CN111303100B - Hydrate of michelia lactone dimethylamine fumarate, preparation method and application thereof - Google Patents
Hydrate of michelia lactone dimethylamine fumarate, preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a hydrate of michelia lactone dimethylamine fumarate, a preparation method and application thereof. The hydrate is of a crystal form D, and has the advantages of high crystallinity, smooth and clean particle surface without coalescence, high bulk density, good fluidity, and good stability and reproducibility; the preparation method comprises the following steps: under the stirring action, adding the michelia lactone dimethylamine and fumaric acid into a mixed solvent system with the constant temperature of 30-70 ℃ for reaction and crystallization, filtering after the reaction is finished, and drying the filtered solid at normal pressure to obtain the michelia lactone dimethylamine fumarate crystal form D.
Description
Technical Field
The invention belongs to the technical field of drug crystallization, and particularly relates to a michelia lactone dimethylamine fumarate hydrate, and a preparation method and application thereof.
Background
Parthenolide (Parthenolide) is a main active ingredient extracted from feverfew and tanacetum parthenium, which are Compositae plants, and is a natural sesquiterpene lactone compound, traditional Parthenolide is mainly used for treating diseases such as fever, rheumatoid arthritis, migraine, toothache and the like, and in recent years, researches at home and abroad find that Parthenolide also has an anti-tumor effect, but the compound is unstable in property under acidic or alkaline conditions.
In order to improve the stability of the compound, micheliolide (MCL) is obtained by modifying a compound, namely parthenolide, and belongs to guaiane type sesquiterpene lactone compounds, and related documents and patents report that the Micheliolide has the effect of treating cancer diseases, but the water solubility is poor. In order to improve water solubility and biological activity, michelia lactone derivative, namely michelia lactone dimethylamine with the molecular formula of C is obtained by heating reaction in methanol solvent under the condition that triethylamine is used as a catalyst 17 H 27 NO 3 The structural formula is shown in the specification, the English name is Dimethylaminomohemiolide (DMAMCL), and the 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. To further enhance its water solubility and stability, which is often prepared in salt form, the inventors have discovered smilactone dimethylamine fumarate which is prepared from derivatives of parthenolide. Meanwhile, patent WO2011/131103A1 discloses michelia lactone derivatives or salts thereof including michelia lactone dimethylamine fumarate, a preparation method of pharmaceutical compositions thereof, and application of pharmaceutical compositions in preparation of medicines for treating cancers.
Sphaelactone dimethylamine fumarate of formula C 21 H 31 NO 7 The molecular weight 409 is white crystalline powder,is odorless, and is soluble in water, methanol, ethanol, tetrahydrofuran, 1, 4-dioxane, acetone, acetonitrile, isopropyl acetate, and hardly soluble in cyclohexane, n-hexane, n-heptane, dichloromethane, isopropyl ether, and toluene. The chemical structural formula is as follows:
polymorphism refers to the existence of different molecular arrangements or conformations of the same substance in its crystal lattice, resulting in different crystal structures, and is statistically present in 80% of commercially available drugs. Different crystal forms of the same medicament have obvious differences in physicochemical properties such as color, solubility, melting point, density, hardness, crystal morphology and the like, so that quality differences such as stability, dissolution rate, bioavailability and the like of the medicament are caused, subsequent processing and treatment of the product are influenced, and the curative effect and safety of the medicament are influenced to a certain extent. In the process of drug quality control and design of new dosage forms, research on drug polymorphism has become an indispensable important component.
Chinese patent CN103724307B discloses michelia lactone dimethylamine fumarate crystal form a and a preparation method thereof, the patent characterizes the crystal form a by using XRPD, and has characteristic peaks expressed by 2 θ at 7.10 °, 7.58 °, 11.72 °, 12.26 °, 13.30 °, 14.24 °, 15.70 °, 16.38 °, 17.04 °, 19.02 °, 19.86 °, 20.14 °, 20.66 °, 21.20 °, 21.78 °, 22.64 °, 23.58 °, 23.8 °, 24.48 °, 25.08 °, 26.24 °, 27.08 °, 27.60 °, 28.40 °, 28.94 °, 34.48 °, 34.82 °, 36.12 °, 38.72 °, and 45 °, the crystal form a is prepared by recrystallization in an ethyl acetate solvent, in which a natural cooling manner is adopted to prepare the product, while the crystallization process is simultaneously controlled by thermodynamics and kinetics, the natural cooling crystallization conditions are greatly influenced by the environment, the temperature reduction rate is difficult to control, the product has a smaller main particle size, the bulk density of 35.8 μm, the difference between batches is smaller, and the bulk density is smaller than the difference of the product quality of the product with 0.270 mL/mL. Meanwhile, the stability of the crystal form A is poor, the crystal form conversion is easy to occur, and the solid powder has strong electrostatic action, so that a dust raising phenomenon exists in the production process, and a lot of problems are brought to later-stage processing and treatment.
Disclosure of Invention
In order to solve the problems, the invention provides a hydrate of michelia lactone dimethylamine fumarate, a preparation method and application thereof, and a reaction crystallization method is adopted to prepare a michelia lactone dimethylamine fumarate hydrate crystal product with high crystallinity, high bulk density, good fluidity, large particle size, smooth and clean crystal surface without coalescence and good stability.
The invention provides a hydrate of michelia lactone dimethylamine fumarate, which is characterized in that the hydrate is a crystal form D, the molar ratio of the michelia lactone dimethylamine fumarate to water is 1 17 H 27 NO 3 ·C 4 H 4 O 4 ·H 2 O, as shown in the thermogravimetric analysis/differential scanning calorimetry diagram, there is a weight loss of 3.97% to 4.22% before decomposition in the thermogravimetric analysis; the hydrate of the michelia lactone dimethylamine fumarate is characterized in that a differential scanning calorimetry analysis chart has a dehydration endothermic peak at 75 +/-5 ℃ and a characteristic melting peak at 148 +/-5 ℃.
