Patent Description:
Parthenolide is a main active ingredient extracted from Asteraceae plant herbs feverfew and tansy, and is a naturally occurring sesquiterpene lactone. Traditionally, feverfew is mainly used to treat diseases such as fever, rheumatoid arthritis, migraine and toothache. In recent years, studies in China and other countries have found that parthenolide also has an anti-tumor effect but is unstable in property under acidic or basic conditions.

In order to improve its stability, the compound parthenolide is modified to obtain micheliolide (MCL), a guaiane-type sesquiterpene lactone. It has been reported in the relevant literature(s) and patent(s) that micheliolide has an effect in treating cancer diseases but has poor solubility in water. In order to improve the solubility in water and the biological activity, with triethylamine as a catalyst, a reaction is performed through heating in a methanol solvent to obtain a micheliolide derivative, i.e., dimethylaminomicheliolide (DMAMCL) with a molecular formula of C<NUM>H<NUM>NO<NUM> and a structural formula below. DMAMCL has improved solubility in water to a certain degree relative to MCL but is unstable as it will degrade after long-term storage. In order to further improve its solubility in water and stability, it is often prepared in the form of a salt. The inventors have discovered dimethylaminomicheliolide fumarate prepared from a parthenolide derivative. Meanwhile, the patent <CIT> discloses a preparation method for micheliolide derivatives or salts thereof or pharmaceutical compositions thereof including dimethylaminomicheliolide fumarate and their use in preparing a medicament for treating cancer. Dimethylaminomicheliolide fumarate has a molecular formula of C<NUM>H<NUM>NO<NUM> and a relative molecular mass of <NUM>. It is a colorless and odorless white crystalline powder. It is soluble in water, methanol, ethanol, tetrahydrofuran, <NUM>,<NUM>-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:
<CHM>.

Polymorphism refers to the existence of a substance in different crystal structures arising from different molecular arrangements or conformations. It occurs among <NUM>% of commercially available drugs according to statistics. Different crystalline forms of a drug are different in physicochemical properties such as color, solubility, melting point, density, hardness and crystal morphology, thereby leading to differences in qualities such as stability, dissolution rate and bioavailability of the drug and thus affecting subsequent processing and treatment, as well as the therapeutic effects and safety of the drug to some extent. In the process of drug quality control and design of new pharmaceutical dosage forms, research on drug polymorphism has become an indispensable important part.

Chinese patent <CIT> (also published as <CIT>) discloses dimethylaminomicheliolide fumarate in a crystalline form A and a preparation method therefor. The crystalline form A is characterized by XRPD in the patent, having characteristic peaks at <NUM>θ of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>° and <NUM>°. The crystalline form A is prepared by recrystallization from an ethyl acetate solvent. In this method, the product is prepared by natural cooling. However, as the recrystallization process is controlled by both of thermodynamics and dynamics, the conditions for the recrystallization by -natural cooling are greatly affected by changes in the environment, and the cooling rate is difficult to control, leading to a small particle size of the product, the primary particle size being <NUM>, a low bulk density of mere <NUM>/mL, an angle of repose of <NUM>°, poor fluidity and big differences in quality between crystal products of different batches. Meanwhile, the crystalline form A has poor stability as it is prone to transformation, and there is electrostatic action in the solid powder, leading to clouds of dust in the production process and thus causing many problems in processing and treatment at a later stage.

The international patent application <CIT> describes the use of a sesquiterpene lactone compound (Formula I) in the preparation of drugs for the treatment in particular of rheumatoid arthritis and a cancer by means of inhibition of cancer stem cells.

The international patent application <CIT> relates to the use of a chelate lactone dimethylamine in the manufacture of medicaments for the treatment of pulmonary fibrosis, whereby said medicaments include smear lactone dimethylamine, smecta lactone dimethylamine in pharmaceutically acceptable salts, esters, hydrates or combinations thereof.

The international patent application <CIT> describes several sphaelactone derivatives of formula (I) or salts, and their pharmaceutical compositions as well as preparation methods and uses for preparing anti-cancer drugs.

The Chinese patent application <CIT> relates to a dimethylamino sphaelactone fumarate compound and its use for treating cancer.

The scientific article of <NPL>) discloses the compound <NUM>-(N,N-Di-methyl-amino)-micheliolide in the free base <NUM> hydrate form.

