Cepharanthine crystal and preparation method thereof

Abstract

The invention belongs to the technical field of medicine refining, and relates to a cepharanthine crystal and a preparation method thereof. Compared with amorphous cepharanthine powder, the crystal provided by the invention is high in stacking density, good in fluidity, high in stability and convenient to store and transport. The cepharanthine crystal form I crystal and the five cepharanthine solvate crystals provided by the invention have better stability, a sample is placed in a dynamic steam adsorption instrument at 40 DEG C, the weight when the mass change is less than 0.01 g within 3 hours is recorded, the hygroscopicity of the cepharanthine crystal form I crystal and the five cepharanthine solvate crystals is far lower than that of amorphous cepharanthine powder, and the stability of the cepharanthine crystal form I crystal and the five cepharanthine solvate crystals is greatly improved. Therefore, compared with amorphous cepharanthine powder, the stability of the cepharanthine crystal provided by the invention is greatly improved.

Description

[0001] This application is a divisional application of the Chinese patent application filed on February 21, 2023, with application number 202310153610.4 and invention name “Cephalothin crystals and preparation method thereof”. Technical Field

[0002] The invention belongs to the technical field of pharmaceutical refining and relates to a cephalaenopsis crystal and a preparation method thereof. Background Art

[0003] Cepharanthine is a dibenzylisoquinoline alkaloid extracted from plants of the Menispermaceae family. 37 H 38 N2O6, relative molecular mass 606.72g / mol, structural formula is as follows:

[0004]

[0005] Stephaniocarbazone was first extracted from plants by Japanese Kondo Heizaburo. Currently, most research focuses on the extraction of stephaniocarbazone, as well as its application in the treatment of new coronavirus, leukopenia, and anti-cancer. Patent CN11304632A reports that stephaniocarbazone has a very good effect in fighting the new coronavirus SARS-COV2. Compared with other drugs, only a small amount of stephaniocarbazone can inhibit the replication of the new coronavirus by about 16,000 times. Patent CN102477041B reports that recent studies have found that stephaniocarbazone has the functions of stimulating the reticuloendothelial system, activating hematopoietic tissue, and promoting bone marrow tissue proliferation, and can treat leukopenia clinically. Patent CN112516143A discloses that stephaniocarbazone can effectively inhibit the infection of cells by a variety of coronaviruses, especially SARS-CoV-2 (S-D614), SARS-CoV-2 (S-G614), SARS-CoV, and MERS-CoV coronavirus infections. It has excellent inhibitory effects. Patent CN110496225A (B) first discovered that the anti-cancer effect of cephalothin hydrochloride in vitro can be enhanced by using autophagy inhibitors, and verified it on an in vivo mouse model, providing a new effective and feasible scheme for treating solid tumors. Patent CN102477041B provides a preparation method of cephalothin hydrochloride. The obtained cephalothin hydrochloride significantly improves the solubility of cephalothin in water and effectively improves many unfavorable factors in the preparation. Patent CN114989186A reports a method for purifying cephalothin. The chemical purity of cephalothin is significantly improved by controlling the recrystallization solvent and its dosage, crystallization temperature and other parameters during the purification process. However, the crystallinity of the resulting product is low.

[0006] The solid powder form and structure of the drug affect the drug's stability, purity, fluidity, dissolution rate, bioavailability and other physicochemical properties. The amorphous form of cephalaenopsis has problems such as poor downstream separation operation and stability. Therefore, it is urgent to develop a solid form with good crystal fluidity and stability to improve production and use needs. Summary of the invention

[0007] The technical problem to be solved by the present invention is to address the deficiencies in the prior art, and provide cephalothin acetonitrile solvate crystals, cephalothin methanol solvate crystals, cephalothin methyl acetate solvate crystals, cephalothin ethyl acetate solvate crystals, cephalothin butyl acetate solvate crystals and cephalothin anhydrous crystalline form I crystals. Compared with the raw material amorphous cephalothin powder, the cephalothin crystals provided by the present invention have high bulk density, good fluidity, strong stability, and are easy to store and transport.

[0008] In order to solve the above technical problems, the technical solution adopted by the present invention is as follows:

[0009] The present invention discloses a cephalaenoside crystal, wherein the cephalaenoside crystal is any one of a cephalaenoside acetonitrile solvate crystal, a cephalaenoside methanol solvate crystal, a cephalaenoside methyl acetate solvate crystal, a cephalaenoside ethyl acetate solvate crystal, a cephalaenoside butyl acetate solvate crystal and a cephalaenoside crystal form I crystal;

[0010] The cephalaenopsis acetonitrile solvate crystal has a molecular formula of C 37 H 38 N2O6·CH3CN, the crystal structure belongs to the orthorhombic system, P212121 space group, the unit cell parameters are α=90°,β=90°,γ=90°,unit cell volume The minimum number of asymmetric units in the unit cell is Z=4, and the minimum asymmetric unit contains 1 cepharanthin molecule and 1 acetonitrile solvent molecule; there are the following X-ray powder diffraction characteristic lines measured after grinding according to 2θ-diffraction angle and I / I0-relative intensity, measured using Cu-Kα rays:

[0011]

[0012] The methanol solvate crystal of cephalaenopsis has the molecular formula C 37 H 38 N2O6·0.5CH3OH, the crystal structure belongs to the triclinic system, P32 space group, unit cell parameters α=90°,β=90°,γ=120°,unit cell volume The minimum number of asymmetric units in the unit cell is Z=3, and the minimum asymmetric unit contains 1 cepharanthin molecule and 0.5 methanol solvent molecule; there are the following X-ray powder diffraction characteristic lines measured after grinding according to 2θ-diffraction angle and I / I0-relative intensity, measured using Cu-Kα rays:

[0013]

[0014] The cephalaenopsis methyl acetate solvate crystal has a molecular formula of C 37 H 38 N2O6·C3H6O2, the crystal structure belongs to the orthorhombic system, P212121 space group, unit cell parameters α=90°,β=90°,γ=90°,unit cell volume The minimum asymmetric unit number Z in the unit cell is 8, and the minimum asymmetric unit contains 2 cephalothin molecules and 2 methyl acetate solvent molecules, wherein the 2 cephalothin molecules are in different conformations, and the 2 methyl acetate solvent molecules are in different conformations; there are the following X-ray powder diffraction characteristic lines measured after grinding according to 2θ-diffraction angle and I / I0-relative intensity, measured using Cu-Kα rays:

[0015]

[0016]