The invention provides a michelia lactone dimethylamine fumarate hydrate, which is characterized in that the hydrate uses Cu-Kalpha radiation, and X-ray powder diffraction represented by 2 theta angles as shown in figure 2 has characteristic peaks at 7.8 +/-0.2 degrees, 11.1 +/-0.2 degrees, 11.4 +/-0.2 degrees, 12.6 +/-0.2 degrees, 12.9 +/-0.2 degrees, 14.4 +/-0.2 degrees, 15.3 +/-0.2 degrees, 17.0 +/-0.2 degrees, 18.7 +/-0.2 degrees, 19.7 +/-0.2 degrees, 20.6 +/-0.2 degrees, 21.0 +/-0.2 degrees, 22.5 +/-0.2 degrees, 23.7 +/-0.2 degrees, 24.3 +/-0.2 degrees, 25.5 +/-0.2 degrees and 26.2 +/-0.2 degrees, wherein 7.8 +/-0.2 degrees is an initial peak, the relative intensity of the characteristic peak at 20.6 +/-0.2 degrees is 100 percent, the crystal system space D is an orthogonal crystal form, and the crystal cell group is 121P
α＝90°，β＝90°，γ＝90 DEG, cell volume of
The invention provides a hydrate of michelia lactone dimethylamine fumarate, which is characterized in that the hydrate uses Cu-Kalpha radiation, and has characteristic peaks at 10.5 +/-0.2 degrees, 11.7 +/-0.2 degrees, 12.0 +/-0.2 degrees, 15.6 +/-0.2 degrees, 15.9 +/-0.2 degrees, 16.2 +/-0.2 degrees, 21.3 +/-0.2 degrees, 22.1 +/-0.2 degrees, 23.0 +/-0.2 degrees, 26.4 +/-0.2 degrees, 27.2 +/-0.2 degrees, 28.2 +/-0.2 degrees, 28.6 +/-0.2 degrees, 29.3 +/-0.2 degrees, 30.4 +/-0.2 degrees and 31.1 +/-0.2 degrees by X-ray powder diffraction represented by 2 theta angles.
The invention also provides a preparation method of the micheliolide dimethylamine fumarate hydrate, which can be realized by a reaction crystallization method: adding dimethylamine michelia lactone and fumaric acid into a mixed solvent system of a solvent S1 and a solvent S2 with the constant temperature of 30-70 ℃ under the stirring action, wherein the mass ratio of the solvent S2 to the solvent S1 is (0-3) to 1, the molar ratio of the dimethylamine michelia lactone to the fumaric acid is (1-1.6) to 1, reacting for 5-10h, filtering, and drying at 25-45 ℃ for 6-10h under normal pressure to obtain the crystal form D of the michelia lactone dimethylamine fumarate.
The solvent S1 is a mixed solvent of any one of acetone, tetrahydrofuran, 1, 4-dioxane, acetonitrile and methyl isobutyl ketone and water
The solvent S2 is a mixed solvent of ester and ether solvents.
The ester solvent is selected from one or two of methyl acetate, ethyl acetate, hexyl acetate and isopropyl acetate.
The ether solvent is one or two selected from diethyl ether, methyl ethyl ether, methyl tert-butyl ether, dipropyl ether, dibutyl ether, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, 1, 4-dioxane, tetrahydrofuran and 2-methyltetrahydrofuran.
The solvent S1 is a mixed solvent of any one of acetone, tetrahydrofuran, 1, 4-dioxane, acetonitrile and methyl isobutyl ketone and water.
The mass ratio of the ester solvent to the ether solvent in the solvent S2 is (1-3) to 1.
The mass ratio of the solid raw material of the michelia lactone dimethylamine to S1 is 1: (6-10).
The crystal habit of the hydrate of the michelia lactone dimethylamine fumarate is researched, a scanning electron microscope image of the crystal is shown in an attached figure 3, the crystal is a regular block crystal habit, the particle surface is smooth and has no coalescence, the average particle size of the crystal is large and can reach 300 mu m, the bulk density is 0.65g/mL, the angle of repose is 32 degrees, the bulk density of a product is high, and the flowability is good. Compared with the crystal form A prepared by adopting the natural cooling recrystallization method disclosed by the patent CN103724307B, the main particle size of the product is 35.8um, the bulk density is only up to 0.270g/mL, the angle of repose is 62 degrees, and a scanning electron microscope image shows that the crystal form D of the michelia lactone dimethylamine fumarate hydrate product provided by the invention is shown in an attached figure 4.
The stability of the hydrate of the michelia lactone dimethylamine fumarate is inspected, the anhydrous crystal compound product is uniformly distributed in an open culture dish, the temperature is controlled at 45 ℃, the humidity is 75%, the thickness of the sample is less than 5mm, the anhydrous crystal compound product is hermetically placed in a dryer for 30 days, then the samples placed for 7 days, 14 days and 30 days are respectively subjected to XRD detection, and the detection result is compared with the detection result of the day 0. The specific spectrum is shown in figure 5, and the result shows that the XRD spectrum does not change obviously, meanwhile, the purity of the samples which are placed for 7 days, 14 days and 30 days is analyzed respectively, and compared with the purity detection result of the day 0, the purity of the samples at the day 7 is only changed by 0.015%, the purity of the samples at the day 14 is only changed by 0.027%, the purity of the samples at the day 30 is only changed by 0.046%, and the purity of the samples is not changed obviously. The XRD pattern and the purity analysis result are integrated, and the stability of the hydrate of the michelide dimethylamine fumarate is proved to be better.
The micheliolide dimethylamine fumarate hydrate provided by the invention can be used for preparing micheliolide dimethylamine fumarate solvent-free compound crystal form B, and the preparation method of the crystal form B is as follows: heating the hydrate of the micheliolide dimethylamine fumarate at the constant temperature of 80-120 ℃ for 10-30 min to obtain micheliolide dimethylamine fumarate solvent-free compound crystal form B, wherein the X-ray powder diffraction pattern of the crystal form B is shown in figure 6, expressed by the angle of 2 theta, the peak has the characteristic peaks at 8.1 +/-0.2 degrees, 10.7 +/-0.2 degrees, 11.5 +/-0.2 degrees, 11.9 +/-0.2 degrees, 13.0 +/-0.2 degrees, 13.3 +/-0.2 degrees, 14.7 +/-0.2 degrees, 15.9 +/-0.2 degrees, 16.1 +/-0.2 degrees, 16.7 +/-0.2 degrees, 17.1 +/-0.2 degrees, 19.0 +/-0.2 degrees, 19.9 +/-0.2 degrees, 20.3 +/-0.2 degrees, 21.2 +/-0.2 degrees, 21.5 +/-0.2 degrees, 22.1 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.5 +/-0.2 degrees, 24.4 +/-0.2 degrees, 26.0 +/-0.2 degrees, 26.6 +/-0.2 degrees, 26.9 +/-0.2 degrees, 27.4 +/-0.2 degrees, 27.9 +/-0.2 degrees, 28.6 +/-0.2 degrees, 29.2 degrees, 30.2 degrees and 30.2 degrees. The scanning electron micrograph is similar to that in the attached figure 5, which shows that the crystal habit and the hydrate are consistent, the crystal habit and the hydrate are blocky, and the particle size is large.
The micheliolide dimethylamine fumarate hydrate also provides a pharmaceutical composition, which comprises pharmaceutically acceptable auxiliary materials and can also comprise one, two or more other pharmacologically active ingredients besides the micheliolide dimethylamine fumarate hydrate.
