CN111303098A - Sphaelactone dimethylamine fumarate crystal form E and preparation method thereof - Google Patents
Sphaelactone dimethylamine fumarate crystal form E and preparation method thereof Download PDFInfo
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Abstract
The invention provides a michelia lactone dimethylamine fumarate crystal form E and a preparation method thereof. The characteristic peaks expressed by X-ray powder diffraction 2 theta are at 6.8 +/-0.2 degrees, 12.0 +/-0.2 degrees, 12.2 +/-0.2 degrees, 14.0 +/-0.2 degrees, 15.5 +/-0.2 degrees, 16.1 +/-0.2 degrees, 18.8 +/-0.2 degrees, 19.6 +/-0.2 degrees, 21.5 +/-0.2 degrees, 22.4 +/-0.2 degrees, 23.3 +/-0.2 degrees, 24.8 +/-0.2 degrees, 26.0 +/-0.2 degrees, 26.8 +/-0.2 degrees, 28.2 +/-0.2 degrees, 29.0 +/-0.2 degrees, 31.5 +/-0.2 degrees and 34.5 +/-0.2 degrees. The product has uniform particle size distribution, high bulk density and good crystallinity, is prepared by evaporation-cooling coupled crystallization, has the purity of over 99 percent, good stability, smooth surface, complete rod-shaped crystal habit, simple preparation process and good repeatability, and is suitable for large-scale production.
Description
Technical Field
The invention belongs to the technical field of medical crystallization, and particularly relates to a michelia lactone dimethylamine fumarate crystal form E and a preparation method thereof.
Background
Polymorphism refers to the presence of different molecular arrangements or conformations of the same substance in its crystal lattice, resulting in different crystal structures being formed. Different crystal forms of the same drug have obvious differences in the aspects of color, solubility, melting point, dissolution rate, fluidity, biological effectiveness and the like, so that the research on the polymorphism of the drug has important value for ensuring the stability of the drug in the production and storage processes and the safety in clinical use.
Michelia lactone dimethylamine fumarate, english name is dimethylamotrichalolide fumarate, molecular formula C21H31NO7The molecular weight 409 is white crystalline powder, is odorless, and is soluble in water, methanol, ethanol, tetrahydrofuran, 1, 4-dioxane, acetone, acetonitrile, and isopropyl acetate, and is almost insoluble in cyclohexane, n-hexane, n-heptane, dichloromethane, isopropyl ether, and toluene. The chemical structural formula is as follows:
michelia lactone, named Micheliolide (MCL) in English, has poor water solubility and belongs to guaiane type sesquiterpene lactoneThe related documents and patents report that michelia lactone has the effect of treating cancer diseases. In order to improve the water solubility and the bioactivity, michelia lactone derivative, namely dimethylamine michelia lactone with the molecular formula of C, is obtained by heating and reacting in methanol solvent under the condition that triethylamine is used as a catalyst17H27NO3The structural formula is as follows, the english name is Dimethylaminomicheliolide (DMAMCL), chinese patent CN101978959A discloses application of a smilactone derivative containing smilactone dimethylamine and a pharmaceutical composition in preparation of an anticancer drug, at present, the smilactone dimethylamine can selectively inhibit growth of acute myeloid leukocyte cells and glioma cells, and DMAMCL has a certain degree of improvement in water solubility compared with MCL, but can be degraded and unstable after being placed for a long time.
In order to further improve the water solubility and stability, the salt is usually prepared into a salt form, including smilactone dimethylamine hydrochloride, smilactone dimethylamine fumarate and the like, wherein the smilactone dimethylamine hydrochloride is extremely hygroscopic and difficult to transport and store although the water solubility is obviously improved. The michelia lactone dimethylamine fumarate can form a stable crystal form, and the physicochemical property of the crystal is more stable, the solubility is higher, the hygroscopicity is lower, the decomposition is not easy, the long-term storage is easy, and the drug effect utilization value is higher. Patent WO2011/131103a1 discloses a michelia lactone derivative containing michelia lactone dimethylamine fumarate or a salt thereof, a preparation method of a pharmaceutical composition of the derivative and an application of the derivative and the salt in preparation of a medicine for treating cancer.