[0017] The cephalaenopsis ethyl acetate solvate crystal has a molecular formula of C 37 H 38 N2O6·C4H8O2, the crystal structure belongs to the monoclinic system, P21 space group, unit cell parameters β=90.821(6)°,γ=90°,the unit cell volume is The minimum asymmetric unit number Z in the unit cell is 4, and the minimum asymmetric unit contains 2 cephalothin molecules and 2 ethyl acetate solvent molecules, wherein the 2 cephalothin molecules are in different conformations, and the 2 ethyl acetate solvent molecules are in different conformations; there are the following X-ray powder diffraction characteristic lines measured after grinding according to 2θ-diffraction angle and I / I0-relative intensity, measured using Cu-Kα rays:

[0018]

[0019] The cephalaenopsis butyl acetate solvate crystal has a molecular formula of 2C 37 H 38 N2O6·C6H 12 O2, the crystal structure belongs to the orthorhombic system, the space group is P212121, the unit cell parameters α=90°,β=90°,γ=90°,unit cell volume The minimum asymmetric unit number Z in the unit cell is 4, and the minimum asymmetric unit contains 2 cephalothin molecules and 1 butyl acetate solvent molecule, wherein the 2 cephalothin molecules are in different conformations; and there are the following X-ray powder diffraction characteristic lines measured after grinding according to 2θ-diffraction angle and I / I0-relative intensity, measured using Cu-Kα rays:

[0020]

[0021]

[0022] The cephalaenopsis crystalline form I crystal has a molecular formula of C 37 H 38 N2O6, the crystal structure belongs to the triclinic system, P31 space group, and the unit cell parameters are , α=90°, β=90°, γ=120.00°, unit cell volume The minimum number of asymmetric units in the unit cell is Z=3, and one cephalothin molecule is contained in the minimum asymmetric unit; there are the following X-ray powder diffraction characteristic lines measured after grinding according to 2θ-diffraction angle and I / I0-relative intensity, measured using Cu-Kα radiation:

[0023]

[0024] The cephalaenopsis acetonitrile solvate crystals, cephalaenopsis methanol solvate crystals, cephalaenopsis methyl acetate solvate crystals, cephalaenopsis ethyl acetate solvate crystals, cephalaenopsis butyl acetate solvate crystals and cephalaenopsis crystal form I crystals are crystalline powders and are colorless.

[0025] Specifically, the cephalaenopsis acetonitrile solvate crystals have a bulk density of more than 0.58 g / cm 3 , preferably greater than 0.64 g / cm 3 , more preferably greater than 0.67 g / cm 3 .

[0026] Specifically, the tap density of the cephalaenopsis acetonitrile solvate crystal is greater than 0.60 g / cm 3 , preferably greater than 0.65 g / cm 3 , more preferably greater than 0.70 g / cm 3 .

[0027] Specifically, the bulk density of the crystalline powder of the cephaladin methanol solvate is greater than 0.82 g / cm 3 , preferably greater than 0.86 g / cm3 , more preferably greater than 0.92 g / cm 3 .

[0028] Specifically, the tap density of the crystalline powder of the cephaladin methanol solvate is greater than 0.85 g / cm 3 , preferably greater than 0.94 g / cm 3 , more preferably greater than 1.0 g / cm 3 .

[0029] Specifically, the cephalaenopsis methyl acetate solvate crystals have a bulk density of more than 0.90 g / cm 3 , preferably greater than 0.94 g / cm 3 , more preferably greater than 1.0 g / cm 3 .

[0030] Specifically, the tap density of the cephalaenopsis methyl acetate solvate crystal is greater than 0.93 g / cm 3 , preferably greater than 0.98 g / cm 3 , more preferably greater than 1.05 g / cm 3 .

[0031] Specifically, the cepharanthin ethyl acetate solvate crystals have a bulk density of more than 0.56 g / cm 3 , preferably greater than 0.66 g / cm 3 , more preferably greater than 0.71 g / cm 3 .

[0032] Specifically, the tap density of the cephalaenopsis ethyl acetate solvate crystal is greater than 0.59 g / cm 3 , preferably greater than 0.67 g / cm 3 , more preferably greater than 0.73 g / cm 3 .

[0033] Specifically, the cephalaenoic acid butyl ester solvate crystals have a bulk density of more than 0.64 g / cm 3 , preferably greater than 0.72 g / cm 3 , more preferably greater than 0.84 g / cm 3 .

[0034] Specifically, the cephalaenopsis butyl acetate solvate crystals have a tap density of more than 0.69 g / cm 3 , preferably greater than 0.78 g / cm 3 , more preferably greater than 0.88 g / cm 3 .

[0035] Specifically, the bulk density of the crystalline powder of the Stephania tetrandra crystal form I is greater than 0.80 g / cm 3 , preferably greater than 0.86 g / cm 3 , more preferably greater than 0.95 g / cm 3 .

[0036] Specifically, the tap density of the crystalline powder of the Stephania tetrandra crystal form I is greater than 0.85 g / cm 3 , preferably greater than 0.92 g / cm 3 , more preferably greater than 1.0 g / cm 3 .

[0037] Furthermore, the present invention discloses a method for preparing the above-mentioned cephalaenopsis crystalline form I crystals, comprising mixing a first raw material with a first solvent, dissolving the first raw material to obtain a first mixed solution; evaporating and crystallizing the first mixed solution at room temperature to precipitate crystals, filtering and drying the crystal system to obtain cephalaenopsis crystalline form I crystals;

[0038] The first raw material is any one of cephalothin, cephalothin acetonitrile solvate crystals, cephalothin methanol solvate crystals and cephalothin ethyl acetate solvate crystals; the first solvent is any one of dimethylacetamide, N-methylformamide and isopropanol or a combination of several thereof.

[0039] Specifically, in the preparation method of the cephalothin crystal form I, the first raw material is any one of amorphous cephalothin, cephalothin acetonitrile solvate crystals, cephalothin methanol solvate crystals and cephalothin ethyl acetate solvate crystals; the mass volume ratio of the first raw material to the first solvent is 0.1-0.4 g:2 mL, preferably 0.2-0.3 g:2 mL, more preferably 0.2:2 mL or 0.3 g:2 mL; the evaporative crystallization, the crystallization time is 2-8 days, preferably 3-7 days.

[0040] Wherein, in the preparation method of the cephalothin crystal form I crystal, the cephalothin crystal form I crystal is a cephalothin anhydrate crystal form I crystal; the dissolving of the first raw material is carried out by ultrasonic dissolution or oscillation dissolution; the ultrasonic dissolution has an ultrasonic power of 50 to 100 W, preferably 50 to 80 W, more preferably 50 to 60 W, and most preferably 50 W, and an ultrasonic temperature of 30 to 40° C., preferably 35 to 40° C., and more preferably 40° C., and the ultrasonic time is until the first raw material solid is completely dissolved; the oscillation dissolution has an oscillation dissolution temperature of 20 to 50° C., preferably 35 to 50° C., and an oscillation speed of 100 to 300 rpm, preferably 100 to 150 rpm, and more preferably 150 rpm, and the oscillation time is until the first raw material solid is completely dissolved; the oscillation dissolution is preferably carried out in a shaking table.