Such pharmaceutical excipients include, but are not limited to, other non-pharmacologically active ingredients in addition to the active ingredient, such as crystalline form of minoxidil fumarate, such as non-pharmacologically active ingredients that may be used in the pharmaceutical compositions of the present invention, including carriers or excipients, such as fillers, glidants, lubricants, binders, stabilizers and/or other excipients.
The filler includes, but is not limited to, at least one of corn starch, glucose, mannitol, sorbitol, silicon dioxide, microcrystalline cellulose, sodium carboxymethyl starch, complex starch, pregelatinized starch.
The flow aid includes, but is not limited to, at least one of silicon dioxide, hydrated silicon dioxide, light anhydrous silicic acid, dried aluminum hydroxide gel, aluminum silicate, magnesium silicate.
The lubricant includes, but is not limited to, at least one of wheat starch, rice starch, corn starch, stearic acid, calcium stearate, magnesium stearate, hydrated silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, dried aluminum hydroxide gel, talc, magnesium aluminum metasilicate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, sucrose fatty acid ester, paraffin, hydrogenated vegetable oil, and polyethylene glycol.
The pharmaceutical composition is used for preparing a pharmaceutical preparation, and is characterized by comprising a tablet, a capsule or a granule of the pharmaceutical composition. More preferably capsules.
The invention also provides the use of said smilacin dimethylamine fumarate hydrate or said pharmaceutical composition in the manufacture of a medicament for the treatment or prevention of a disease or condition, preferably a cancer, selected from leukemia, breast cancer, prostate cancer, nasopharyngeal cancer, colorectal cancer, lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, renal cancer, oral cancer, hodgkin lymphoma, pancreatic cancer, colorectal cancer, cervical cancer, non-hodgkin lymphoma, glioma, melanoma, bladder cancer, ovarian cancer, thyroid cancer or kaposi sarcoma.
Advantageous effects
The hydrate of the invention has better fluidity and is more suitable for preparing patent medicine at the later stage. It is known that the flowability of active ingredients per se is generally difficult to satisfy the filling conditions of capsules or microcapsules, and auxiliary materials such as pregelatinized starch, silicon dioxide and magnesium stearate are required to satisfy the requirements of the filling conditions on the flowability so as to achieve the desired dosage form quality and production efficiency. Taking the specification of 100mg capsules as an example, if other forms such as crystal form a are taken as active ingredients, and auxiliary materials are added, the weight of the content of the capsules reaches about 310mg, the largest 0# capsule shell must be used, and larger capsules such as capsules containing 200mg of active ingredients cannot be prepared. For this reason, patients would have to achieve high dose administration by increasing the amount of capsules taken or the number of administrations, which would significantly reduce patient compliance. However, the inventors have found that the superior flowability of the micheliolide dimethylamine fumarate hydrate form D allows it to reach an angle of repose of 32 ° even without the addition of adjuvants, for which reason the flowability required for the filling conditions of capsules or microcapsules can be achieved with a significantly reduced amount of adjuvants, even without the addition of any adjuvants. Moreover, the reduction in the amount of excipients makes it possible to produce capsules of high dosage specification, significantly improving patient compliance.
Furthermore, the addition amount of auxiliary materials can be reduced even no auxiliary materials are added due to the michelide dimethylamine fumarate hydrate crystal form D. The crystal form A has the same fluidity as the hydrate crystal form D only by adding a large amount of auxiliary materials, and the stability is poor, so the hydrate crystal form D also improves the stability of the preparation.
In addition, the preparation method of the crystal form D of the michelia lactone dimethylamine fumarate hydrate has the advantages of simple operation steps, high product yield, good reproducibility, high crystallinity, smooth and clean particle surfaces without coalescence, no static electricity among particles and high bulk density, and is more favorable for large-scale production.
Drawings
FIG. 1 is a thermogravimetric/differential scanning calorimetry trace of micheliolide dimethylamine fumarate hydrate according to the invention.
FIG. 2 is an X-ray diffraction pattern of michelilactone dimethylamine fumarate hydrate according to the invention.
FIG. 3 is a scanning electron microscope image (40 times magnification) of micheliolide dimethylamine fumarate hydrate according to the invention.
FIG. 4 is a scanning electron microscope image (magnification 200 times) of a crystal form A product prepared according to the method disclosed in patent CN 103724307B.
FIG. 5 is a comparison of stability test patterns of the michelia lactone dimethylamine fumarate hydrate of the invention, wherein the XRD patterns of the samples are placed for 0 day, 7 days, 14 days and 30 days from bottom to top.
FIG. 6 is an X-ray diffraction pattern of crystalline form B of micheliolide dimethylamine fumarate of the present invention.
Detailed Description
The foregoing and other aspects of the present invention will be apparent from, and elucidated with reference to, the embodiments described hereinafter, without being construed as limited by the scope of the subject matter of the invention set forth in the claims. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Example 1
Preparation of hydrate of michelia lactone dimethylamine fumarate
Under the stirring action, 0.293g of dimethylamine michelia lactone and 0.116g of fumaric acid are added into a mixed solvent system of a solvent S1 and a solvent S2 at a constant temperature of 30 ℃, the mass of the solvent S1 is the same as that of the solvent S2, wherein the solvent S1 consists of 1.598g of acetone solvent and 0.16g of water, and the solvent S2 consists of 0.879g of ethyl acetate and 0.879g of diethyl ether, and after 5 hours of reaction, filtration and normal-pressure drying at 25 ℃ are carried out for 6 hours, so as to obtain the michelia lactone dimethylamine fumarate D crystal form product. The thermogravimetric analysis/differential scanning calorimetry analysis of the product is consistent with that shown in figure 1, the thermogravimetric analysis shows that 4.22% of weight loss exists before decomposition, the differential scanning calorimetry analysis shows that a dehydration endothermic peak exists at 75 ℃, and a characteristic melting peak exists at 148 ℃. The X-ray powder diffraction pattern of the product is consistent with that of figure 2, and the characteristic peaks expressed by the diffraction angle 2 theta at 7.8 degrees, 11.1 degrees, 11.4 degrees, 12.6 degrees, 12.9 degrees, 14.4 degrees, 15.3 degrees, 17.0 degrees, 18.7 degrees, 19.7 degrees, 20.6 degrees, 21.0 degrees, 22.5 degrees, 23.7 degrees, 24.3 degrees, 25.5 degrees and 26.2 degrees are shown, wherein 7.8 degrees is an initial peak, and the relative intensity of the characteristic peak at 20.6 degrees is 100 percent. The X-ray powder diffraction pattern of the product has characteristic peaks at the angles of 2 theta of 10.5 +/-0.2 degrees, 11.7 +/-0.2 degrees, 12.0 +/-0.2 degrees, 15.6 +/-0.2 degrees, 15.9 +/-0.2 degrees, 16.2 +/-0.2 degrees, 21.3 +/-0.2 degrees, 22.1 +/-0.2 degrees, 23.0 +/-0.2 degrees, 26.4 +/-0.2 degrees, 27.2 +/-0.2 degrees, 28.2 +/-0.2 degrees, 28.6 +/-0.2 degrees, 29.3 +/-0.2 degrees, 30.4 +/-0.2 degrees and 31.1 +/-0.2 degrees. The SEM picture of the crystal morphology is consistent with that shown in figure 4, the crystal is a blocky crystal, the average particle size of the particles is large and can reach 300 mu m, the bulk density is 0.646g/mL, and the angle of repose is 32.5 degrees.