The main structure of michelia lactone dimethylamine fumarate is michelia lactone, Chinese patent CN103724307B discloses michelia lactone dimethylamine fumarate crystal form A and a preparation method thereof, wherein XRPD is used for characterizing the crystal form A, 2 theta indicates that characteristic peaks exist at 7.10 degrees, 7.58 degrees, 11.72 degrees, 12.26 degrees, 13.30 degrees, 14.24 degrees, 15.70 degrees, 16.38 degrees, 17.04 degrees, 19.02 degrees, 19.86 degrees, 20.14 degrees, 20.66 degrees, 21.20 degrees, 21.78 degrees, 22.64 degrees, 23.58 degrees, 23.8 degrees, 24.48 degrees, 25.08 degrees, 26.24 degrees, 27.08 degrees, 27.60 degrees, 28.40 degrees, 28.94 degrees, 34.48 degrees, 34.82 degrees, 36.12 degrees, 38.72 degrees and 45 degrees, the crystal form A is prepared by recrystallization in ethyl acetate solvent, a natural cooling mode is adopted for preparing the product, the crystallization process is simultaneously controlled by natural cooling crystallization conditions and thermodynamics, the temperature reduction rate is not easily controlled, the bulk density is small and only reaches 0.270g/mL, the main particle size is 35.8 mu m, the angle of repose is 62 degrees, the fluidity is poor, and the quality of crystal products has large difference among different batches. Meanwhile, the crystal form A is easy to generate crystal form transformation, and a plurality of problems are brought to later processing and treatment.
Disclosure of Invention
In order to overcome the problems of low purity, uneven product particle size distribution, small bulk density, poor fluidity, large batch difference, poor stability and the like in the crystal form A of the smile lactone dimethylamine fumarate prepared by natural cooling crystallization in CN103724307B, the invention provides the crystal form E of the smile lactone dimethylamine fumarate and a preparation method thereof, and the crystal form E of the smile lactone dimethylamine fumarate has the advantages of uniform product particle size distribution, purity higher than 99%, smooth surface, high crystallinity and good stability, and aims to widen the selection range of the smile lactone dimethylamine fumarate in the subsequent drug development.
The invention provides a michelia lactone dimethylamine fumarate crystal form E, which is characterized in that an X-ray powder diffraction pattern obtained by using Cu-K α ray measurement is shown in figure 1, and diffraction angles 2 theta represent that characteristic peaks exist at 6.8 +/-0.2 degrees, 12.0 +/-0.2 degrees, 12.2 +/-0.2 degrees, 14.0 +/-0.2 degrees, 15.5 +/-0.2 degrees, 16.1 +/-0.2 degrees, 18.8 +/-0.2 degrees, 19.6 +/-0.2 degrees, 21.5 +/-0.2 degrees, 22.4 +/-0.2 degrees, 23.3 +/-0.2 degrees, 24.8 +/-0.2 degrees, 26.0 +/-0.2 degrees, 26.8 +/-0.2 degrees, 28.2 +/-0.2 degrees, 29.0 +/-0.2 degrees, 31.5 +/-0.2 degrees and 34.5 +/-0.2 degrees, wherein the relative intensity of the characteristic peak at 15.5 +/-0.2 degrees is 100%.