[0041] Furthermore, the present invention discloses a method for preparing the above-mentioned cephalaenopsis acetonitrile solvate crystals, comprising dissolving a second raw material in a second solvent to obtain a second mixed solution; subjecting the second mixed solution to suspension crystallization or ultrasonic cooling crystallization to precipitate crystals, filtering and drying the crystal system to obtain cephalaenopsis acetonitrile solvate crystals;

[0042] The second raw material is cephalanthrin or cephalanthrin crystal form I; the second solvent is acetonitrile or a mixture of acetonitrile and water in a volume ratio of 3:1 to 3.

[0043] Specifically, in the preparation method of the cephalothin acetonitrile solvate crystals, the second raw material is amorphous cephalothin or cephalothin form I crystals; the second solvent is acetonitrile or a mixture of acetonitrile and water in a volume ratio of 3:2; the mass volume ratio of the second raw material to the second solvent is 0.1-0.4 g:2-5 mL, preferably 0.2-0.3 g:2-5 mL.

[0044] Among them, in the preparation method of the acetonitrile solvate crystal of Stephania tetrazolium, the suspended crystallization is performed, and the second mixed solution is stirred at 25-40°C for 4 minutes to 4 hours, preferably for 4 minutes or 4 hours, and crystallization is performed during the stirring process; the ultrasonic cooling crystallization is performed, and the second mixed solution is ultrasonically dissolved, the ultrasonic power is 50-100W, preferably 70-100W, more preferably 70-80W, and most preferably 75W, the ultrasonic temperature is 20-40°C, preferably 30-40°C, and more preferably 40°C, and the ultrasonic time is until the solid in the second mixed solution is completely dissolved. After the ultrasonic dissolution is completed, the second mixed solution is cooled to -20-4°C, preferably 0-4°C, and more preferably 0°C at a cooling rate of 5-10°C / min, and the crystallization system is maintained at this temperature for 8-24h for crystallization, preferably the crystallization system is maintained for 8-12h for crystallization, and more preferably the crystallization system is maintained for 10h for crystallization.

[0045] Furthermore, the present invention discloses a method for preparing the above-mentioned cephalaenopsis methanol solvate crystals, comprising dissolving a third raw material in anhydrous methanol to obtain a third mixed solution; cooling the third mixed solution for crystallization or suspension crystallization to precipitate crystals, filtering and drying the crystal system to obtain cephalaenopsis methanol solvate crystals;

[0046] The third raw material is any one of cephalaenopsis crystalline form I crystals, cephalaenopsis acetonitrile solvate crystals, cephalaenopsis methyl acetate solvate crystals, cephalaenopsis ethyl acetate solvate crystals and cephalaenopsis butyl acetate solvate crystals.

[0047] Specifically, in the preparation method of the cephalothin methanol solvate crystals, the third raw material is any one of cephalothin form I crystals, cephalothin acetonitrile solvate crystals, cephalothin methyl acetate solvate crystals, cephalothin ethyl acetate solvate crystals and cephalothin butyl acetate solvate crystals; the mass volume ratio of the third raw material to anhydrous methanol is 0.05-0.25 g:1-2 mL, preferably 0.1-0.2 g:1-2 mL.

[0048] Among them, in the preparation method of the methanol solvate crystals of cephaladin, the cooling crystallization is to place the third mixed solution at -20 to 6°C for 1 to 5 days for crystallization, preferably to place the third mixed solution at 0 to 6°C for 1 to 3 days for crystallization, and more preferably to place the third mixed solution at 4°C for 1 day for crystallization; the suspension crystallization is to place the third mixed solution at room temperature for 1 to 7 days for crystallization, preferably for 3 to 5 days.

[0049] Furthermore, the present invention discloses a method for preparing the above-mentioned cephalaenopsis methyl acetate solvate crystals, which comprises dissolving a fourth raw material in methyl acetate to dissolve the fourth raw material to obtain a fourth mixed solution; cooling the fourth mixed solution for crystallization or evaporation crystallization to precipitate crystals, filtering and drying the crystal system to obtain cephalaenopsis methyl acetate solvate crystals;

[0050] The fourth raw material is any one of cephalaenopsis, cephalaenopsis crystal form I crystals, cephalaenopsis acetonitrile solvate crystals and cephalaenopsis methanol solvate crystals.

[0051] Specifically, in the preparation method of the cephalothin methyl acetate solvate crystals, the fourth raw material is any one of amorphous cephalothin, cephalothin form I crystals, cephalothin acetonitrile solvate crystals and cephalothin methanol solvate crystals; the mass volume ratio of the fourth raw material to methyl acetate is 0.2-0.6 g:2 mL, preferably 0.3-0.4 g:2 mL, and more preferably 0.3:2 mL or 0.4 g:2 mL.

[0052] Among them, in the preparation method of the cephaladin methyl acetate solvate crystal, the dissolving method of the fourth raw material is ultrasonic dissolution or oscillation dissolution; the ultrasonic dissolution, the ultrasonic power is 50-100W, preferably 80-100W, more preferably 100W, the ultrasonic temperature is 20-40°C, preferably 30-40°C, more preferably 40°C, and the ultrasonic time is until the solid in the fourth mixed solution is completely dissolved; the oscillation dissolution, the oscillation dissolution temperature is 20-50°C, preferably 35-50°C, more preferably 50°C, and the oscillation time is until the solid in the fourth mixed solution is completely dissolved; the oscillation dissolution is preferably carried out in a shaking table; the cooling crystallization, the fourth mixed solution is placed at -20-4°C for 1-8 days for crystallization, preferably the fourth mixed solution is placed at -10-4°C for 1-7 days for crystallization; the evaporation crystallization, the evaporation crystallization temperature is room temperature, and the evaporation crystallization time is 2-8 days, preferably 3-7 days.

[0053] Furthermore, the present invention discloses a method for preparing the above-mentioned cephalaenopsis ethyl acetate solvate crystals, which comprises dissolving the fifth raw material in ethyl acetate to obtain a fifth mixed solution; cooling the fifth mixed solution for crystallization or evaporation crystallization to precipitate crystals, filtering and drying the crystal system to obtain cephalaenopsis ethyl acetate solvate crystals;

[0054] The fifth raw material is any one of cephalaenopsis, cephalaenopsis crystal form I crystals, cephalaenopsis acetonitrile solvate crystals, cephalaenopsis methanol solvate crystals and cephalaenopsis methyl acetate solvate crystals.

