic acid. The cocrystal form of baloxavir marboxil and tropic acid has both stability and high solubility. On the one hand, it can avoid the risk of crystal transformation, and on the other hand, it facilitates drug absorption and improves bioavailability.

[0022] XRPD (X-ray powder diffraction) patterns were collected on a Bruker D2 PHASER X-ray powder diffractometer. X-ray powder diffraction parameters were as follows: X-ray source: Cu Ka; Ka1 (A): 1.54060; Ka2 (A) 1.54439; Ka2 / Ka1 intensity ratio: 0.50; voltage: 30 kilovolts (kV); current: 10 milliamperes (mA); scan range: 3.0-40.0°.

[0023] DSC, or differential scanning calorimetry, is a technique used to analyze the surface of a sample using a TA DSC X3. The DSC parameters are as follows: scanning rate: 10 °C / min; protective gas: nitrogen.

[0024] TGA, namely thermogravimetric analysis, the thermogravimetric analysis (TGA) graph of the present application was collected on a TA TGA55, and the method parameters of the thermogravimetric analysis (TGA) were as follows: scanning rate: 10 °C / min; protective gas: nitrogen.

[0025] Unless otherwise specified, the following examples are all operated at room temperature. The “room temperature” is not a specific temperature value, but refers to a temperature range of 10-30°C.

[0026] The "stirring" described in the following examples is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50-1800 rpm, wherein the magnetic stirring is preferably 300-900 rpm and the mechanical stirring is preferably 100-300 rpm.

[0027] The "separation" described in the following examples is accomplished by conventional methods in the art, such as centrifugation or filtration. The "centrifugation" operation is as follows: the sample to be separated is placed in a centrifuge tube and centrifuged at a speed of 10,000 rpm until all the solids sink to the bottom of the centrifuge tube.

[0028] The drying described in the following examples can be performed at room temperature or higher. The drying temperature is from room temperature to about 50°C, or up to 40°C. The drying time can be 2 to 48 hours, or overnight. Drying can be performed in a fume hood, forced air oven, or vacuum oven.

[0029] The "crystals" described in the following examples refer to solids characterized and confirmed by X-ray powder diffraction patterns. It will be understood by those skilled in the art that the physicochemical properties discussed herein can be characterized, and the experimental errors therein depend on the conditions of the instrument, the preparation of the sample, and the purity of the sample. In particular, it is well known to those skilled in the art that X-ray powder diffraction patterns generally vary with different instrument conditions. It should be noted in particular that the relative intensities of the diffraction peaks in the X-ray powder diffraction pattern may also vary with changes in the experimental conditions, so the order of the diffraction peak intensities cannot be used as the only or decisive factor. In fact, the relative intensities of the diffraction peaks in the X-ray powder diffraction pattern are related to the preferred orientation of the crystals. The diffraction peak intensities shown in the present invention are illustrative and not for absolute comparison. In addition, the experimental error of the diffraction peak position is generally 5% or less, and the errors at these positions should also be taken into account, and an error of ±0.2 is generally allowed. In addition, due to the influence of experimental factors such as sample thickness, the overall offset of the diffraction peak angle will be caused, and a certain offset is generally allowed. Therefore, it will be understood by those skilled in the art that the X-ray powder diffraction pattern of the protected crystal form of the present invention does not necessarily have to be completely consistent with the X-ray powder diffraction patterns in the embodiments referred to herein, and any crystal form having an X-ray powder diffraction pattern that is identical or similar to the characteristic peaks in these patterns falls within the scope of the present invention.

[0030] A person skilled in the art can compare the X-ray powder diffraction patterns listed in the present invention with the X-ray powder diffraction patterns of an unknown crystal form to confirm whether the two sets of patterns reflect the same or different crystal forms.

[0031] The co-crystal form with tropic acid of the present invention is pure and substantially free of any other crystalline forms. As used herein, "substantially free," when referring to a novel crystalline form, means that the crystalline form contains less than 20% (by weight) of other crystalline forms, particularly less than 10% (by weight) of other crystalline forms, more particularly less than 5% (by weight) of other crystalline forms, and even more particularly less than 1% (by weight) of other crystalline forms.

[0032] The term "about" in the present invention, when used to refer to a measurable value, such as mass, time, temperature, etc., means that there is a certain floating range around the specific value, which can be ±10%, ±5%, ±1%, ±0.5% or ±0.1%.