The invention provides a crystal form E of michelia lactone dimethylamine fumarate, which is characterized in that the crystal form is an orthorhombic system, and the space group is P212121Cell parameter of
α -90 °, β -90 °, γ -90 °, unit cell volume
The invention provides a crystal form E of michelia lactone dimethylamine fumarate, which is characterized in that differential scanning calorimetry analysis of the crystal form is shown in figure 2, the analysis result shows that a characteristic endothermic peak is present at 160 +/-2 ℃, the characteristic endothermic peak is the melting point of the crystal form E, the thermal weight loss analysis is shown in figure 3, no weight loss exists before the melting temperature, the crystal form E is a solvent-free compound,
the invention provides a preparation method of crystal form E of michelia lactone dimethylamine fumarate, which can be realized by evaporation-cooling coupled crystallization and comprises the following steps:
(1) adding the raw material of the michelia lactone dimethylamine fumarate into a mixed solvent of a first solvent and a second solvent under the stirring action, heating to 50-60 ℃, and completely dissolving the solid raw material, wherein the concentration of the solution is as follows: the mixed solvent is 0.010-0.027 g/mL;
(2) vacuum evaporation crystallization is adopted, the michelia lactone dimethylamine fumarate solution is evaporated, the vacuum degree is 0.01-0.05MPa, the evaporation rate is 20-30% per hour of the volume of the mixed solvent, after crystals are separated out, the crystals are grown for 0.5-1 hour, and the evaporation is finished when the volume of distillate is 50-60% of the volume of the mixed solvent;
(3) and then cooling and crystallizing at the cooling rate of 5-10 ℃/h to reduce the temperature to-5 ℃, and filtering, washing and drying the crystal mush to obtain the crystal form E product of the micheliolide dimethylamine fumarate, wherein the product is a rod-shaped crystal habit.
The first solvent is any one solvent selected from acetone, isopropyl acetate and 1, 4-dioxane.
The second solvent is selected from alkane organic solvents, preferably n-hexane and cyclohexane.
The volume of the second solvent is 30-50% of the first solvent.
The drying condition is forced air drying, the drying temperature is 40-50 ℃, and the drying time is 3-5 h.
An electron microscope scanning photograph of a michelia lactone dimethylamine fumarate A crystal form product reported in the prior patent is shown in an attached figure 4, and the product is prepared by a natural cooling recrystallization method, and has small particle size and uneven distribution, the main particle size is 35.8 mu m, the bulk density is only 0.270g/mL, the angle of repose is 62 degrees, and the flowability is poor. According to the method for preparing the smilax lactone dimethylamine fumarate E crystal form by adopting evaporation-cooling coupled crystallization, provided by the invention, the evaporation rate can be controlled by the volume of distillate, the cooling rate can be controlled by program temperature control, the supersaturation degree of a system can be accurately controlled, the crystal growing time in the evaporation-cooling coupled crystallization process is controlled to promote the crystal growth, the preparation process is simple, the repeatability is high, the method is suitable for large-scale production, the bulk density of the obtained crystal product is more than 0.376g/mL, the main particle size is 48.6 micrometers, the angle of repose is 48 degrees, the surface is smooth and clean, and no coalescence exists. The optical microscope photograph of the product of crystal form E is shown in figure 5. Meanwhile, the purity of the E crystal form is higher than 99%, and the crystal structure is analyzed, compared with the A crystal form product, the E crystal form provided by the invention improves the quality of the crystal product to a certain extent, and solves the problems of low bulk density, small granularity and poor fluidity of the A crystal form.
The invention inspects the stability of the crystal form E of the michelia lactone dimethylamine fumarate, and evenly distributes the compound product in an open culture dish at 25 ℃ and P2O5And (3) sealing the sample with the thickness of less than 5mm under the constant temperature and humidity condition, placing the sample in a dryer for 30 days, then respectively carrying out XRPD detection on the samples placed for 7 days, 14 days and 30 days, and comparing the detection result with the detection result on the 0 th day. The specific map is shown in figure 6, the result shows that the XRPD map is not obviously changed, meanwhile, the purity of the sample placed for 7 days, 14 days and 30 days is respectively analyzed, and compared with the purity detection result of the day 0, the purity of the sample at the day 7 is only changed by 0.01 percent, and the purity of the sample at the day 14 is only changed by 0.01 percentThe change is 0.03%, and the purity of the sample at the 30 th day is only 0.07%, which shows that the purity of the sample is not obviously changed. The XRD spectrum and the purity analysis result are combined, so that the michelia lactone dimethylamine fumarate E is proved to have good stability and good application prospect.
Drawings
FIG. 1 is an X-ray diffraction pattern of crystalline form E of sphaelactone dimethylamine fumarate of the present invention.
Figure 2 is a differential scanning calorimetry thermogram of the crystalline form E of sphaelactone dimethylamine fumarate of the present invention.
FIG. 3 is a thermogravimetric analysis of the crystalline form E of sphaelactone dimethylamine fumarate of the present invention.