Example 2
Preparation of hydrate of michelia lactone dimethylamine fumarate
Under the stirring action, 1.758g of michelia lactone dimethylamine and 0.58g of fumaric acid are added into a mixed solvent system of a solvent S1 and a solvent S2 with the constant temperature of 50 ℃, the mass of the solvent S2 is 2 times of that of the solvent S1, wherein the solvent S1 consists of 12.306g of tetrahydrofuran solvent and 1.758g of water, and the solvent S2 consists of 21.096g of isopropyl acetate and 7.032g of methyl tert-butyl ether, and after 8 hours of reaction, filtration and normal pressure drying at 30 ℃ are carried out for 10 hours, so as to obtain the michelia lactone dimethylamine fumarate D crystal form product. The thermogravimetric analysis/differential scanning calorimetry analysis of the product is consistent with that shown in figure 1, the thermogravimetric analysis shows that 4.20% of weight loss exists before decomposition, the differential scanning calorimetry analysis shows that dehydration endothermic peak exists at 78 ℃, and characteristic melting peak exists at 150 ℃. The X-ray powder diffraction pattern of the product is consistent with that of figure 2, and the characteristic peaks expressed by the diffraction angle 2 theta at 8.0 degrees, 11.2 degrees, 11.5 degrees, 12.7 degrees, 12.9 degrees, 14.5 degrees, 15.4 degrees, 17.1 degrees, 18.8 degrees, 19.8 degrees, 20.6 degrees, 21.1 degrees, 22.5 degrees, 23.7 degrees, 24.5 degrees, 25.6 degrees and 26.3 degrees are shown, wherein 7.8 degrees is an initial peak, and the relative intensity of the characteristic peak at 20.6 degrees is 100 percent. The X-ray powder diffraction pattern of the product also has characteristic peaks at 10.6 degrees, 11.8 degrees, 12.2 degrees, 15.1 degrees, 15.7 degrees, 16.0 degrees, 21.4 degrees, 22.0 degrees, 22.3 degrees, 23.1 degrees, 27.3 degrees, 28.2 degrees, 28.7 degrees, 29.4 degrees, 30.5 degrees, 30.6 degrees and 31.3 degrees which are expressed by 2 theta angles. The SEM photograph of the crystal morphology is consistent with the attached figure 4, the crystal is a blocky crystal, the average particle size of the particles is large and can reach 300 mu m, the bulk density is 0.655g/mL, and the angle of repose is 32 degrees.
Example 3
Preparation of hydrate of michelia lactone dimethylamine fumarate
Under the stirring action, 4.688g of michelia lactone dimethylamine and 1.16g of fumaric acid are added into a mixed solvent system of a solvent S1 and a solvent S2 with the constant temperature of 70 ℃, the mass of the solvent S2 is 3 times of that of the solvent S1, wherein the solvent S1 consists of 39g of 1, 4-dioxane solvent and 7.88g of water, the solvent S2 consists of 93.76g of methyl acetate and 46.88g of methyl ethyl ether, the mixture is filtered after 10 hours of reaction, and the mixture is dried at 45 ℃ under normal pressure for 8 hours to obtain the michelia lactone dimethylamine fumarate D crystal form product. The thermogravimetric analysis/differential scanning calorimetry analysis of the product is consistent with that shown in figure 1, the thermogravimetric analysis shows that 3.97% of weight loss exists before decomposition, the differential scanning calorimetry analysis shows that dehydration endothermic peak exists at 75 ℃, and characteristic melting peak exists at 145 ℃. The X-ray powder diffraction pattern of the product is consistent with that of figure 2, and the characteristic peaks expressed by the diffraction angle 2 theta at 7.8 degrees, 11.0 degrees, 11.4 degrees, 12.5 degrees, 12.8 degrees, 14.4 degrees, 15.3 degrees, 17.0 degrees, 18.7 degrees, 19.7 degrees, 20.6 degrees, 21.0 degrees, 22.4 degrees, 23.7 degrees, 24.3 degrees, 25.4 degrees and 26.2 degrees are shown, wherein 7.8 degrees is an initial peak, and the relative intensity of the characteristic peak at 20.6 degrees is 100 percent. The X-ray powder diffraction pattern of the product also has characteristic peaks at 10.5 degrees, 11.7 degrees, 12.0 degrees, 15.6 degrees, 15.9 degrees, 16.2 degrees, 21.3 degrees, 22.2 degrees, 22.9 degrees, 26.4 degrees, 27.3 degrees, 28.2 degrees, 28.6 degrees, 29.3 degrees, 30.4 degrees and 31.1 degrees in terms of 2 theta angles. The SEM photograph of the crystal morphology is consistent with that of the attached figure 4, the crystal is a blocky crystal, the average particle size of the particles is large and can reach 300 mu m, the bulk density is 0.65g/mL, and the angle of repose is 32 degrees.
Example 4
Preparation of hydrate of michelia lactone dimethylamine fumarate
Under the stirring action, 4.102g of michelia lactone dimethylamine and 1.16g of fumaric acid are added into a mixed solvent system of a solvent S1 and a solvent S2 with the constant temperature of 60 ℃, the mass of the solvent S2 is 3 times of that of the solvent S1, wherein the solvent S1 consists of 35.8925g of acetonitrile solvent and 5.1275g of water, and the solvent S2 consists of 87.9g of hexyl acetate and 35.16g of ethylene glycol dimethyl ether, and after 10 hours of reaction, filtration and normal-pressure drying at 45 ℃ for 9 hours are carried out, so that a michelia lactone dimethylamine fumarate D crystal form product is obtained. The thermogravimetric analysis/differential scanning calorimetry analysis of the product is consistent with that shown in figure 1, the thermogravimetric analysis shows that 4.10% of weight loss exists before decomposition, the differential scanning calorimetry analysis shows that dehydration endothermic peak exists at 80 ℃, and characteristic melting peak exists at 150 ℃. The X-ray powder diffraction pattern of the product is consistent with that of figure 2, and the characteristic peaks expressed by the diffraction angle 2 theta at 7.8 degrees, 11.1 degrees, 11.4 degrees, 12.6 degrees, 12.9 degrees, 14.4 degrees, 15.4 degrees, 17.0 degrees, 18.8 degrees, 19.8 degrees, 20.6 degrees, 21.0 degrees, 22.5 degrees, 23.7 degrees, 24.4 degrees, 25.5 degrees and 26.2 degrees are shown, wherein 7.8 degrees is an initial peak, and the relative intensity of the characteristic peak at 20.6 degrees is 100 percent. The X-ray powder diffraction pattern of the product also has characteristic peaks at 10.6 degrees, 11.8 degrees, 12.1 degrees, 15.9 degrees, 16.3 degrees, 21.4 degrees, 22.2 degrees, 23.0 degrees, 26.5 degrees, 27.3 degrees, 28.7 degrees, 29.3 degrees, 30.4 degrees and 31.1 degrees in terms of 2 theta angles. The SEM photograph of the crystal morphology is consistent with the attached figure 4, the crystal is a blocky crystal, the average particle size of the particles is large and can reach 300 mu m, the bulk density is 0.659g/mL, and the angle of repose is 32.2 degrees.