[0033] Baloxavir marboxil as a raw material includes, but is not limited to, solid form (crystalline or amorphous), oily form, liquid form and solution. Preferably, it is in solid form.

[0034] The preparation method of the baloxavir marboxil and tropic acid cocrystal DCTRI of the present application is as follows: 1000 mg of baloxavir marboxil and ~203.3 mg of tropic acid are weighed and added to a 40 ml vial, followed by adding a solvent to obtain a suspension. The suspension is stirred at room temperature for 48 hours, and the solid is separated by centrifugation and dried to obtain the baloxavir marboxil and tropic acid cocrystal DCTRI.

[0035] In the present application, the different crystallization times during the preparation of the co-crystal of Baloxavir marboxil and tropic acid also affect the degree of crystallization or the yield of crystals, and can be flexibly selected according to actual needs.

[0036] Example 1

[0037] 1000 mg of baloxavir marboxil and ~203.3 mg of tropic acid were weighed and added to a 40 ml vial. A solvent (see Table 1 for details) was then added to obtain a suspension. The suspension was stirred at room temperature for 48 hours. The solid was separated by centrifugation and dried. XRPD analysis showed that the obtained solid was the cocrystal form DCTRI of the present invention. The XRPD pattern is shown below. Figure 1 The XRPD data are shown in Table 2, and the DSC diagram is shown in Figure 2 shown.

[0038] Table 1 serial number Sample mass (mg) Citric acid mass (mg) solvent Solvent volume (ml) XRPD Sample 1 1000 203.3 acetic acid 5 Eutectic DCTRI Sample 2 1000 203.3 Isopropyl alcohol 5 Eutectic DCTRI Sample 3 1000 203.3 dichloromethane 5 Eutectic DCTRI Sample 4 1000 203.3 Acetonitrile 5 Eutectic DCTRI

[0039] Table 2 Diffraction angle 2theta d value Relative Strength Diffraction angle 2theta d value Relative Strength Diffraction angle 2theta d value Relative Strength 4.68 18.86 3.50% 17.45 5.08 13.60% 26.19 3.40 5.60% 9.09 9.72 100.00% 18.03 4.92 20.90% 26.63 3.34 10.40% 10.02 8.82 1.30% 19.05 4.65 14.20% 27.53 3.24 3.20% 10.77 8.21 2.90% 19.86 4.47 5.60% 28.13 3.17 16.40% 11.92 7.42 2.40% 20.52 4.33 21.80% 29.74 3.00 3.00% 13.43 6.59 4.30% 21.51 4.13 4.70% 30.23 2.95 5.80% 14.11 6.27 4.40% 22.50 3.95 61.60% 30.75 2.91 3.20% 14.97 5.91 4.70% 23.79 3.74 10.80% 31.59 2.83 24.40% 16.41 5.40 5.00% 24.47 3.63 33.10%

[0040] from Figure 2As can be seen from the figures, the co-crystal of Baloxavir marboxil and tropic acid prepared in Example 1 has endothermic peaks at around 104°C.

[0041] NMR images Figure 3 The specific data are as follows: 1 H-NMR (400 MHz, DMSO-D6) δ 7.45-7.40 (m,2H), 7.18-7.00 (m, 3H), 6.86 (t, J = 7.3 Hz, 1H), 5.75-5.66 (m, 4H), 5.42 (d,J = 15.7 Hz, 1H), 4.47-4.39 (m, 2H), 4.08-3.98 (m, 2H), 3.92 (t, J = 9.2 Hz,1H), 3.73-3.62 (m, 5H), 3.56 (dd, J = 10.2, 5.8 Hz, 1H), 3.45 (t, J = 10.3Hz, 1H), 2.99-2.92 (m, 1H).

[0042] Example 2: Solubility of the Crystalline DCTRI in Biological Media

[0043] When conducting drug solubility tests to predict in vivo performance, it is important to simulate in vivo conditions as closely as possible. For oral drugs, SGF (simulated gastric fluid), FaSSIF (fasted state simulated intestinal fluid), and FeSSIF (fed state simulated intestinal fluid) can simulate in vivo conditions and predict the effects of feeding. The solubility tested in such media is closer to the solubility in the human body environment.