[0055] Specifically, in the preparation method of the cephalothin ethyl acetate solvate crystals, the fifth raw material is any one of amorphous cephalothin, cephalothin form I crystals, cephalothin acetonitrile solvate crystals, cephalothin methanol solvate crystals and cephalothin methyl acetate solvate crystals; the mass volume ratio of the fifth raw material to ethyl acetate is 0.2-0.7 g:2 mL, preferably 0.4-0.5 g:2 mL, more preferably 0.4 g:2 mL or 0.5 g:2 mL.

[0056] Among them, in the preparation method of the ethyl acetate solvate crystal of cephalaenopsis acetosporin, the dissolving method of the fifth raw material is ultrasonic dissolution or oscillation dissolution; the ultrasonic dissolution, the ultrasonic power is 50-100W, preferably 70-100W, more preferably 75-100W, further preferably 75W or 100W, the ultrasonic temperature is 20-40°C, preferably 30-40°C, and the ultrasonic time is until the solid in the fifth mixed solution is completely dissolved; the oscillation dissolution, the oscillation dissolution temperature is 20-50°C, preferably 35-50°C, more preferably 50°C, and the oscillation time is until the solid in the fifth mixed solution is completely dissolved; the oscillation dissolution is preferably carried out in a shaking table; the cooling crystallization, the fifth mixed solution is placed at -20-4°C for 1-8 days for crystallization, preferably the fifth mixed solution is placed at 0-4°C for 3-7 days for crystallization; the evaporation crystallization, the evaporation crystallization temperature is room temperature, and the evaporation crystallization time is 2-10 days, preferably 6-8 days, more preferably 7 days.

[0057] Furthermore, the present invention discloses a method for preparing the above-mentioned cephalaenopsis butyl acetate solvate crystals, which comprises dissolving a sixth raw material in butyl acetate to dissolve the sixth raw material to obtain a sixth mixed solution; cooling the sixth mixed solution for crystallization or evaporation crystallization to precipitate crystals, filtering and drying the crystal system to obtain cephalaenopsis butyl acetate solvate crystals;

[0058] The sixth raw material is any one of cephalaenopsis, cephalaenopsis crystal form I crystals, cephalaenopsis acetonitrile solvate crystals, cephalaenopsis methanol solvate crystals and cephalaenopsis methyl acetate solvate crystals.

[0059] Specifically, in the preparation method of the cephalothin butyl acetate solvate crystals, the sixth raw material is any one of amorphous cephalothin, cephalothin form I crystals, cephalothin acetonitrile solvate crystals, cephalothin methanol solvate crystals and cephalothin methyl acetate solvate crystals; the mass volume ratio of the sixth raw material to butyl acetate is 0.2-0.8 g:2 mL, preferably 0.4-0.5 g:2 mL, more preferably 0.4 g:2 mL or 0.5 g:2 mL.

[0060] Among them, in the preparation method of the cephaladin butyl acetate solvate crystal, the dissolving method of the sixth raw material is ultrasonic dissolution or oscillation dissolution; the ultrasonic dissolution, the ultrasonic power is 50-100W, preferably 60-100W, more preferably 75-100W, further preferably 75W or 100W, the ultrasonic temperature is 20-40°C, preferably 30-40°C, more preferably 30-35°C, further preferably 30°C or 35°C, and the ultrasonic time is until the solid in the sixth mixed solution is completely dissolved; the oscillation dissolution, the oscillation dissolution temperature is 20-50°C, preferably 35-50°C, more preferably 50°C, and the oscillation time is until the solid in the sixth mixed solution is completely dissolved; the oscillation dissolution is preferably carried out in a shaker; the cooling crystallization, the sixth mixed solution is placed at -20-4°C for 2-8 days for crystallization, preferably for 3-7 days for crystallization; the evaporation crystallization, the evaporation crystallization temperature is room temperature, and the evaporation crystallization time is 5-10 days, preferably 6-8 days, more preferably 7 days.

[0061] The bulk density and tap density are quantities related to the properties of a powder. In general, high bulk density and tap density values ​​are desired. The bulk density refers to the weight of a unit of powder per volume under predetermined conditions, expressed as the weight per unit of volume usually in g / mL. The tap density also indicates the weight of a unit of powder per volume, in a holder of the powder, subjected to tapping or vibration under predetermined conditions. Therefore, for the same powder, its tap density is higher than the bulk density.

[0062] Crystals with high bulk density and tap density tend to have a larger specific gravity, which reflects that the crystal product is relatively thick and has a better texture, and its stability is also relatively good. From another perspective, products with high bulk density generally have better fluidity of particles and are also easy to store and transport.

[0063] Specifically, the measuring methods of the bulk density and tap density of the crystalline powder are as follows:

[0064] The bulk density of the granules was determined according to USP Method II (page 1914);

[0065] The tap density of the particles is measured by a FZS4-4 economical tap density tester according to GB / T 5162-2006. Specifically, the test conditions are: the vibration stroke of the beating device is 3±0.1MM, and the vibration frequency is 250±15 times per minute.

[0066] Beneficial effects:

[0067] (1) Compared with amorphous cephalaenopsis powder, the crystals provided by the present invention have high bulk density, good fluidity, strong stability, and are easy to store and transport.

[0068] (2) The cephalaenopsis crystalline form I and five cephalaenopsis solvate crystals provided by the present invention have good stability. The sample was placed in a dynamic vapor adsorption instrument at 40°C, and the weight was recorded when the mass change was less than 0.01g within 3 hours. The hygroscopicity of the cephalaenopsis crystalline form I and five cephalaenopsis solvate crystals was much lower than that of the amorphous cephalaenopsis powder, indicating that the stability of the cephalaenopsis crystals provided by the present invention is greatly improved compared with the amorphous cephalaenopsis powder. BRIEF DESCRIPTION OF THE DRAWINGS

[0069] The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments, and the above and / or other advantages of the present invention will become more clear.

[0070] Figure 1 It is the powder diffraction pattern of cephalaenopsis crystalline form I and 5 cephalaenopsis solvate crystals.

[0071] Figure 2 This is the molecular ellipsoid diagram of the smallest asymmetric unit of the crystalline form I of Stephania tetrandra.

[0072] Figure 3 This is the unit cell stacking diagram of cephalaenopsis crystalline form I.

[0073] Figure 4 This is the thermogravimetric / differential scanning analysis diagram of cephalaenopsis crystalline form I.

[0074] Figure 5 This is a crystal morphology picture of the cephalothin crystal form I.

[0075] Figure 6 This is the molecular ellipsoid diagram of the smallest asymmetric unit of the crystal of cephalaenopsis acetonitrile solvate.

[0076] Figure 7 This is the unit cell packing diagram of the crystals of cephalaenopsis acetonitrile solvate.

[0077] Figure 8 This is the thermogravimetric / differential scanning analysis chart of cephalaenopsis acetonitrile solvate crystals.