Example 5
Preparation of hydrate of michelia lactone dimethylamine fumarate
Under the stirring action, 0.293g of dimethylamine michelia lactone and 0.116g of fumaric acid are added into a mixed solvent system of a solvent S1 and a solvent S2 at a constant temperature of 30 ℃, the mass of the solvent S1 is the same as that of the solvent S2, wherein the solvent S1 consists of 1.598g of acetonitrile solvent and 0.16g of water, and the solvent S2 consists of 0.879g of isopropyl acetate and 0.879g of ethylene glycol monomethyl ether, and after 5 hours of reaction, filtration and normal-pressure drying at 25 ℃ are carried out for 6 hours, so as to obtain the michelia lactone dimethylamine fumarate D crystal form product. The thermogravimetric analysis/differential scanning calorimetry analysis of the product is consistent with that shown in figure 1, the thermogravimetric analysis shows that 4.22% of weight loss exists before decomposition, the differential scanning calorimetry analysis shows that a dehydration endothermic peak exists at 75 ℃, and a characteristic melting peak exists at 148 ℃. The X-ray powder diffraction pattern of the product is consistent with that shown in figure 2, and the characteristic peaks are represented by diffraction angles 2 theta at 7.8 degrees, 11.1 degrees, 11.4 degrees, 12.6 degrees, 12.9 degrees, 14.4 degrees, 15.3 degrees, 17.0 degrees, 18.7 degrees, 19.7 degrees, 20.6 degrees, 21.0 degrees, 22.5 degrees, 23.7 degrees, 24.3 degrees, 25.5 degrees and 26.2 degrees, wherein 7.8 degrees is an initial peak, and the relative intensity of the characteristic peaks at 20.6 degrees is 100 percent. The X-ray powder diffraction pattern of the product has characteristic peaks expressed by 2 theta angles at 10.5 +/-0.2 degrees, 11.7 +/-0.2 degrees, 12.0 +/-0.2 degrees, 15.6 +/-0.2 degrees, 15.9 +/-0.2 degrees, 16.2 +/-0.2 degrees, 21.3 +/-0.2 degrees, 22.1 +/-0.2 degrees, 23.0 +/-0.2 degrees, 26.4 +/-0.2 degrees, 27.2 +/-0.2 degrees, 28.2 +/-0.2 degrees, 28.6 +/-0.2 degrees, 29.3 +/-0.2 degrees, 30.4 +/-0.2 degrees and 31.1 +/-0.2 degrees. The SEM photograph of the crystal morphology is consistent with that shown in figure 4, the crystal is a blocky crystal, the average particle size of the particles is large and can reach 300 mu m, the bulk density is 0.645g/mL, and the angle of repose is 32 degrees.
Example 6
Preparation of hydrate of michelia lactone dimethylamine fumarate
Under the stirring action, 4.688g of michelia lactone dimethylamine and 1.16g of fumaric acid are added into a mixed solvent system of a solvent S1 and a solvent S2 with the temperature constant at 70 ℃, the mass of the solvent S2 is 3 times of that of the solvent S1, wherein the solvent S1 consists of 39g of methyl isobutyl ketone solvent and 7.88g of water, and the solvent S2 consists of 46.88g of methyl acetate, 46.88g of isopropyl acetate, 23.44g of tetrahydrofuran and 23.44g of dibutyl ether, and after 10 hours of reaction, the mixture is filtered and dried at 45 ℃ under normal pressure for 8 hours to obtain the michelia lactone dimethylamine fumarate D crystal form product. The thermogravimetric analysis/differential scanning calorimetry analysis of the product is consistent with that shown in figure 1, the thermogravimetric analysis shows that 3.97% of weight loss exists before decomposition, the differential scanning calorimetry analysis shows that dehydration endothermic peak exists at 75 ℃, and characteristic melting peak exists at 145 ℃. The X-ray powder diffraction pattern of the product is consistent with that shown in figure 2, and the characteristic peaks are represented by diffraction angles 2 theta at 7.8 degrees, 11.0 degrees, 11.4 degrees, 12.5 degrees, 12.8 degrees, 14.4 degrees, 15.3 degrees, 17.0 degrees, 18.7 degrees, 19.7 degrees, 20.6 degrees, 21.0 degrees, 22.4 degrees, 23.7 degrees, 24.3 degrees, 25.4 degrees and 26.2 degrees, wherein 7.8 degrees is an initial peak, and the relative intensity of the characteristic peaks at 20.6 degrees is 100 percent. The X-ray powder diffraction pattern of the product has characteristic peaks at the angles of 2 theta of 10.5 degrees, 11.7 degrees, 12.0 degrees, 15.6 degrees, 15.9 degrees, 16.2 degrees, 21.3 degrees, 22.2 degrees, 22.9 degrees, 26.4 degrees, 27.3 degrees, 28.2 degrees, 28.6 degrees, 29.3 degrees, 30.4 degrees and 31.1 degrees. The SEM photograph of the crystal morphology is consistent with the attached figure 4, the crystal is a blocky crystal, the average particle size of the particles is large and can reach 300 mu m, the bulk density is 0.65g/mL, and the angle of repose is 32.3 degrees.