[0044] To compare the solubility of Form I of the original patented crystalline form WO2018030463 and the crystalline form of DCTRI of this application in biological media, an experiment was conducted referring to the USP method for determining biological solubility. Experimental method: Approximately 25 mg of the crystalline form DCTRI prepared in Example 1 was weighed and added to 1 mL of pre-prepared SGF (simulated gastric fluid), FaSSIF (fasted state simulated intestinal fluid), and FeSSIF (fed state simulated intestinal fluid). The mixture was stirred at a constant temperature of 37°C ± 1°C. Samples were taken after 1 hour and 2 hours, and the supernatant was analyzed by HPLC. Samples were also collected from Form I of WO2018030463 using the same procedure. The experimental conditions and results are shown in Table 3.

[0045] Table 3

[0046] Solubility experiments in biological media demonstrate that compared to Form I in WO2018030463, the crystalline DCTRI of the present invention exhibits higher solubility in SGF (simulated gastric fluid), FeSSIF (fasted simulated intestinal fluid), and FeSSIF (fed simulated intestinal fluid). Within 4 hours, the solubility of the crystalline DCTRI of the present invention is 2 to 2.5 times that of Form I reported in WO2018030463. This higher solubility improves drug absorption and bioavailability in the human body, enabling better therapeutic effects with a lower drug loading. Furthermore, while ensuring drug efficacy, reducing the drug loading can reduce drug toxicity and side effects, improving drug safety, which has important clinical significance.

[0047] Example 3 Mechanical stability of the crystalline DCTRI of the present application

[0048] 10 mg of the crystalline DCTRI prepared in Example 1 was placed in a mortar and manually ground for 15 minutes. XRPD analysis was performed before and after grinding. Figure 4 shown.

[0049] according to Figure 4 As can be seen, the crystal form of the DCTRI of the present invention remains unchanged after grinding, and no significant decrease in crystallinity is observed, indicating that the DCTRI crystal form has good mechanical stability. Good mechanical stability ensures that the sample will not easily undergo crystal transformation due to external forces such as mechanical grinding and crushing during the later formulation process, reducing the risk of crystal transformation during the formulation process and improving the developability of the formulation process.

[0050] Example 4 Packaging stability of the crystalline DCTRI of the present application

[0051] About 5 mg of the crystalline DCTRI prepared in Example 1 was weighed and placed at room temperature (25°C / 60% RH) and accelerated conditions (40°C / 75% RH and 60°C / 75% RH). The crystalline form was determined by XRPD. The experimental conditions and results are shown in Table 6. The XRPD overlay is shown in Table 6. Figure 5 shown.

[0052] Table 6 Placement conditions Placement time Crystal form Purity (peak area %) Start —— Crystalline DCTRI 99.54 25℃ / 60%RH 8 weeks Crystalline DCTRI 99.58 40℃ / 75%RH 8 weeks Crystalline DCTRI 99.63 60℃ / 75%RH 4 weeks Crystalline DCTRI 99.55

[0053] Results showed that the crystalline DCTRI of the present invention maintained its crystal form after 4 to 8 weeks at 25°C / 60% RH, 40°C / 75% RH, and 60°C / 75% RH, respectively. This demonstrates the excellent physical stability of the crystalline DCTRI. In particular, the crystal form remained stable after 4 weeks at the accelerated temperature of 60°C / 75% RH, with no crystal transformation. This further demonstrates the excellent physical stability of the crystalline DCTRI even under high temperature and high humidity conditions, ensuring that the drug is less susceptible to crystal transformation during subsequent processing, production, and transportation. Furthermore, the chemical purity of the crystalline DCTRI remained unchanged before and after storage at 40°C / 75% RH (relative humidity), remaining above 99%, demonstrating its excellent chemical stability. Furthermore, the chemical purity did not significantly decrease even at the accelerated temperature of 60°C / 75% RH, further demonstrating the excellent chemical stability of the crystalline DCTRI. Good physical and chemical stability ensures that the drug can maintain stable quality during the subsequent formulation development and process production, as well as the drug production and transportation process, ensuring the quality and efficacy of the drug, which is of great significance.

[0054] Example 5: Hygroscopicity of the Crystalline DCTRI of the Present Application

[0055] The hygroscopicity was determined according to the guidelines for drug hygroscopicity experiments in the General Chapter 9103 of the 2020 edition of the Chinese Pharmacopoeia. The test conditions were: 25 ± 1 °C and 80% relative humidity.