[0078] Fig. 9 This is the molecular ellipsoid diagram of the smallest asymmetric unit of the crystal of cephalaenopsis methanol solvate.

[0079] Fig.10 This is the unit cell packing diagram of the crystals of cephaladin methanol solvate.

[0080] Fig.11 This is a thermogravimetric / differential scanning analysis diagram of the methanol solvate crystals of cephalaenopsis indole.

[0081] Fig.12 This is the molecular ellipsoid diagram of the smallest asymmetric unit of the crystal of cephalaenopsis methyl acetate solvate.

[0082] Fig.13 This is the unit cell packing diagram of the crystals of cephalaenopsis methyl acetate solvate.

[0083] Fig.14 This is a thermogravimetric / differential scanning analysis chart of cephalaenopsis methyl acetate solvate crystals.

[0084] Fig.15 This is the molecular ellipsoid diagram of the smallest asymmetric unit of the crystal of ethyl acetate solvate of cephalaenopsis indole.

[0085] Fig.16 This is the unit cell packing diagram of the crystals of cephalaenopsis ethyl acetate solvate.

[0086] Fig.17 This is a thermogravimetric / differential scanning analysis chart of cephalaenopsis ethyl acetate solvate crystals.

[0087] Fig.18 This is the molecular ellipsoid diagram of the smallest asymmetric unit of the crystalline form of cephalaenopsis butyl acetate solvate.

[0088] Fig.19 This is the unit cell packing diagram of the crystals of cephalaenopsis butyl acetate solvate.

[0089] Fig. 20 This is a thermogravimetric / differential scanning analysis chart of cephalaenopsis butyl acetate solvate crystals.

[0090] Fig.21 This is a diagram of information related to the crystal structure of cephalothin Form I.

[0091] Fig. 22 This is a diagram of information related to the crystal structure of cetonitrile solvate of cetonitrile.

[0092] Fig.23 This is a diagram of information related to the crystal structure of cephalaenopsis methanol solvate.

[0093] Fig.24 This is a diagram of information related to the crystal structure of cephalaenopsis methyl acetate solvate.

[0094] Fig.25 This is a diagram of information related to the crystal structure of cephalaenopsis ethyl acetate solvate.

[0095] Fig.26 This is a diagram of information related to the crystal structure of cephalaenopsis butyl acetate solvate.

[0096] Fig. 27 This is a crystal morphology diagram of the product obtained in Comparative Example 1.

[0097] Fig.28 This is the thermogravimetric analysis diagram of the product obtained in Example 3. DETAILED DESCRIPTION

[0098] The cephalaenopsis crystalline powder and preparation method of the present invention will be further illustrated by the following non-limiting examples. The following examples are only descriptive and not restrictive, and cannot be used to limit the scope of protection of the present invention.

[0099] The X-ray powder diffraction test conditions in the embodiments of the present invention are as follows: Rigaku SmartLabSE model X-ray powder diffractometer, Cu-Kα radiation, tube voltage 40KV, current 40mA, scan speed 10° / min, and scan range 5-40°.

[0100] The TG / DSC data in the embodiment of the present invention were obtained by analyzing a NETZSCH STA 449F3 instrument. The analysis conditions were: 5 to 10 mg of sample was placed in a ceramic crucible, N2 was used as the protective gas, the heating rate was 10°C / min, and the temperature range was 40 to 300°C or 40 to 350°C.

[0101] The detection methods and instruments for the crystal structures of the cephalaenopsis crystalline form I and five cephalaenopsis crystalline solvates obtained in the examples of the present invention are as follows:

[0102] Single crystal X-ray diffraction determination of crystal structure and analysis method: Take the cultured single crystals of better quality cephalaenopsis crystal form I and five cephalaenopsis solvate crystals and cut them into pieces of about 0.45×0.30×0.14mm 3 The blocks of different sizes were analyzed by Bruker APEX-IICCD diffractometer with Mo Kα radiation source (graphite monochromator, ) to irradiate the sample and collect diffraction data. The diffraction data were reduced by SAINT and then directly analyzed by SHELXL-97 software. 2 The full matrix least squares refinement was performed, and all non-hydrogen atoms were refined by anisotropic refinement. The final data were plotted using Mercury 3.3 or Materials studio 7.02 software.

[0103] The amorphous stephania powder raw material used in the embodiment of the present invention is prepared by referring to the experimental method of patent CN 102146083 A. The bulk density of the obtained amorphous stephania powder raw material is 0.15 g / cm 3 , tap density is 0.17g / cm 3 .

[0104] The cephalaenopsis crystalline form I crystals, cephalaenopsis acetonitrile solvate crystals, cephalaenopsis methanol solvate crystals, cephalaenopsis methyl acetate solvate crystals, cephalaenopsis ethyl acetate solvate crystals and cephalaenopsis butyl acetate solvate crystals used in the embodiments of the present invention are all homemade in the laboratory and prepared according to the method of the embodiments of the present invention.

[0105] The anhydrous methanol used in the examples of the present invention was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd., with a purity of ≥99.5%.

[0106] Example 1: Preparation of Stephania tetrandra Form I Crystals

[0107] 0.2 g of amorphous cephalaenopsis powder was added to 2 mL of dimethylacetamide solvent to obtain a first mixed solution; the first mixed solution was placed in a 50 W, 40 ° C ultrasonic cleaning instrument for ultrasonication until all the solids in the first mixed solution were dissolved, and the clarified first mixed solution was placed at room temperature for slow evaporation and crystallization for 5 days to precipitate crystals, and the crystal system was filtered and dried at 20 ° C and normal pressure for 4 hours to obtain colorless cephalaenopsis crystal form I crystals. There are 0.186 g of cephalaenopsis crystal form I crystals, and the molar yield is 93%. The bulk density of the obtained cephalaenopsis crystal form I crystals is 0.98 g / cm 3 , tap density is 1.02g / cm 3 .

[0108] X-ray powder diffraction characteristic lines measured for the cephalad form I crystals according to the 2θ-diffraction angle and I / I0-relative intensity, measured using Cu-Kα radiation:

[0109] Table 1 X-ray powder diffraction characteristic spectrum of Stephania tetrandra crystal form I

[0110]

[0111] The X-ray diffraction pattern of Stephania tetrandra crystal form I is as follows: Figure 1 a, the molecular ellipsoid diagram of the minimum asymmetric unit of the crystalline form I of Stephania tetrandra is shown in Figure 2 As shown, the unit cell stacking diagram of the crystalline form I of Stephania tetrandra is as follows Figure 3 The TGA and DSC analysis results of the cephalaenopsis crystalline form I are shown in Figure 4 It is shown that there is an endothermic characteristic peak at 184.3℃ on the DSC curve, which corresponds to the melting point of the crystalline form I of Stephania quinata, and an exothermic characteristic peak at 335.3℃, which corresponds to the decomposition point of the crystalline form I of Stephania quinata. There is no obvious weight loss step on the TGA curve, which proves that there is no crystalline form I of Stephania quinata. The crystal morphology of the crystalline form I of Stephania quinata, such as Figure 5 As shown. Stephania truncatula crystal form I, molecular formula is C 37 H38 N2O6, the crystal structure belongs to the triclinic system, P31 space group, and the unit cell parameters are , α=90°, β=90°, γ=120.00°, unit cell volume The minimum asymmetric unit number Z in the unit cell is 3, and there is one cephalothin molecule in the minimum asymmetric unit. The specific information about the crystal structure of cephalothin crystal form I is shown in the figure. Fig.21 .