FIG. 4 is a scanning electron micrograph (magnification 200 times) of a product of crystal form A prepared according to the method reported in patent CN103724307B
Figure 5 optical microscope image (40 x magnification) of crystalline form E of micheliolide dimethylamine fumarate according to the invention.
Figure 6 is a comparison of stability test spectra of crystalline form E of sphaelactone dimethylamine fumarate of the present invention, wherein XRPD spectra of samples placed for 0 day, 7 days, 14 days, and 30 days are shown from bottom to top.
Detailed Description
The foregoing and other objects of the present invention will be more fully understood from the following detailed description of the embodiments, taken in conjunction with the accompanying drawings, which are included to illustrate, but are not to be construed as the limit of the invention. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Example 1
Under the stirring action, 1.248g of michelia lactone dimethylamine fumarate raw material is added into a mixed solvent of 80mL of acetone and 24mL of n-hexane, and the temperature is raised to 50 ℃ to completely dissolve the solid raw material; vacuum evaporation crystallization is adopted, the michelia lactone dimethylamine fumarate solution is evaporated, the vacuum degree is 0.01MPa, the evaporation rate is 20.8mL/h, crystal growth is carried out for 0.5h when crystals are separated out, and evaporation is stopped when the volume of distillate reaches 52 mL; and cooling and crystallizing at the cooling rate of 5 ℃/h, filtering crystal mush, washing and drying at 50 ℃ for 3h when the temperature reaches 5 ℃, so as to obtain the michelia lactone dimethylamine fumarate E crystal form product.
The X-ray powder diffraction pattern of the product is expressed by 2 theta, and has characteristic peaks at 6.8 degrees, 12.0 degrees, 12.2 degrees, 14.0 degrees, 15.5 degrees, 16.1 degrees, 18.8 degrees, 19.6 degrees, 21.5 degrees, 22.4 degrees, 23.3 degrees, 24.8 degrees, 26.0 degrees, 26.8 degrees, 28.2 degrees, 29.0 degrees, 31.5 degrees and 34.5 degrees, wherein the relative intensity of the characteristic peaks at 15.5 degrees is 100 percent, which is consistent with the figure 1, and the DSC pattern has a characteristic endothermic peak at 160.5 degrees, which is consistent with the figure 2, thereby proving that the obtained product is the crystal form of the smilactone dimethylamine fumarate. The crystals were rod-shaped and similar to FIG. 5, had a bulk density of 0.376 g/mL. The crystal form E product of the micheliolide dimethylamine fumarate has high crystallinity, good stability and purity of 99.5 percent, and is prepared at 25 ℃ under the condition of P2O5The product is placed for 30 days under the condition, the color of the product is not changed, and the purity of the product is only changed by 0.063%.
Example 2
Under the stirring action, 2.016g of michelia lactone dimethylamine fumarate raw material is added into a mixed solvent of 80mL of isopropyl acetate and 32mL of n-hexane, and the temperature is raised to 60 ℃ to completely dissolve the solid raw material; vacuum evaporation crystallization is adopted, the michelia lactone dimethylamine fumarate solution is evaporated, the vacuum degree is 0.02MPa, the evaporation rate is 28mL/h, when crystals are separated out, the crystals are grown for 1h, and the evaporation is stopped when the volume of distillate reaches 61.6 mL; and cooling and crystallizing at the cooling rate of 10 ℃/h, filtering crystal mush, washing and drying at the temperature of 45 ℃ for 4h when the temperature reaches-5 ℃, so as to obtain the michelia lactone dimethylamine fumarate E crystal form product.
The X-ray powder diffraction pattern of the product is expressed by 2 theta, and has characteristic peaks at 6.8 degrees, 12.1 degrees, 14.0 degrees, 14.1 degrees, 15.4 degrees, 16.1 degrees, 18.7 degrees, 19.6 degrees, 21.5 degrees, 22.4 degrees, 23.5 degrees, 24.8 degrees, 25.8 degrees, 26.8 degrees, 28.2 degrees, 29.0 degrees, 31.5 degrees and 34.6 degrees, wherein the relative intensity of the characteristic peak at 15.5 degrees is 100 percent, which is consistent with the figure 1, and the DSC pattern has a characteristic endothermic peak at 158.4 degrees, which is consistent with the figure 2, thereby proving that the obtained product is the crystal form of the smilactone dimethylamine fumarate. The crystals were rod-shaped and had a bulk density of 0.379g/mL, similar to that of FIG. 5. Prepared crystal form E of michelia lactone dimethylamine fumarateThe product has high crystallinity, good stability, purity of 99.8 percent and P content at 25 DEG C2O5The product is placed for 30 days under the condition, the color of the product is not changed, and the purity of the product is only changed by 0.068 percent.