Example 7
Preparation of hydrate of michelia lactone dimethylamine fumarate
Under the stirring action, 1.758g of michelia lactone dimethylamine and 0.58g of fumaric acid are added into a mixed solvent system of a solvent S1 and a solvent S2 with the constant temperature of 50 ℃, the mass of the solvent S2 is 2 times of that of the solvent S1, wherein the solvent S1 consists of 12.306g of methyl isobutyl ketone solvent and 1.758g of water, the solvent S2 consists of 21.096g of methyl acetate and 7.032g of 2-methyl tetrahydrofuran, and after 9 hours of reaction, filtration and normal-pressure drying at 30 ℃ are carried out for 10 hours, so as to obtain the michelia lactone dimethylamine fumarate D crystal form product. The thermogravimetric analysis/differential scanning calorimetry analysis of the product is consistent with that shown in figure 1, the thermogravimetric analysis shows that 4.20% of weight loss exists before decomposition, the differential scanning calorimetry analysis shows that dehydration endothermic peak exists at 78 ℃, and characteristic melting peak exists at 150 ℃. The X-ray powder diffraction pattern of the product is consistent with that of figure 2, and the characteristic peaks expressed by the diffraction angle 2 theta at 8.0 degrees, 11.2 degrees, 11.5 degrees, 12.7 degrees, 12.9 degrees, 14.5 degrees, 15.4 degrees, 17.1 degrees, 18.8 degrees, 19.8 degrees, 20.6 degrees, 21.1 degrees, 22.5 degrees, 23.7 degrees, 24.5 degrees, 25.6 degrees and 26.3 degrees are shown, wherein 7.8 degrees is an initial peak, and the relative intensity of the characteristic peak at 20.6 degrees is 100 percent. The X-ray powder diffraction pattern of the product also has characteristic peaks at 10.6 degrees, 11.8 degrees, 12.2 degrees, 15.1 degrees, 15.7 degrees, 16.0 degrees, 21.4 degrees, 22.0 degrees, 22.3 degrees, 23.1 degrees, 27.3 degrees, 28.2 degrees, 28.7 degrees, 29.4 degrees, 30.5 degrees, 30.6 degrees and 31.3 degrees which are expressed by 2 theta angles. The SEM photograph of the crystal morphology is consistent with that of the attached figure 4, the crystal is a blocky crystal, the average particle size of the particles is large and can reach 300 mu m, the bulk density is 0.65g/mL, and the angle of repose is 32 degrees.
Example 8
Preparation of hydrate of michelia lactone dimethylamine fumarate
Under the stirring action, 4.102g of michelia lactone dimethylamine and 1.16g of fumaric acid are added into a mixed solvent system of a solvent S1 and a solvent S2 with the constant temperature of 60 ℃, the mass of the solvent S2 is 3 times of that of the solvent S1, wherein the solvent S1 consists of 35.8925g of tetrahydrofuran solvent and 5.1275g of water, the solvent S2 consists of 87.9g of methyl acetate and 35.16g of 1, 4-dioxane, and after the reaction is carried out for 10 hours, the mixture is filtered and dried at 45 ℃ under normal pressure for 9 hours to obtain the michelia lactone dimethylamine fumarate D crystal form product. The thermogravimetric analysis/differential scanning calorimetry analysis of the product is consistent with that shown in figure 1, the thermogravimetric analysis shows that 4.10% of weight loss exists before decomposition, the differential scanning calorimetry analysis shows that dehydration endothermic peak exists at 80 ℃, and characteristic melting peak exists at 150 ℃. The X-ray powder diffraction pattern of the product is consistent with that shown in figure 2, and the characteristic peaks are represented by diffraction angles 2 theta at 7.8 degrees, 11.1 degrees, 11.4 degrees, 12.6 degrees, 12.9 degrees, 14.4 degrees, 15.3 degrees, 17.0 degrees, 18.7 degrees, 19.7 degrees, 20.6 degrees, 21.0 degrees, 22.5 degrees, 23.7 degrees, 24.3 degrees, 25.5 degrees and 26.2 degrees, wherein 7.8 degrees is an initial peak, and the relative intensity of the characteristic peaks at 20.6 degrees is 100 percent. The X-ray powder diffraction pattern of the product has characteristic peaks expressed by 2 theta angles at 10.5 +/-0.2 degrees, 11.7 +/-0.2 degrees, 12.0 +/-0.2 degrees, 15.6 +/-0.2 degrees, 15.9 +/-0.2 degrees, 16.2 +/-0.2 degrees, 21.3 +/-0.2 degrees, 22.1 +/-0.2 degrees, 23.0 +/-0.2 degrees, 26.4 +/-0.2 degrees, 27.2 +/-0.2 degrees, 28.2 +/-0.2 degrees, 28.6 +/-0.2 degrees, 29.3 +/-0.2 degrees, 30.4 +/-0.2 degrees and 31.1 +/-0.2 degrees. The SEM photograph of the crystal morphology is consistent with that of the attached figure 4, the crystal is a blocky crystal, the average particle size of the particles is large and can reach 300 mu m, the bulk density is 0.654g/mL, and the angle of repose is 32.1 degrees.
Example 9
Preparation of hydrate of michelia lactone dimethylamine fumarate
Under the stirring action, 0.293g of michelia lactone dimethylamine and 0.116g of fumaric acid are added into a mixed solvent system of a solvent S1 and a solvent S2 with the constant temperature of 30 ℃, the mass of the solvent S1 is the same as that of the solvent S2, wherein the solvent S1 consists of 1.598g of an acetone solvent and 0.16g of water, and the solvent S2 consists of 0.879g of isopropyl acetate and 0.879g of dipropyl ether, and after 7 hours of reaction, filtration and normal pressure drying at 25 ℃ for 6 hours are carried out, so as to obtain the michelia lactone dimethylamine fumarate D crystal form product. The thermogravimetric analysis/differential scanning calorimetry analysis of the product is consistent with that shown in figure 1, the thermogravimetric analysis shows that 4.22% of weight loss exists before decomposition, the differential scanning calorimetry analysis shows that a dehydration endothermic peak exists at 75 ℃, and a characteristic melting peak exists at 148 ℃. The X-ray powder diffraction pattern of the product is consistent with that shown in figure 2, and the characteristic peaks are represented by diffraction angles 2 theta at 7.8 degrees, 11.0 degrees, 11.4 degrees, 12.5 degrees, 12.8 degrees, 14.4 degrees, 15.3 degrees, 17.0 degrees, 18.7 degrees, 19.7 degrees, 20.6 degrees, 21.0 degrees, 22.4 degrees, 23.7 degrees, 24.3 degrees, 25.4 degrees and 26.2 degrees, wherein 7.8 degrees is an initial peak, and the relative intensity of the characteristic peaks at 20.6 degrees is 100 percent. The X-ray powder diffraction pattern of the product also has characteristic peaks at 10.5 degrees, 11.7 degrees, 12.0 degrees, 15.6 degrees, 15.9 degrees, 16.2 degrees, 21.3 degrees, 22.2 degrees, 22.9 degrees, 26.4 degrees, 27.3 degrees, 28.2 degrees, 28.6 degrees, 29.3 degrees, 30.4 degrees and 31.1 degrees in terms of 2 theta angles. The SEM photograph of the crystal morphology is consistent with that of the attached figure 4, the crystal is a blocky crystal, the average particle size of the particles is large and can reach 300 mu m, the bulk density is 0.645g/mL, and the angle of repose is 32.3 degrees.