[0112] Example 2: Preparation of Cephalaenopsis crystalline form I

[0113] 0.2 g of amorphous cephalaenopsis powder was added to 2 mL of N-methylformamide solvent to obtain a first mixed solution; the shaker temperature was set to 25 ° C, the oscillation speed was 150 rpm, and the first mixed solution was oscillated in the shaker until the solid was completely dissolved, and the clarified first mixed solution was placed at room temperature for slow evaporation and crystallization for 5 days to precipitate crystals, and the crystal system was filtered and dried at 20 ° C and normal pressure for 4 hours to obtain colorless cephalaenopsis crystal form I crystals. There are 0.18 g of cephalaenopsis crystal form I crystals, and the molar yield is 90%. The bulk density of the obtained cephalaenopsis crystal form I crystals is 0.96 g / cm 3 , tap density is 1.01g / cm 3 .

[0114] Example 3: Preparation of Cephalaenopsis Form I Crystals

[0115] 0.3 g of acetonitrile solvate crystals of celastrol were added to 2 mL of isopropanol solvent to obtain a first mixed solution; the temperature of the shaker was set at 35 ° C, the oscillation speed was 150 rpm, and the first mixed solution was oscillated in the shaker until the solid was completely dissolved, and the clarified first mixed solution was placed at room temperature for slow evaporation and crystallization for 3 days to precipitate crystals, and the crystal system was filtered and dried at 20 ° C and normal pressure for 4 hours to obtain colorless celastrol crystals I. There are 0.256 g of celastrol crystals I, and the molar yield is 91%. The bulk density of the obtained celastrol crystals I is 0.89 g / cm 3 , tap density is 0.92g / cm 3 .

[0116] Example 4: Preparation of Cephalaenopsis crystalline form I

[0117] 0.3 g of acetonitrile solvate crystals of celastrol were added to 2 mL of dimethylacetamide solvent to obtain a first mixed solution; the temperature of the shaker was set at 45 ° C, the oscillation speed was 150 rpm, and the first mixed solution was shaken in the shaker until the solid was completely dissolved, and the clarified first mixed solution was placed at room temperature for slow evaporation and crystallization for 7 days to precipitate crystals, and the crystal system was filtered and dried at 20 ° C and normal pressure for 4 hours to obtain colorless celastrol crystals of form I. There are 0.259 g of celastrol crystals of form I, and the molar yield is 92%. The bulk density of the obtained celastrol crystals of form I is 0.90 g / cm 3 , tap density is 0.98g / cm 3 .

[0118] Example 5: Preparation of Cephalaenopsis crystalline form I

[0119] 0.3 g of methanol solvate crystals of celastrol were added to 2 mL of isopropanol solvent to obtain a first mixed solution; the temperature of the shaker was set at 35 ° C, the oscillation speed was 150 rpm, and the first mixed solution was shaken in the shaker until the solid was completely dissolved, and the clarified first mixed solution was placed at room temperature for slow evaporation and crystallization for 3 days to precipitate crystals, and the crystal system was filtered and dried at 20 ° C and normal pressure for 4 hours to obtain colorless celastrol crystals of form I. There are 0.263 g of celastrol crystals of form I, and the molar yield is 90%. The bulk density of the obtained celastrol crystals of form I is 0.88 g / cm 3 , tap density is 0.95g / cm 3 .

[0120] Example 6: Preparation of Cephalaenopsis cerana Form I Crystals

[0121] 0.3 g of ethyl acetate solvate crystals of celastrol were added to 2 mL of isopropanol solvent to obtain a first mixed solution; the temperature of the shaker was set to 35 ° C, the oscillation speed was 150 rpm, and the first mixed solution was oscillated in the shaker until the solid was completely dissolved, and the clarified first mixed solution was placed at room temperature for slow evaporation and crystallization for 3 days to precipitate crystals, and the crystal system was filtered and dried at 20 ° C and normal pressure for 4 hours to obtain colorless celastrol crystal form I crystals. There are 0.241 g of celastrol crystal form I crystals, and the molar yield is 92%. The bulk density of the obtained celastrol crystal form I crystals is 0.92 g / cm 3 , tap density is 0.99g / cm 3 .

[0122] Example 7: Preparation of Cephalaenopsis Form I Crystals

[0123] 0.3 g of cephalaenopsis ethyl acetate solvate crystals were added to 2 mL of isopropanol solvent to obtain a first mixed solution; the temperature of the shaker was set to 45 ° C, the oscillation speed was 150 rpm, and the first mixed solution was oscillated in the shaker until the solid was completely dissolved, and the clarified first mixed solution was placed at room temperature for slow evaporation and crystallization for 7 days to precipitate crystals, and the crystal system was filtered and dried at 20 ° C and normal pressure for 4 hours to obtain colorless cephalaenopsis crystal form I crystals. There are 0.238 g of cephalaenopsis crystal form I crystals, and the molar yield is 90%. The bulk density of the obtained cephalaenopsis crystal form I crystals is 0.91 g / cm 3 , tap density is 0.98g / cm 3 .

[0124] Comparative Example 1: Preparation method Referring to Example 1 in patent CN 115260210 A, 12.0 g of cephalaenopsis was taken, 150 mL of methanol and 10 mL of acetone were added, stirred, heated at 55 ° C for 1 h, filtered, the filtrate was allowed to stand, cooled to room temperature, and then crystallized at 0 ° C for 10 h, filtered, and dried at 50 ° C for 2 h to obtain cephalaenopsis crystal form I crystals with a mass of 9.3 g and a molar yield of 78%. After testing, the bulk density is 0.48 g / cm 3 , tap density is 0.54g / cm 3 The overall crystal particles are relatively small and the texture is not strong. The specific crystal morphology is shown in the figure Fig. 27 shown.