[0056] Definition of hygroscopic weight gain: extremely hygroscopic: hygroscopic weight gain is not less than 15.0%; hygroscopic: hygroscopic weight gain is less than 15.0% but not less than 2.0%; slightly hygroscopic: hygroscopic weight gain is less than 2.0% but not less than 0.2%; no or almost no hygroscopic: hygroscopic weight gain is less than 0.2%.

[0057] Weigh approximately 20 mg of the crystalline DCTRI prepared in Example 1 of the present application and place it at 25 ± 1 ° C and 80% relative humidity for 24 hours. The mass of the sample before and after is recorded, and the crystal form is determined by XRPD. The specific results are shown in Table 7 below, and the XRPD overlay is shown in Table 7. Figure 6 shown.

[0058] Table 7 Starting mass (mg) Placement conditions Placement time Mass after placement (mg) Weight gain (mg) Percentage of weight gain 22.2 25 ± 1 ℃, 80% RH 24 hours 22.3 0.10 0.45% As can be seen from Table 6, the crystalline DCTRI of the present invention has no or almost no hygroscopicity, which indicates that the crystalline DCTRI is not prone to deliquescence during drug production and storage.

[0059] Crystal stability is of great significance to drug development. If crystal transformation occurs, it will directly affect the drug's solubility and thus its bioavailability, thereby changing the drug's efficacy. Good chemical stability can ensure that the drug produces almost no new impurities or that the impurity content hardly increases during storage, thereby ensuring the safety of the drug. Good humidity stability can ensure that the sample will not easily undergo crystal transformation due to changes in ambient humidity during later storage, transportation, and formulation process preparation, reducing the risk of crystal transformation during sample storage, transportation, and formulation process, and improving the product's developability. Low hygroscopicity can ensure that the sample can maintain a low moisture weight gain and avoid deliquescence during later production, processing, storage, and transportation, thereby ensuring stable drug quality.

[0060] Therefore, the good physical stability and humidity stability of crystalline DCTRI, with almost no hygroscopicity, provide guarantees for the subsequent production and development of drugs and have high industrial development value.

[0061] The preferred embodiments of the present invention have been described in detail above. It should be understood that numerous modifications and variations based on the concepts of the present invention are possible without inventive effort by those skilled in the art. Therefore, any technical solution that can be derived by one skilled in the art through logical analysis, reasoning, or limited experimentation based on the concepts of the present invention and the prior art should be within the scope of protection defined by the claims.

Claims

1. A baloxavir marboxil and tropic acid cocrystal form DCTRI, characterized in that The X-ray powder diffraction spectrum of the baloxavirmarboxil and tropic acid cocrystal DCTRI under Cu-Ka radiation has diffraction angles of 2theta of 4.7±0.2°, 9.1±0.2°, 10.0±0.2°, 10.8±0.2°, 11.9±0.2°, 13.4±0.2°, 14.1±0.2°, 15.0±0.2°, 16.4±0.2°, 17.5±0.2°, 18. There are characteristic peaks at 0±0.2°, 19.1±0.2°, 19.9±0.2°, 20.5±0.2°, 21.5±0.2°, 22.5±0.2°, 23.8±0.2°, 24.5±0.2°, 26.2±0.2°, 26.6±0.2°, 27.5±0.2°, 28.1±0.2°, 29.7±0.2°, 30.2±0.2°, 30.7±0.2°, and 31.6±0.2°.

2. A method for preparing a baloxavir marboxil and tropic acid cocrystal form DCTRI, characterized in that: Baloxavir marboxil and tropic acid are placed in an organic solvent at a molar ratio of 1:1 to obtain a suspension, and the obtained suspension is stirred, separated, and dried to obtain a cocrystal form of Baloxavir marboxil and tropic acid, DCTRI.

3. The baloxavir marboxil and tropic acid cocrystal DCTRI according to claim 1, wherein: The differential scanning calorimetry spectrum of the baloxavir marboxil and tropic acid cocrystal form DCTRI shows an endothermic peak at 104±3°C.

4. The method for preparing a baloxavir marboxil and tropic acid cocrystal form DCTRI according to claim 2, wherein: The organic solvent is selected from any one of acetic acid, dichloromethane, methanol, ethanol, isopropanol, n-propanol, acetone, tetrahydrofuran, and acetonitrile.

5. The method for preparing a baloxavir marboxil and tropic acid cocrystal form DCTRI according to claim 2, wherein: The crystallization temperature is 0-40℃.

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