In order to solve the above problems, the present disclosure provides a hydrate of dimethylaminomicheliolide fumarate, a preparation method therefor and use thereof. A crystal product of the hydrate of dimethylaminomicheliolide fumarate with high crystallinity, high bulk density, good fluidity, large particle size, smooth and clean crystal surfaces without agglomeration, and good stability is prepared by reactive crystallization. The preparation method is simple and features high product yield and good reproducibility, favoring large-scale production.

The present disclosure provides a hydrate of dimethylaminomicheliolide fumarate, wherein the hydrate is in a crystalline form D, the molar ratio of dimethylaminomicheliolide fumarate to water is <NUM>:<NUM>, and the hydrate has a molecular formula of C<NUM>H<NUM>NO<NUM>·C<NUM>H<NUM>O<NUM>·H<NUM>O; as shown in thermogravimetric analysis/differential scanning calorimetry analysis patterns, the thermogravimetric analysis shows a weight loss of <NUM>%-<NUM>% before decomposition; the differential scanning calorimetry pattern shows a dehydration endothermic peak at <NUM>±<NUM> and a characteristic melting peak at <NUM>±<NUM>.

The present disclosure provides a hydrate of dimethylaminomicheliolide fumarate, wherein the hydrate has characteristic peaks at <NUM>θ angles of <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>° and <NUM>±<NUM>° in an X-ray powder diffraction pattern using Cu-Kα radiation, wherein the peak at <NUM>±<NUM>° is an initial peak; the characteristic peak at <NUM>±<NUM>° has a relative intensity of <NUM>%; the crystalline form D is in an orthorhombic crystal system and has a space group of P<NUM><NUM><NUM><NUM><NUM><NUM>, a cell parameter of a = <NUM>(<NUM>) Å, b = <NUM>(<NUM>) Å, c= <NUM>(<NUM>) Å, α = <NUM>°, β = <NUM>°, and γ = <NUM>°; and a cell volume of <NUM>(<NUM>) Å<NUM>.

The present disclosure provides a hydrate of dimethylaminomicheliolide fumarate, wherein the hydrate also has characteristic peaks at <NUM>θ angles of <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>° and <NUM>±<NUM>° in an X-ray powder diffraction pattern using Cu-Ka radiation.

The present disclosure also provides a preparation method for a hydrate of dimethylaminomicheliolide fumarate, which can be implemented by reactive crystallization: under the action of stirring, adding dimethylaminomicheliolide and fumaric acid to a mixed solvent system of a solvent S1 and a solvent S2 at a constant temperature of <NUM>-<NUM>, with the mass ratio of the solvent S2 to the solvent S1 being (<NUM>-<NUM>):<NUM> and the molar ratio of dimethylaminomicheliolide to fumaric acid being (<NUM>-<NUM>):<NUM>; after <NUM>-<NUM> of reaction, filtering the reaction mixture and drying the residue at <NUM>-<NUM> under normal pressure for <NUM>-<NUM> to obtain dimethylaminomicheliolide fumarate in a crystalline form D.

The solvent S1 is a mixed solvent of water and any one of acetone, tetrahydrofuran, <NUM>,<NUM>-dioxane, acetonitrile and methyl isobutyl ketone.

The solvent S2 is a mixed solvent of ester and ether solvents.

The ester solvent is selected from any one or two of methyl acetate, ethyl acetate, hexyl acetate and isopropyl acetate.

The ether solvent is selected from any 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, <NUM>,<NUM>-dioxane, tetrahydrofuran and <NUM>-methyl tetrahydrofuran.

The mass ratio of the ester solvent to the ether solvent in the solvent S2 is (<NUM>-<NUM>):<NUM>.

The mass ratio of the solid starting material dimethylaminomicheliolide to S1 is <NUM>:(<NUM>-<NUM>).