Example 3
Under the stirring action, 3.24g of michelia lactone dimethylamine fumarate raw material is added into a mixed solvent of 80mL of 1, 4-dioxane and 40mL of normal hexane, and the temperature is raised to 60 ℃ to completely dissolve the solid raw material; vacuum evaporation crystallization is adopted, the michelia lactone dimethylamine fumarate solution is evaporated, the vacuum degree is 0.05MPa, the evaporation rate is 36mL/h, when crystals are separated out, the crystals are grown for 0.8h, and the evaporation is stopped when the volume of distillate reaches 72 mL; and cooling and crystallizing at the cooling rate of 10 ℃/h, filtering crystal mush and washing when the temperature reaches 5 ℃, and carrying out forced air drying at 50 ℃ for 3h to obtain the michelia lactone dimethylamine fumarate E crystal form product.
The X-ray powder diffraction pattern of the product is expressed by 2 theta, and has characteristic peaks at 6.8 degrees, 12.2 degrees, 14.0 degrees, 14.2 degrees, 15.4 degrees, 16.1 degrees, 18.8 degrees, 19.6 degrees, 21.5 degrees, 22.4 degrees, 23.3 degrees, 24.9 degrees, 25.9 degrees, 26.8 degrees, 28.1 degrees, 29.0 degrees, 31.5 degrees and 34.5 degrees, wherein the relative intensity of the characteristic peak at 15.5 degrees is 100 percent, which is consistent with the figure 1, and the DSC pattern has a characteristic endothermic peak at 159.5 degrees, which is consistent with the figure 2, thereby proving that the obtained product is the crystal form of the smilactone dimethylamine fumarate. The crystals were rod-shaped and, similar to FIG. 5, had a bulk density of 0.380 g/mL. The crystal form E product of the micheliolide dimethylamine fumarate has high crystallinity, good stability and purity of 99.9 percent, and is prepared at 25 ℃ under the condition of P2O5The product is placed for 30 days under the condition, the color of the product is not changed, and the purity of the product is only changed by 0.071%.
Example 4
Under the stirring action, 1.2g of michelia lactone dimethylamine fumarate raw material is added into a mixed solvent of 80mL of acetone and 40mL of cyclohexane, and the temperature is raised to 60 ℃ to completely dissolve the solid raw material; vacuum evaporation crystallization is adopted, the michelia lactone dimethylamine fumarate solution is evaporated, the vacuum degree is 0.01MPa, the evaporation rate is 24mL/h, when crystals are separated out, the crystals are grown for 0.5h, and the evaporation is stopped when the volume of distillate reaches 60 mL; and cooling and crystallizing at the cooling rate of 8 ℃/h, filtering crystal mush, washing and drying at the temperature of 45 ℃ for 5h when the temperature reaches 5 ℃, thus obtaining the crystal form E product of the michelia lactone dimethylamine fumarate.
The X-ray powder diffraction pattern of the product is expressed by 2 theta, and has characteristic peaks at 6.8 degrees, 12.0 degrees, 12.2 degrees, 14.0 degrees, 15.4 degrees, 16.2 degrees, 18.8 degrees, 19.6 degrees, 21.3 degrees, 22.4 degrees, 23.3 degrees, 24.9 degrees, 26.0 degrees, 26.8 degrees, 28.1 degrees, 29.0 degrees, 31.5 degrees and 34.6 degrees, wherein the relative intensity of the characteristic peak at 15.5 degrees is 100 percent, which is consistent with the figure 1, and the DSC pattern has a characteristic endothermic peak at 160.3 degrees, which is consistent with the figure 2, thereby proving that the obtained product is the crystal form of the smilactone dimethylamine fumarate. The crystals were rod-shaped and similar to FIG. 5, had a bulk density of 0.382 g/mL. The crystal form E product of the micheliolide dimethylamine fumarate has high crystallinity, good stability and purity of 99.5 percent, and is prepared at 25 ℃ under the condition of P2O5The product is placed for 30 days under the condition, the color of the product is not changed, and the purity of the product is only changed by 0.07 percent.