Example 10
Preparation of michelia lactone dimethylamine fumarate solvent-free compound B crystal form
Weighing 0.1g of the product obtained in the example 1, placing the product in a variable-temperature X-ray diffractometer, heating the product at the constant temperature of 80 ℃ for 30min, and sampling and analyzing an XRD (X-ray diffraction) spectrum to be consistent with that shown in the attached figure 6, thereby proving that the michelide dimethylamine fumarate solvent-free compound crystal form B is obtained, the solid scanning electron micrograph is consistent with that shown in the attached figure 5, and the blocky crystal habit is still maintained.
Example 11
Preparation of michelia lactone dimethylamine fumarate solvent-free compound B crystal form
Weighing 0.15g of the product obtained in the example 3, placing the product in a variable temperature X-ray diffractometer, heating the product at the constant temperature of 120 ℃ for 10min, and sampling and analyzing an XRD (X-ray diffraction) spectrum to be consistent with that shown in the attached figure 6, so that the crystalline form B of the michelia lactone dimethylamine fumarate solvent-free compound is obtained, a scanning electron micrograph of the solid is consistent with that shown in the attached figure 5, and the crystal habit of the solid is still kept.
Example 12
Preparation of michelia lactone dimethylamine fumarate solvent-free compound B crystal form
Weighing 0.1g of the product obtained in the example 4, placing the product in a variable temperature X-ray diffractometer, heating the product at the constant temperature of 100 ℃ for 20min, and sampling and analyzing an XRD (X-ray diffraction) spectrum to be consistent with that shown in the attached figure 6, so that the crystalline form B of the michelia lactone dimethylamine fumarate solvent-free compound is obtained, a scanning electron micrograph of the solid is consistent with that shown in the attached figure 5, and the crystal habit of the solid is still kept.
Example 13
The preparation formula of the crystal form A capsule 1 is as follows:
the process comprises the following steps: (1) The crystal form A is sieved by a 100-mesh sieve, and is difficult to sieve, has more residues and has large static electricity after sieving;
(2) Sieving the pre-crosslinked starch and the silicon dioxide by a sieve of 80 meshes, and mixing the pre-crosslinked starch and the silicon dioxide with the crystal form A valve bag for 5 minutes; (3) Sieving magnesium stearate with a 80-mesh sieve, and mixing with the powder-mixed self-sealing bag for 1 minute; and (4) filling the 0# gelatin capsule by hand.
The detection result shows that the angle of repose of the capsule in the embodiment is 32.91 degrees, which is close to the fluidity data of the hydrate crystal form D measured in the embodiment 1.
Example 14
Preparation of Crystal form A Capsule 2
The formulation of example 13 was repeated using the following procedure: (1) The crystal form A and the pre-crosslinked starch are sieved by a sieve of 80 meshes, the sieving effect is improved, but the sieving effect is not ideal, and the static electricity is larger; (2) Sieving silicon dioxide with a 80-mesh sieve, and mixing with the mixed powder in a self-sealing bag for 3 minutes; (3) Sieving magnesium stearate with 80 mesh sieve, and mixing with the above mixed powder in a self-sealing bag for 1 min; and (4) filling the 0# gelatin capsule by hand.
The detection result shows that the angle of repose of the capsule in the embodiment is 32.88 degrees, which is close to the fluidity of the hydrate crystal form D in the embodiment 5, and the influence factor experiment is further carried out.
Example 15
The preparation formula of the hydrate crystal form D capsule is as follows without other auxiliary materials:
| prescription | mg/granule |
| Form D (example 1) | 100 |
The process comprises the following steps: (1) Taking a prescribed amount of the hydrate crystal form D prepared in example 1, and sieving the hydrate crystal form D through a 80-mesh sieve; (2) Filling 3# gelatin capsule, spreading the raw materials gently, covering the capsule cover, and carrying out influencing factor experiment.
Example 16
Experiment of influence factor
A. High temperature test
100 capsules of the capsule products of examples 14 and 15 were placed in an open petri dish at 60 ℃ in a thermostat and sampled for 5 days and 10 days, respectively. Observing properties, examining related substances, and measuring content.
B. High humidity test
100 capsules of the capsule products of examples 14 and 15 were placed in an open petri dish in a closed container with a relative humidity of 90. + -. 5% (saturated solution of potassium nitrate), and sampled for 5 days and 10 days, respectively. Observing properties, examining related substances, and measuring content.
C. Test by intense light irradiation
100 capsules of the products of examples 14 and 15 were placed in an open petri dish and irradiated under a fluorescent lamp of 4500 + -500 LX, and samples were taken for 5 days and 10 days, respectively. Observing the characters, checking related substances, and measuring the content.
The results are summarized below:
example 14 Crystal form A Capsule influencing factor Experimental results
Example 15 hydrate form D capsule influencing factor experimental results
The results show that under similar fluidity, the MCL (sphaelactone) content in 5 days in each influencing factor experiment of the hydrate crystal form D capsule has no obvious change, and the MCL content in more than 5 days in the crystal form A capsule experiment is obviously increased. Therefore, due to the excellent fluidity of the hydrate crystal form D, the hydrate crystal form D can be prepared into capsules without adding auxiliary materials, and can be clinically applied. On the contrary, even if the fluidity of the crystal form A capsule is improved by adding auxiliary materials and optimizing the process, the stability of the crystal form A capsule is obviously inferior to that of the hydrate crystal form D. Therefore, the hydrate crystal form D is superior to the capsule of the crystal form A in the aspects of preparation process, stability and compliance.
Claims (12)
1. A hydrate of micheliolide dimethylamine fumarate is characterized in that the hydrate is a crystal form D, the molar ratio of the micheliolide dimethylamine fumarate to water is 1, and the molecular formula is C 17 H 27 NO 3 ·C 4 H 4 O 4 ·H 2 O, weight loss of 3.97-4.22% before decomposition in thermogravimetric analysis; the differential scanning calorimetry analysis chart has a dehydration endothermic peak at 75 +/-5 ℃ and a characteristic melting peak at 148 +/-5 ℃;
<xnotran> Cu-K α , 2 θ X- 7.8 ± 0.2 °, 10.5 ± 0.2 °, 11.1 ± 0.2 °, 11.4 ± 0.2 °, 11.7 ± 0.2 °, 12.0 ± 0.2 °, 12.6 ± 0.2 °, 12.9 ± 0.2 °, 14.4 ± 0.2 °, 15.3 ± 0.2 °, 15.6 ± 0.2 °, 15.9 ± 0.2 °, 16.2 ± 0.2 °, 17.0 ± 0.2 °, 18.7 ± 0.2 °, 19.7 ± 0.2 °,20.6 ± 0.2 °, 21.0 ± 0.2 °, 21.3 ± 0.2 °, 22.1 ± 0.2 °, 22.5 ± 0.2 °, 23.0 ± 0.2 °, 23.7 ± 0.2 °, 24.3 ± 0.2 °, 25.5 ± 0.2 °, 26.2 ± 0.2 °, 26.4 ± 0.2 °, 27.2 ± 0.2 °, 28.2 ± 0.2 °, 28.6 ± 0.2 °, 29.3 ± 0.2 °, 30.4 ± 0.2 °, 31.1 ± 0.2 ° , 7.8 ± 0.2 ° ,20.6 ± 0.2 ° 100%, D , P2 </xnotran> 1 2 1 2 1 Unit cell parameters a =8.8346 (18) a, b =14.796 (3) a, c =16.385 (3) a; α =90 °, β =90 °, γ =90 °, and the unit cell volume is 2141.8 (8) a 3.