[0125] Example 8: Preparation of Cephalaenopsis acetonitrile solvate crystals

[0126] Add 0.3 g of amorphous cephalanthrin powder raw material to 3 mL of acetonitrile solvent to obtain a second mixed solution; place the second mixed solution at 25°C and stir for 4 minutes to perform suspension crystallization, and perform crystallization during the stirring process. After the stirring is completed, filter the crystal system, and dry the crystals at 20°C and normal pressure for 4 hours to obtain colorless cephalanthrin acetonitrile solvate crystals. 0.282 g of acetonitrile solvate is obtained, and the molar yield is 88%. The bulk density of the cephalanthrin acetonitrile solvate crystals is 0.69 g / cm 3 , tap density is 0.72g / cm 3 .

[0127] X-ray powder diffraction characteristic lines of the acetonitrile solvate crystals of Stephania tetrazolium measured according to 2θ-diffraction angle and I / I0-relative intensity, measured using Cu-Kα radiation:

[0128] Table 2 X-ray powder diffraction characteristic spectrum of cephalaenopsis acetonitrile solvate crystals

[0129]

[0130] The X-ray diffraction pattern of the acetonitrile solvate crystals of Stephania Figure 1 b shows the molecular ellipsoid diagram of the minimum asymmetric unit of the acetonitrile solvate crystal of Stephania tetrazolium. Figure 6 The unit cell packing diagram of the acetonitrile solvate crystal of Stephania tetrazolium is shown in Figure 7 The TGA and DSC analysis results of the acetonitrile solvate crystals of Stephania tetrazolium are shown in Figure 8 It shows that there is an endothermic characteristic peak at 115.88℃ on the DSC curve, which corresponds to the desolvation point of the cephalanthrin acetonitrile solvate crystals; there is an exothermic characteristic peak at T=323.78℃, which corresponds to the decomposition point of the cephalanthrin acetonitrile solvate crystals; there is an obvious weight loss step on the TGA curve, with a value of 5.853%, which is consistent with the theoretical weight loss calculated by single crystal analysis. The cephalanthrin acetonitrile solvate crystals, with the molecular formula of C 37 H 38 N2O6·CH3CN, the crystal structure belongs to the orthorhombic system, P212121 space group, the unit cell parameters are α=90°,β=90°,γ=90°,unit cell volume The minimum asymmetric unit number Z in the unit cell is 4, and the minimum asymmetric unit contains 1 cephalanthrin molecule and 1 acetonitrile solvent molecule. The specific information about the crystal structure of cephalanthrin acetonitrile solvate is shown in Fig. 22 .

[0131] Example 9: Preparation of Cephalaenopsis acetonitrile solvate crystals

[0132] Add 0.3 g of cephalaenopsis crystalline form I to 3 mL of acetonitrile solvent, then take 2 mL of water and add it to the system to obtain a second mixed solution; maintain the temperature of the second mixed solution at 40°C, stir with a magnetic stirrer for 4 hours for suspension crystallization, filter the crystal system after stirring, and dry the crystal at 30°C and normal pressure for 2 hours to obtain colorless cephalaenopsis acetonitrile solvate crystals. There are 0.285 g of cephalaenopsis acetonitrile solvate crystals, and the molar yield is 88%. The bulk density of cephalaenopsis acetonitrile solvate crystals is 0.68 g / cm 3 , tap density is 0.71g / cm 3 .

[0133] Example 10: Preparation of Cephalaenopsis acetonitrile solvate crystals

[0134] Add 0.2 g of cephalaenopsis crystalline form I to 2 mL of acetonitrile solvent to obtain a second mixed solution; place the second mixed solution in a 75W, 40°C ultrasonic cleaner for 5 minutes to obtain a clarified second mixed solution. Cool the clarified second mixed solution to 0°C at a cooling rate of 10°C / min, maintain the solution at 0°C for 10 hours for cooling and crystallization, precipitate crystals, filter the crystal system, and dry at 20°C and normal pressure for 4 hours to obtain colorless cephalaenopsis acetonitrile solvate crystals. 0.186 g of cephalaenopsis acetonitrile solvate crystals, with a yield of 87%. The bulk density of cephalaenopsis acetonitrile solvate crystals is 0.66 g / cm 3 , tap density is 0.69g / cm 3 .

[0135] Example 11: Preparation of Cephalaenopsis cephalaenol methanol solvate crystals

[0136] Add 0.1 g of celastrol form I crystals to 2 mL of anhydrous methanol to obtain a third mixed solution; set the temperature of the shaker to 40°C and the oscillation speed to 150 rpm; place the third mixed solution in a shaker and oscillate until all the solids are dissolved; place the clarified third mixed solution in a low temperature environment of 4°C to cool and crystallize for 1 day; precipitate crystals; filter the crystal system, and dry at 20°C and normal pressure for 4 hours to obtain colorless celastrol methanol solvate crystals. There are 0.091 g of celastrol methanol solvate crystals, and the molar yield is 87%. The bulk density of celastrol methanol solvate crystals is 0.93 g / cm 3 , tap density is 1.02g / cm 3 .

[0137] X-ray powder diffraction characteristic lines of the measured celastrol methanol solvate crystals expressed in terms of 2θ-diffraction angle and I / I0-relative intensity, measured using Cu-Kα radiation:

[0138] Table 3 X-ray powder diffraction characteristic spectrum of cephalaenopsis methanol solvate crystals

[0139]

[0140] The X-ray diffraction pattern of the methanol solvate crystal of Stephania tetrandra is shown in Figure 1 c, the molecular ellipsoid diagram of the minimum asymmetric unit of the crystal of cephalaenopsis methanol solvate is shown in Fig. 9 The crystal cell packing diagram of the methanol solvate of cephalaenopsis is shown in Fig.10 The TGA and DSC analysis results of the methanol solvate crystals of cephalaenopsis cephalaenopsis are shown in Fig.11It is shown that there is an endothermic characteristic peak at T = 112.5 ° C on the DSC curve, which corresponds to the starting desolvation point of the methanol solvate crystal of cephalaenopsis, and at T = 328.94 ° C it corresponds to the decomposition hotspot of the methanol solvate crystal of cephalaenopsis; there are two obvious weight loss steps on the TGA curve, the first weight loss is 7.252% (methanol solvent on the surface of the crystal), and the second weight loss is 2.869%. The results are basically consistent with the single crystal analysis theoretical calculation. The methanol solvate crystal of cephalaenopsis, the molecular formula is C 37 H 38 N2O6·0.5CH3OH, the crystal structure belongs to the triclinic system, P32 space group, unit cell parameters α=90°,β=90°,γ=120°,unit cell volume The minimum asymmetric unit number in the unit cell is Z=3, and the minimum asymmetric unit contains 1 cephalaenopsis molecule and 0.5 methanol solvent molecule. The specific information about the crystal structure of cephalaenopsis methanol solvate is shown in the figure. Fig.23 .