The crystal habit of the hydrate of dimethylaminomicheliolide fumarate is studied in the present disclosure, and a scanning electron micrograph thereof is shown in <FIG>. - The crystal has a regular block crystal habit, and the surface of the particle is smooth without agglomeration, meanwhile, the crystal has a large average particle size that can reach <NUM>, a bulk density of <NUM>/mL, and an angle of repose of <NUM>°. The product features high bulk density and good fluidity. In comparison, the crystalline form A prepared using the natural cooling recrystallization method disclosed in patent <CIT> has a primary particle size of <NUM>, a bulk density of mere <NUM>/mL and an angle of repose of <NUM>°, and a scanning electron micrograph thereof is shown in <FIG>. The dimethylaminomicheliolide fumarate product in the crystalline form D provided in the present disclosure has a significantly improved particle size, solving the problems of the low bulk density and poor fluidity of the product in the crystalline form A.

The stability of the hydrate of dimethylaminomicheliolide fumarate is investigated in the present disclosure. The anhydrous crystal compound product is uniformly distributed in an open Petri dish. The temperature is controlled at <NUM>, the humidity is <NUM>%, and the sample thickness is less than <NUM>. The Petri dish is hermetically placed in a drier for <NUM> days. Then the samples placed for <NUM>, <NUM> and <NUM> days were examined by XRD and compared with the results on day <NUM>. The specific pattern is shown in <FIG>. The results show no significant change in the XRD pattern. Meanwhile, the samples at days <NUM>, <NUM> and <NUM> are subjected to purity analysis. By comparison with the results of the purity detection at day <NUM>, a change of mere <NUM>% is observed in the purity of the sample at day <NUM>, a change of mere <NUM>% is observed in the purity of the sample at day <NUM>, and a change of mere <NUM>% is observed in the purity of the sample at day <NUM>, suggesting no significant change in the purity of the sample. By combining the XRD patterns and the results of the purity analysis, the hydrate of dimethylaminomicheliolide fumarate is shown to have good stability.

The hydrate of dimethylaminomicheliolide fumarate provided in the present disclosure can be used to prepare a solventless compound of dimethylaminomicheliolide fumarate in a crystalline form B. The preparation method for the crystalline form B comprises: heating the hydrate of dimethylaminomicheliolide fumarate at a constant temperature of <NUM>-<NUM> for <NUM>-<NUM> to obtain the solventless compound of dimethylaminomicheliolide fumarate in a crystalline form B, whose X-ray powder diffraction pattern is shown in <FIG>, showing characteristic peaks at <NUM>θ angles of <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>° and <NUM>±<NUM>°. The scanning electron micrograph is similar to that in <FIG>, indicating that the crystal habit is consistent with the hydrate and the particle size is large.

The present disclosure also provides a pharmaceutical composition comprising the hydrate of dimethylaminomicheliolide fumarate according to the present invention, which comprises a pharmaceutically acceptable auxiliary material and may also comprise one, two or more other pharmacologically active ingredients other than the hydrate of dimethylaminomicheliolide fumarate.

The pharmaceutically acceptable auxiliary material comprises other non-pharmacologically active ingredients other than active ingredients such as dimethylaminomicheliolide fumarate in a crystalline form, e.g., non-pharmacologically active ingredients that may be used for the pharmaceutical composition of the present disclosure, including carriers or excipients such as fillers, glidants, lubricants, binders, stabilizers and/or other auxiliary materials.

The fillers comprise at least one of maize starch, glucose, mannitol, sorbitol, silica, microcrystalline cellulose, sodium carboxymethyl starch, composite starch and pregelatinized starch.

The flow aidscomprise at least one of silica, hydrated silica, light anhydrous silicic acid, dry aluminum hydroxide gel, aluminum silicate and magnesium silicate.

The lubricantscomprise at least one of wheat starch, rice starch, maize starch, stearic acid, calcium stearate, magnesium stearate, hydrated silica, light anhydrous silicic acid, synthetic aluminum silicate, dry aluminum hydroxide gel, talc, magnesium aluminometasilicate, dicalcium phosphate, anhydrous dicalcium phosphate, sucrose fatty acid esters, paraffins, hydrogenated vegetable oil and polyethylene glycol.

The pharmaceutical composition according to the present disclosure is used for preparing a pharmaceutical preparation, wherein the pharmaceutical preparation includes the pharmaceutical composition in a tablet, capsule or granule dosage form. The pharmaceutical preparation is more preferably a capsule.