2. A method for preparing the hydrate of smilactone dimethylamine fumarate of claim 1, which comprises the steps of: adding dimethylamine michelia lactone and fumaric acid into a mixed solvent system of a solvent S1 and a solvent S2 at a constant temperature of 30-70 ℃ under the stirring action, wherein the mass ratio of the solvent S2 to the solvent S1 is 0-3, the molar ratio of the dimethylamine michelia lactone to the fumaric acid is 1-1.6, reacting for 5-10h, filtering, and drying at 25-45 ℃ for 6-10h under a normal pressure condition to obtain a michelia lactone dimethylamine fumarate crystal form D;
the solvent S1 is a mixed solvent of any one of acetone, tetrahydrofuran, 1, 4-dioxane, acetonitrile and methyl isobutyl ketone and water;
the solvent S2 is a mixed solvent of esters and ethers;
the ester solvent is selected from one or two of methyl acetate, ethyl acetate, hexyl acetate and isopropyl acetate;
the ether solvent is selected from one or two of diethyl ether, methyl ethyl ether, methyl tert-butyl ether, dipropyl ether, dibutyl ether, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, 1, 4-dioxane, tetrahydrofuran and 2-methyl tetrahydrofuran.
3. The method for preparing the hydrate of smilactone dimethylamine fumarate according to claim 2, wherein the mass ratio of any one solvent of acetone, tetrahydrofuran, 1, 4-dioxane, acetonitrile and methyl isobutyl ketone to water in the solvent S1 is 5-10;
the mass ratio of the ester solvent to the ether solvent in the solvent S2 is 1-3:1;
the mass ratio of the solid raw material of the michelia lactone dimethylamine to the solvent S1 is 1.
4. A method for preparing smilacin dimethylamine fumarate solvent-free compound crystalline form B from smilacin dimethylamine fumarate hydrate of claim 1: heating the hydrate of the michelia lactone dimethylamine fumarate at the constant temperature of 80-120 ℃ for 10-30 min to obtain a crystal form B of the michelia lactone dimethylamine fumarate solvent-free compound.
5. A pharmaceutical composition comprising the hydrate of smilactone dimethylamine fumarate of claim 1, which comprises pharmaceutically acceptable excipients and one, two or more pharmacologically active ingredients other than the hydrate of smilactone dimethylamine fumarate.
6. The pharmaceutical composition of claim 5, wherein the pharmaceutical excipient is a non-pharmacologically active ingredient other than crystalline form of smilactone dimethylamine fumarate, including a carrier or excipient.
7. The pharmaceutical composition according to claim 6, wherein the carrier or excipient is a filler, glidant, lubricant, binder, stabilizer and/or other excipients;
the filler is at least one of corn starch, glucose, mannitol, sorbitol, silicon dioxide, microcrystalline cellulose, sodium carboxymethyl starch, composite starch and pregelatinized starch;
the flow aid is at least one of silicon dioxide, hydrated silicon dioxide, light anhydrous silicic acid, dry aluminum hydroxide gel, aluminum silicate and magnesium silicate;
the lubricant is at least one of wheat starch, rice starch, corn starch, stearic acid, calcium stearate, magnesium stearate, hydrated silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, dry aluminum hydroxide gel, talc, magnesium aluminum metasilicate, calcium hydrogen phosphate, sucrose fatty acid ester, paraffin, hydrogenated vegetable oil and polyethylene glycol.
8. The pharmaceutical composition of claim 6, wherein the carrier or excipient is a lubricant and the lubricant is anhydrous dibasic calcium phosphate.
9. A pharmaceutical preparation prepared from the pharmaceutical composition of claim 5, wherein the pharmaceutical preparation is selected from a tablet, capsule or granule formulation of the pharmaceutical composition.
10. Use of the hydrate of michelilactone dimethylamine fumarate of claim 1 or the pharmaceutical composition of claim 5 in the manufacture of a medicament for treating or preventing cancer.
11. Use according to claim 10, wherein the cancer is selected from leukemia, breast cancer, prostate cancer, nasopharyngeal cancer, colorectal cancer, lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, kidney cancer, oral cancer, hodgkin's lymphoma, pancreatic cancer, cervical cancer, non-hodgkin's lymphoma, glioma, melanoma, bladder cancer, ovarian cancer, thyroid cancer or kaposi's sarcoma.
12. Use according to claim 10, wherein the cancer is colorectal cancer.
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| CN103417532A (en) * | 2012-05-16 | 2013-12-04 | 天津尚德药缘科技有限公司 | Sesquiterpene lactone compound and uses of derivative thereof in preparation of drugs |
| CN103724307A (en) * | 2012-10-12 | 2014-04-16 | 天津尚德药缘科技有限公司 | Sphaelactone dimethylamine fumarate crystal form and preparation method thereof |
| CN104876899A (en) * | 2014-02-28 | 2015-09-02 | 天津尚德药缘科技股份有限公司 | Dimethylamino sphaelactone fumarate and use thereof |
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| CN102234259A (en) * | 2010-04-23 | 2011-11-09 | 天津尚德药缘科技有限公司 | Sphaelactone derivatives, their pharmaceutical compositions, preparation method thereof and application thereof |
| CN103417532A (en) * | 2012-05-16 | 2013-12-04 | 天津尚德药缘科技有限公司 | Sesquiterpene lactone compound and uses of derivative thereof in preparation of drugs |
| CN103724307A (en) * | 2012-10-12 | 2014-04-16 | 天津尚德药缘科技有限公司 | Sphaelactone dimethylamine fumarate crystal form and preparation method thereof |
| CN104876899A (en) * | 2014-02-28 | 2015-09-02 | 天津尚德药缘科技股份有限公司 | Dimethylamino sphaelactone fumarate and use thereof |
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