Example 5
Under the stirring action, 1.21g of michelia lactone dimethylamine fumarate raw material is added into a mixed solvent of 80mL of isopropyl acetate and 30mL of cyclohexane, and the temperature is raised to 55 ℃ to completely dissolve the solid raw material; vacuum evaporation crystallization is adopted, the michelia lactone dimethylamine fumarate solution is evaporated, the vacuum degree is 0.01MPa, the evaporation rate is 22mL/h, when crystals are separated out, the crystals are grown for 0.5h, and the evaporation is stopped when the volume of distillate reaches 55 mL; and cooling and crystallizing at the cooling rate of 5 ℃/h, filtering crystal mush, washing and drying at 50 ℃ for 3h when the temperature reaches 0 ℃, so as to obtain the michelia lactone dimethylamine fumarate E crystal form product.
The X-ray powder diffraction pattern of the product is expressed by 2 theta, and has characteristic peaks at 6.9 degrees, 12.0 degrees, 12.2 degrees, 14.0 degrees, 15.5 degrees, 16.1 degrees, 18.7 degrees, 19.6 degrees, 21.5 degrees, 22.4 degrees, 23.1 degrees, 24.8 degrees, 25.8 degrees, 26.8 degrees, 28.1 degrees, 29.0 degrees, 31.4 degrees and 34.5 degrees, wherein the relative intensity of the characteristic peak at 15.5 degrees is 100 percent, which is consistent with the figure 1, and the DSC pattern has a characteristic endothermic peak at 160.7 degrees, which is consistent with the figure 2, thereby proving that the obtained product is the crystal form of the smilactone dimethylamine fumarate. The crystal is in a rod shape,similar to FIG. 5, the bulk density was 0.380 g/mL. The crystal form E product of the micheliolide dimethylamine fumarate has high crystallinity, good stability and purity of 99.3 percent, and is prepared at 25 ℃ under the condition of P2O5The product is placed for 30 days under the condition, the color of the product is not changed, and the purity of the product is only changed by 0.068 percent.
Example 6
Under the stirring action, 3.24g of michelia lactone dimethylamine fumarate raw material is added into a mixed solvent of 80mL of 1, 4-dioxane and 40mL of cyclohexane, and the temperature is raised to 50 ℃ to completely dissolve the solid raw material; vacuum evaporation crystallization is adopted, the michelia lactone dimethylamine fumarate solution is evaporated, the vacuum degree is 0.01MPa, the evaporation rate is 24mL/h, when crystals are separated out, the crystals are grown for 1h, and the evaporation is stopped when the volume of distillate reaches 72 mL; and cooling and crystallizing at the cooling rate of 5 ℃/h, filtering crystal mush, washing and drying at 40 ℃ for 5h when the temperature reaches 5 ℃, so as to obtain the smilactone dimethylamine fumarate E crystal form product.
The X-ray powder diffraction pattern of the product is expressed by 2 theta, and characteristic peaks are arranged at 6.8 degrees, 12.0 degrees, 12.2 degrees, 14.0 degrees, 15.5 degrees, 16.1 degrees, 18.8 degrees, 19.6 degrees, 21.5 degrees, 22.4 degrees, 23.3 degrees, 24.8 degrees, 26.0 degrees, 26.8 degrees, 28.2 degrees, 29.0 degrees, 31.5 degrees and 34.5 degrees, wherein the relative intensity of the characteristic peak at 15.5 degrees is 100 percent, which is consistent with the figure 1, and the DSC pattern has a characteristic endothermic peak at 161.5 degrees, which is consistent with the figure 2, thereby proving that the obtained product is the crystal form of the smilactone dimethylamine fumarate. The crystals were rod-shaped and, similar to FIG. 5, had a bulk density of 0.384 g/mL. The crystal form E product of the micheliolide dimethylamine fumarate has high crystallinity, good stability and purity of 99.6 percent, and is prepared at 25 ℃ under the condition of P2O5The product is placed for 30 days under the condition, the color of the product is not changed, and the purity of the product is only changed by 0.071%.