The present disclosure also provides the hydrate of dimethylaminomicheliolide fumarate according to the present invention or the pharmaceutical composition according to the present invention for use in the treatment or prevention of a disease or condition, wherein the disease or condition is preferably cancer selected from leukemia, breast cancer, prostate cancer, nasopharyngeal cancer, large intestine cancer, lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, renal cancer, oral cancer, Hodgkin's lymphoma, pancreatic cancer, colorectal cancer, cervical cancer, non-Hodgkin's lymphoma, glioma, melanoma, bladder cancer, ovarian cancer, thyroid cancer and Kaposi's sarcoma.

The hydrate of the present disclosure has good fluidity and is more suitable for being prepared as a medicament at a later stage. It is well known that the fluidity of an active ingredient per se is generally hard to meet the filling conditions of capsules or microcapsules, and auxiliary materials such as pregelatinized starch, silica and magnesium stearate are required to meet the requirements for fluidity by the filling conditions so as to achieve the desired quality of dosage forms and production efficiency. Taking the specification of <NUM> capsules as an example, if other forms such as crystalline form A are used as active ingredients, the weight of capsule contents reaches about <NUM> after auxiliary materials are added, and thus the largest <NUM># capsule shell must be used, and larger specification such as capsules containing <NUM> of active ingredients cannot be prepared. For this reason, patients would have to achieve high dose administration by increasing the number of capsules taken or the frequency of administrations, which would significantly reduce patient compliance. However, the inventors have found that an angle of repose of <NUM>° can be achieved due to the excellent fluidity of the hydrate of dimethylaminomicheliolide fumarate in the crystalline form D even without adding auxiliary materials. For this reason, the required fluidity for the filling conditions of capsules or microcapsules can be achieved with significantly reduced amounts of auxiliary materials and even without adding any auxiliary material. Moreover, the reduction in the amounts of auxiliary materials makes it possible to produce capsules of high-dose specifications, significantly improving patient compliance.

Furthermore, due to the fact that the hydrate of dimethylaminomicheliolide fumarate in the crystalline form D can significantly or even completely reduce the addition of auxiliary materials, and that a large amount of auxiliary materials are required for the crystalline form A to achieve the same fluidity as the crystalline form D, resulting in poor stability, the hydrate in the crystalline form D improves the stability of the preparation.

In addition, the preparation method for the hydrate of dimethylaminomicheliolide fumarate in the crystalline form D is simple and features high product yield and good reproducibility, and the resulting product has high crystallinity, smooth and clean particle surfaces without agglomeration, no static electricity between particles and high bulk density, favoring large-scale production.

The above description of the present disclosure will be further explained in detail through specific embodiments in the form of examples.

Under the action of stirring, <NUM> of dimethylaminomicheliolide and <NUM> of fumaric acid were added to a mixed solvent system of a solvent S1 and a solvent S2 at a constant temperature of <NUM>, with the mass of the solvent S1 being the same as that of the solvent S2, wherein the solvent S1 consisted of <NUM> of acetone solvent and <NUM> of water, and the solvent S2 consisted of <NUM> of ethyl acetate and <NUM> of diethyl ether. After <NUM> of reaction, the reaction mixture was filtered, and the residue was dried at <NUM> under normal pressure for <NUM> to obtain a product of dimethylaminomicheliolide fumarate in the crystalline form D. The thermogravimetric analysis/differential scanning calorimetry of the product is consistent with <FIG>. The thermogravimetric analysis shows a weight loss of <NUM>% before decomposition, and the differential scanning calorimetry analysis shows a dehydration endothermic peak at <NUM> and a characteristic melting peak at <NUM>. The X-ray powder diffraction pattern of the product is consistent with <FIG>, showing characteristic peaks at diffraction angles <NUM>θ of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>° and <NUM>°, wherein the peak at <NUM>° is an initial peak, and the characteristic peak at <NUM>° has a relative intensity of <NUM>%. The X-ray powder diffraction pattern of the product also shows characteristic peaks at <NUM>θ angles of <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>° and <NUM>±<NUM>°. The SEM image of the crystal morphology is consistent with <FIG>, indicating bulk crystals with a large average particle size that may reach <NUM>, a tested bulk density of <NUM>/mL and an angle of repose of <NUM>°.

Under the action of stirring, <NUM> of dimethylaminomicheliolide and <NUM> of fumaric acid were added to a mixed solvent system of a solvent S1 and a solvent S2 at a constant temperature of <NUM>, with the mass of the solvent S2 being <NUM> times that of the solvent S1, wherein the solvent S1 consisted of <NUM> of tetrahydrofuran solvent and <NUM> of water, and the solvent S2 consisted of <NUM> of isopropyl acetate and <NUM> of methyl tert-butyl ether. After <NUM> of reaction, the reaction mixture was filtered, and the residue was dried at <NUM> under normal pressure for <NUM> to obtain a product of dimethylaminomicheliolide fumarate in the crystalline form D. The thermogravimetric analysis/differential scanning calorimetry of the product is consistent with <FIG>. The thermogravimetric analysis shows a weight loss of <NUM>% before decomposition, and the differential scanning calorimetry analysis shows a dehydration endothermic peak at <NUM> and a characteristic melting peak at <NUM>. The X-ray powder diffraction pattern of the product is consistent with <FIG>, showing characteristic peaks at diffraction angles <NUM>θ of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>° and <NUM>°, wherein the peak at <NUM>° is an initial peak, and the characteristic peak at <NUM>° has a relative intensity of <NUM>%. The X-ray powder diffraction pattern of the product also shows characteristic peaks at <NUM>θ angles of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>° and <NUM>°. The SEM image of the crystal morphology is consistent with <FIG>, indicating bulk crystals with a large average particle size that may reach <NUM>, a tested bulk density of <NUM>/mL and an angle of repose of <NUM>°.

Under the action of stirring, <NUM> of dimethylaminomicheliolide and <NUM> of fumaric acid were added to a mixed solvent system of a solvent S1 and a solvent S2 at a constant temperature of <NUM>, with the mass of the solvent S2 being <NUM> times that of the solvent S1, wherein the solvent S1 consisted of <NUM> of <NUM>,<NUM>-dioxane solvent and <NUM> of water, and the solvent S2 consisted of <NUM> of methyl acetate and <NUM> of methyl ethyl ether. After <NUM> of reaction, the reaction mixture was filtered, and the residue was dried at <NUM> under normal pressure for <NUM> to obtain a product of dimethylaminomicheliolide fumarate in the crystalline form D. The thermogravimetric analysis/differential scanning calorimetry of the product is consistent with <FIG>. The thermogravimetric analysis shows a weight loss of <NUM>% before decomposition, and the differential scanning calorimetry analysis shows a dehydration endothermic peak at <NUM> and a characteristic melting peak at <NUM>. The X-ray powder diffraction pattern of the product is consistent with <FIG>, showing characteristic peaks at diffraction angles <NUM>θ of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>° and <NUM>°, wherein the peak at <NUM>° is an initial peak, and the characteristic peak at <NUM>° has a relative intensity of <NUM>%. The X-ray powder diffraction pattern of the product also shows characteristic peaks at <NUM>θ angles of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>° and <NUM>°. The SEM image of the crystal morphology is consistent with <FIG>, indicating bulk crystals with a large average particle size that may reach <NUM>, a tested bulk density of <NUM>/mL and an angle of repose of <NUM>°.

Under the action of stirring, <NUM> of dimethylaminomicheliolide and <NUM> of fumaric acid were added to a mixed solvent system of a solvent S1 and a solvent S2 at a constant temperature of <NUM>, with the mass of the solvent S2 being <NUM> times that of the solvent S1, wherein the solvent S1 consisted of <NUM> of acetonitrile solvent and <NUM> of water, and the solvent S2 consisted of <NUM> of hexyl acetate and <NUM> of ethylene glycol dimethyl ether. After <NUM> of reaction, the reaction mixture was filtered, and the residue was dried at <NUM> under normal pressure for <NUM> to obtain a product of dimethylaminomicheliolide fumarate in the crystalline form D. The thermogravimetric analysis/differential scanning calorimetry of the product is consistent with <FIG>. The thermogravimetric analysis shows a weight loss of <NUM>% before decomposition, and the differential scanning calorimetry analysis shows a dehydration endothermic peak at <NUM> and a characteristic melting peak at <NUM>. The X-ray powder diffraction pattern of the product is consistent with <FIG>, showing characteristic peaks at diffraction angles <NUM>θ of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>° and <NUM>°, wherein the peak at <NUM>° is an initial peak, and the characteristic peak at <NUM>° has a relative intensity of <NUM>%. The X-ray powder diffraction pattern of the product also shows characteristic peaks at <NUM>θ angles of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>° and <NUM>°. The SEM image of the crystal morphology is consistent with <FIG>, indicating bulk crystals with a large average particle size that may reach <NUM>, a tested bulk density of <NUM>/mL and an angle of repose of <NUM>°.