Claims (6)
1. A michelia lactone dimethylamine fumarate crystal form E is characterized in that diffraction angles expressed by 2 theta angles of an X-ray powder diffraction pattern obtained by Cu-K α ray measurement have characteristic peaks at 6.8 +/-0.2 degrees, 12.0 +/-0.2 degrees, 12.2 +/-0.2 degrees, 14.0 +/-0.2 degrees, 15.5 +/-0.2 degrees, 16.1 +/-0.2 degrees, 18.8 +/-0.2 degrees, 19.6 +/-0.2 degrees, 21.5 +/-0.2 degrees, 22.4 +/-0.2 degrees, 23.3 +/-0.2 degrees, 24.8 +/-0.2 degrees, 26.0 +/-0.2 degrees, 26.8 +/-0.2 degrees, 28.2 +/-0.2 degrees, 29.0 +/-0.2 degrees, 31.5 +/-0.2 degrees and 34.5 +/-0.2 degrees, wherein the relative intensity of the characteristic peaks at 15.5 +/-0.2 degrees is 100 percent.
2. The crystalline form E of micheliolide dimethylamine fumarate of claim 1, wherein said crystalline form is orthorhombic and has space group P212121Cell parameter of
α -90 °, β -90 °, γ -90 °, unit cell volume
3. Crystalline form E of micheliolide dimethylamine fumarate according to claim 1, characterized in that said crystalline form has a characteristic endothermic peak at 160 ± 2 ℃ which is the melting point of the crystalline form, no weight loss before the melting temperature and is a solvent free compound.
4. The preparation method of crystalline smilactone dimethylamine fumarate E according to any of claims 1-3, which is characterized by comprising the following steps: (1) adding the raw material of the michelia lactone dimethylamine fumarate into a mixed solvent of a first solvent and a second solvent under the stirring action, heating to 50-60 ℃, and completely dissolving the solid raw material, wherein the concentration of the solution is as follows: the mixed solvent is 0.010-0.027 g/mL; (2) vacuum evaporation crystallization is adopted, the michelia lactone dimethylamine fumarate solution is evaporated, the vacuum degree is 0.01-0.05MPa, the evaporation rate is 20-30% per hour of the volume of the mixed solvent, after crystals are separated out, the crystals are grown for 0.5-1 hour, and the evaporation is finished when the volume of distillate is 50-60% of the volume of the mixed solvent; (3) and then cooling and crystallizing at the cooling rate of 5-10 ℃/h to reduce the temperature to-5 ℃, and filtering, washing and drying the crystal mush to obtain the crystal form E product of the micheliolide dimethylamine fumarate, wherein the product is a rod-shaped crystal habit.
5. The first solvent according to claim 4 is selected from any one of acetone, isopropyl acetate and 1, 4-dioxane, the second solvent is selected from alkane organic solvents, preferably n-hexane and cyclohexane, and the volume of the second solvent is 30-50% of the volume of the first solvent.
6. The drying temperature of claim 4 is 40-50 ℃ and the drying time is 3-5 h.
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| CN113149946A (en) * | 2021-04-16 | 2021-07-23 | 天津大学 | Michellac dimethylamine lactone-m-hydroxybenzoate and preparation method and application thereof |
| CN113149947A (en) * | 2021-04-16 | 2021-07-23 | 天津大学 | Michellac dimethylamine lactone-p-hydroxybenzoate as well as preparation method and application thereof |
| EP4071143A4 (en) * | 2020-03-26 | 2023-01-11 | Accendatech | Hydrate of dimethylaminomicheliolide fumarate and preparation method therefor and use thereof |
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| CN113149947A (en) * | 2021-04-16 | 2021-07-23 | 天津大学 | Michellac dimethylamine lactone-p-hydroxybenzoate as well as preparation method and application thereof |
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