Under the action of stirring, <NUM> of dimethylaminomicheliolide and <NUM> of fumaric acid were added to a mixed solvent system of a solvent S1 and a solvent S2 at a constant temperature of <NUM>, with the mass of the solvent S1 being the same as that of the solvent S2, wherein the solvent S1 consisted of <NUM> of acetonitrile solvent and <NUM> of water, and the solvent S2 consisted of <NUM> of isopropyl acetate and <NUM> of ethylene glycol monomethyl ether. After <NUM> of reaction, the reaction mixture was filtered, and the residue was dried at <NUM> under normal pressure for <NUM> to obtain a product of dimethylaminomicheliolide fumarate in the crystalline form D. The thermogravimetric analysis/differential scanning calorimetry of the product is consistent with <FIG>. The thermogravimetric analysis shows a weight loss of <NUM>% before decomposition, and the differential scanning calorimetry analysis shows a dehydration endothermic peak at <NUM> and a characteristic melting peak at <NUM>. The X-ray powder diffraction pattern of the product is consistent with <FIG>, showing characteristic peaks at diffraction angles <NUM>θ of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>° and <NUM>°, wherein the peak at <NUM>° is an initial peak, and the characteristic peak at <NUM>° has a relative intensity of <NUM>%. The X-ray powder diffraction pattern of the product also shows characteristic peaks at <NUM>θ angles of <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>° and <NUM>±<NUM>°. The SEM image of the crystal morphology is consistent with <FIG>, indicating bulk crystals with a large average particle size that may reach <NUM>, a tested bulk density of <NUM>/mL and an angle of repose of <NUM>°.

Under the action of stirring, <NUM> of dimethylaminomicheliolide and <NUM> of fumaric acid were added to a mixed solvent system of a solvent S1 and a solvent S2 at a constant temperature of <NUM>, with the mass of the solvent S2 being <NUM> times that of the solvent S1, wherein the solvent S1 consisted of <NUM> of methyl isobutyl ketone solvent and <NUM> of water, and the solvent S2 consisted of <NUM> of methyl acetate, <NUM> of isopropyl acetate, <NUM> of tetrahydrofuran and <NUM> of dibutyl ether. After <NUM> of reaction, the reaction mixture was filtered, and the residue was dried at <NUM> under normal pressure for <NUM> to obtain a product of dimethylaminomicheliolide fumarate in the crystalline form D. The thermogravimetric analysis/differential scanning calorimetry of the product is consistent with <FIG>. The thermogravimetric analysis shows a weight loss of <NUM>% before decomposition, and the differential scanning calorimetry analysis shows a dehydration endothermic peak at <NUM> and a characteristic melting peak at <NUM>. The X-ray powder diffraction pattern of the product is consistent with <FIG>, showing characteristic peaks at diffraction angles <NUM>θ of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>° and <NUM>°, wherein the peak at <NUM>° is an initial peak, and the characteristic peak at <NUM>° has a relative intensity of <NUM>%. The X-ray powder diffraction pattern of the product also shows characteristic peaks at <NUM>θ angles of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>° and <NUM>°. The SEM image of the crystal morphology is consistent with <FIG>, indicating bulk crystals with a large average particle size that may reach <NUM>, a tested bulk density of <NUM>/mL and an angle of repose of <NUM>°.

Under the action of stirring, <NUM> of dimethylaminomicheliolide and <NUM> of fumaric acid were added to a mixed solvent system of a solvent S1 and a solvent S2 at a constant temperature of <NUM>, with the mass of the solvent S2 being <NUM> times that of the solvent S1, wherein the solvent S1 consisted of <NUM> of methyl isobutyl ketone solvent and <NUM> of water, and the solvent S2 consisted of <NUM> of methyl acetate and <NUM> of <NUM>-methyl tetrahydrofuran. After <NUM> of reaction, the reaction mixture was filtered, and the residue was dried at <NUM> under normal pressure for <NUM> to obtain a product of dimethylaminomicheliolide fumarate in the crystalline form D. The thermogravimetric analysis/differential scanning calorimetry of the product is consistent with <FIG>. The thermogravimetric analysis shows a weight loss of <NUM>% before decomposition, and the differential scanning calorimetry analysis shows a dehydration endothermic peak at <NUM> and a characteristic melting peak at <NUM>. The X-ray powder diffraction pattern of the product is consistent with <FIG>, showing characteristic peaks at diffraction angles <NUM>θ of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>° and <NUM>°, wherein the peak at <NUM>° is an initial peak, and the characteristic peak at <NUM>° has a relative intensity of <NUM>%. The X-ray powder diffraction pattern of the product also shows characteristic peaks at <NUM>θ angles of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>° and <NUM>°. The SEM image of the crystal morphology is consistent with <FIG>, indicating bulk crystals with a large average particle size that may reach <NUM>, a tested bulk density of <NUM>/mL and an angle of repose of <NUM>°.

Under the action of stirring, <NUM> of dimethylaminomicheliolide and <NUM> of fumaric acid were added to a mixed solvent system of a solvent S1 and a solvent S2 at a constant temperature of <NUM>, with the mass of the solvent S2 being <NUM> times that of the solvent S1, wherein the solvent S1 consisted of <NUM> of tetrahydrofuran solvent and <NUM> of water, and the solvent S2 consisted of <NUM> of methyl acetate and <NUM> of <NUM>,<NUM>-dioxane. After <NUM> of reaction, the reaction mixture was filtered, and the residue was dried at <NUM> under normal pressure for <NUM> to obtain a product of dimethylaminomicheliolide fumarate in the crystalline form D. The thermogravimetric analysis/differential scanning calorimetry of the product is consistent with <FIG>. The thermogravimetric analysis shows a weight loss of <NUM>% before decomposition, and the differential scanning calorimetry analysis shows a dehydration endothermic peak at <NUM> and a characteristic melting peak at <NUM>. The X-ray powder diffraction pattern of the product is consistent with <FIG>, showing characteristic peaks at diffraction angles <NUM>θ of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>° and <NUM>°, wherein the peak at <NUM>° is an initial peak, and the characteristic peak at <NUM>° has a relative intensity of <NUM>%. The X-ray powder diffraction pattern of the product also shows characteristic peaks at <NUM>θ angles of <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>° and <NUM>±<NUM>°. The SEM image of the crystal morphology is consistent with <FIG>, indicating bulk crystals with a large average particle size that may reach <NUM>, a tested bulk density of <NUM>/mL and an angle of repose of <NUM>°.

Under the action of stirring, <NUM> of dimethylaminomicheliolide and <NUM> of fumaric acid were added to a mixed solvent system of a solvent S1 and a solvent S2 at a constant temperature of <NUM>, with the mass of the solvent S1 being the same as that of the solvent S2, wherein the solvent S1 consisted of <NUM> of acetone solvent and <NUM> of water, and the solvent S2 consisted of <NUM> of isopropyl acetate and <NUM> of dipropyl ether. After <NUM> of reaction, the reaction mixture was filtered, and the residue was dried at <NUM> under normal pressure for <NUM> to obtain a product of dimethylaminomicheliolide fumarate in the crystalline form D. The thermogravimetric analysis/differential scanning calorimetry of the product is consistent with <FIG>. The thermogravimetric analysis shows a weight loss of <NUM>% before decomposition, and the differential scanning calorimetry analysis shows a dehydration endothermic peak at <NUM> and a characteristic melting peak at <NUM>. The X-ray powder diffraction pattern of the product is consistent with <FIG>, showing characteristic peaks at diffraction angles <NUM>θ of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>° and <NUM>°, wherein the peak at <NUM>° is an initial peak, and the characteristic peak at <NUM>° has a relative intensity of <NUM>%. The X-ray powder diffraction pattern of the product also shows characteristic peaks at <NUM>θ angles of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>° and <NUM>°. The SEM image of the crystal morphology is consistent with <FIG>, indicating bulk crystals with a large average particle size that may reach <NUM>, a tested bulk density of <NUM>/mL and an angle of repose of <NUM>°.

<NUM> of the product of Example <NUM> was weighed into a variable-temperature X-ray diffractometer, and heated at a constant temperature of <NUM> for <NUM>. A sample was taken for XRD analysis, and the resulting pattern is consistent with <FIG>, indicating a solventless compound of dimethylaminomicheliolide fumarate in the crystalline form B. The scanning electron micrograph of the solid shows a morphology consistent with that shown in <FIG>, indicating that the blockshaped crystal habit was retained.

The preparation formula for crystalline form A capsule <NUM> is as follows:.

Process: (<NUM>) during passing the crystalline form A through a <NUM>-mesh sieve, it was found that the sieving was difficult to perform, and much residue remained; after the sieving, much static electricity was produced; (<NUM>) pregelatinized starch and silica were passed through an <NUM>-mesh sieve and then mixed with the crystalline form A in a zipper bag for <NUM>; (<NUM>) magnesium stearate was passed through a <NUM>-mesh sieve and then mixed with the powder mixture above in a zipper bag for <NUM>; (<NUM>) <NUM># gelatin capsules were filled with the resulting mixture manually.

The detection results show that the capsules of this example have an angle of repose of <NUM>°, which is close to the fluidity data of the hydrate in the crystalline form D measured in Example <NUM>.

The formula of Example <NUM> was adopted again and the process below was used: (<NUM>) when the crystalline form A, together with pregelatinized starch, was passed through a <NUM>-mesh sieve, the sieving results were somewhat improved but still not ideal, and much static electricity was produced; (<NUM>) silica was passed through an <NUM>-mesh sieve and then mixed with the powder mixture above in a zipper bag for <NUM>; (<NUM>) magnesium stearate was passed through a <NUM>-mesh sieve and then mixed with the powder mixture above in a zipper bag for <NUM>; (<NUM>) <NUM># gelatin capsules were filled with the resulting mixture manually.

The detection results show that the capsules of this example have an angle of repose of <NUM>°, which is close to the fluidity of the hydrate in the crystalline form D of Example <NUM>. Influencing factor experiments were further conducted.

The preparation formula for capsules of the hydrate in the crystalline form D is as follows, no other auxiliary materials involved:.

Process: (<NUM>) a formula amount of the hydrate in the crystalline form D prepared in Example <NUM> was taken and passed through an <NUM>-mesh sieve; (<NUM>) <NUM># gelatin capsules were filled, the starting materials were gently leveled, and capsule lids were put on; influencing factor experiments were conducted.

<NUM> capsules of the products of Examples <NUM> and <NUM> were placed in an open Petri dish in an incubator at <NUM>, and samples were taken at days <NUM> and <NUM>. The characteristics and appearance were observed, the related substances were detected, and the content was determined.

<NUM> capsules of the products of Examples <NUM> and <NUM> were placed in an open Petri dish in a closed container with a relative humidity of <NUM>±<NUM>% (saturated solution of potassium nitrate), and samples were taken at days <NUM> and <NUM>. The characteristics and appearance were observed, the related substances were detected, and the content was determined.

<NUM> capsules of the products of Examples <NUM> and <NUM> were placed in an open Petri dish and irradiated using a <NUM>±<NUM> LX fluorescent lamp, and samples were taken at days <NUM> and <NUM>. The characteristics and appearance were observed, the related substances were detected, and the content was determined.

The results are summarized below:
The results of the influencing factor experiments of the crystalline form A capsules of Example <NUM>.

The results of the influencing factor experiments of the capsules of the hydrate in the crystalline form D of Example <NUM>.

Claim 1:
A hydrate of dimethylaminomicheliolide fumarate, characterized in that, the hydrate has characteristic peaks at 2θ angles of <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>° and <NUM>±<NUM>° in an X-ray powder diffraction pattern using Cu-Kα radiation, wherein the peak at <NUM>±<NUM>° is an initial peak; the characteristic peak at <NUM>±<NUM>° has a relative intensity of <NUM>%; the crystalline form D is in an orthorhombic crystal system and has a space group of P<NUM><NUM><NUM><NUM><NUM><NUM>, a cell parameter of a = <NUM>(<NUM>) Å, b = <NUM>(<NUM>) Å, c= <NUM>(<NUM>) Å, α = <NUM>°, β = <NUM>°, and γ = <NUM>°; and a cell volume of <NUM>(<NUM>) Å3.