[0141] Example 12: Preparation of Cephalaenopsis cephalaenol methanol solvate crystals

[0142] Add 0.15 g of cetonitrile solvate crystals of cetonitrile to 2 mL of anhydrous methanol to obtain a third mixed solution; place the third mixed solution at room temperature for 4 days for suspension crystallization to precipitate crystals, filter the crystal system, and dry at 20°C and normal pressure for 4 hours to obtain colorless cetonitrile solvate crystals of methanol. There are 0.14 g of cetonitrile solvate crystals, and the molar yield is 90%. The bulk density of cetonitrile solvate crystals is 0.94 g / cm 3 , tap density is 1.03g / cm 3 .

[0143] Example 13: Preparation of Cephalaenopsis cephalaenol methanol solvate crystals

[0144] Add 0.2 g of cephalaenopsis methyl acetate solvate crystals to 2 mL of anhydrous methanol solvent to obtain a third mixed solution; place the third mixed solution at room temperature for 3 days for suspension crystallization to precipitate crystals, filter the crystal system, and dry at 20°C and normal pressure for 4 hours to obtain colorless cephalaenopsis methanol solvate crystals. The cephalaenopsis methanol solvate crystals are 0.157 g, and the molar yield is 88%. The bulk density of the cephalaenopsis methanol solvate crystals is 0.95 g / cm 3 , tap density is 1.04g / cm 3 .

[0145] Example 14: Preparation of Cephalaenopsis cephalaenol methanol solvate crystals

[0146] Add 0.1 g of cephalaenopsis ethyl acetate solvate crystals to 2 mL of anhydrous methanol solvent to obtain a third mixed solution; place the third mixed solution at room temperature for 5 days for suspension crystallization to precipitate crystals, filter the crystal system, and dry at 20°C and normal pressure for 4 hours to obtain colorless cephalaenopsis methanol solvate crystals. The cephalaenopsis methanol solvate crystals are 0.072 g, and the molar yield is 86%. The bulk density of the cephalaenopsis methanol solvate crystals is 0.89 g / cm 3 , tap density is 0.96g / cm 3 .

[0147] Example 15: Preparation of Cephalaenopsis acetosporin methanol solvate crystals

[0148] Add 0.1 g of cephalaenopsis butyl acetate solvate crystals to 1 mL of anhydrous methanol solvent to obtain a third mixed solution; place the third mixed solution at room temperature for 4 days for suspension crystallization to precipitate crystals, filter the crystal system, and dry at 20°C and normal pressure for 4 hours to obtain colorless cephalaenopsis methanol solvate crystals. The cephalaenopsis methanol solvate crystals are 0.072 g, and the molar yield is 89%. The bulk density of the cephalaenopsis methanol solvate crystals is 0.88 g / cm 3 , tap density is 0.95g / cm 3 .

[0149] Comparative Example 2: The preparation method is the same as that of Example 11, except that anhydrous methanol is replaced by 75% MeOH, 85% MeOH or 95% MeOH. The obtained product is an amorphous cephalaenopsis powder, and the bulk density of the product is 0.16-0.18 g / cm 3 , tap density is 0.20~0.23g / cm 3 .

[0150] Comparative Example 3: The preparation method is the same as that of Experimental Example 1 of Patent CN 114989186 A. 20 g of crude product A of cephalaenopsis benzene adduct and anhydrous methanol are mixed (the solid-liquid ratio of crude product A of cephalaenopsis benzene adduct and anhydrous methanol is 1:1), heated at 70°C until all the solid is dissolved, stirred and cooled to 25°C, stirred and crystallized for 1 hour, filtered and dried to obtain a cephalaenopsis product, the bulk density of which is 0.27 g / cm 3 , tap density is 0.33g / cm 3 The product was subjected to thermogravimetric analysis. Fig.28 As shown, there is no obvious weight loss on the TGA curve of the product, indicating that the product is not a crystal of methanol solvate of cephalaenopsis indole.

[0151] Example 16: Preparation of Cephalaenopsis methyl acetate solvate crystals

[0152] Add 0.4 g of amorphous cephalaenopsis powder raw material to 2 mL of methyl acetate solvent to obtain a fourth mixed solution; subject the fourth mixed solution to water bath ultrasound, maintain the power at 100 W, and maintain the temperature at 40°C. After the solid in the fourth mixed solution is completely dissolved, turn off the ultrasonic equipment. Then, place the fourth mixed solution at a low temperature of 4°C for cooling and crystallization for 2 days to precipitate crystals, filter the crystal system, and dry it at 20°C and normal pressure for 4 hours to obtain colorless cephalaenopsis methyl acetate solvate crystals. There are 0.432 g of cephalaenopsis methyl acetate solvate crystals, and the molar yield is 93%. The bulk density of cephalaenopsis methyl acetate solvate crystals is 1.05 g / cm 3 , tap density is 1.08g / cm 3 .

[0153] X-ray powder diffraction characteristic lines of the measured cephalaenopsis methyl acetate solvate crystals expressed in terms of 2θ-diffraction angle and I / I0-relative intensity, measured using Cu-Kα radiation:

[0154] Table 4 X-ray powder diffraction characteristic spectrum of cephalaenopsis methyl acetate solvate crystals

[0155]

[0156] The X-ray diffraction pattern of the methyl acetate solvate crystals of cepharanthin is as follows: Figure 1 d shows the molecular ellipsoid diagram of the minimum asymmetric unit of the cephalaenoic acid methyl ester solvate crystal. Fig.12 The unit cell packing diagram of the cephalaenoic acid methyl ester solvate crystal is shown in Fig.13 The TGA and DSC analysis results of the cephalaenopsis methyl acetate solvate crystals are shown in Fig.14 It is shown that there is an endothermic characteristic peak at T=83.84℃ on the DSC curve, which corresponds to the starting desolvation point of the cephalaenoic acid methyl ester solvate crystals. According to the subsequent hot stage experiment, it can also be proved that the cephalaenoic acid methyl ester solvate crystals melt while desolvating during the heating process; there are two obvious weight loss steps on the TGA curve, the first weight loss is 8.9%, and the second weight loss is 0.3%. The results are completely consistent with the theoretical weight loss calculated by single crystal analysis. The cephalaenoic acid methyl ester solvate crystals, with the molecular formula of C 37 H 38 N2O6·C3H6O2, the crystal structure belongs to the orthorhombic system, P212121 space group, unit cell parameters , α=90°, β=90°, γ=90°, unit cell volume The minimum asymmetric unit number Z in the unit cell is 8, and the minimum asymmetric unit contains 2 cephalothin molecules and 2 methyl acetate solvent molecules, wherein the 2 cephalothin molecules are in different conformations, and the 2 methyl acetate solvent molecules are in different conformations; the specific information related to the crystal structure of cephalothin methyl acetate solvate is shown in the figure. Fig.24 .

[0157] Example 17: Preparation of Cephalaenopsis methyl acetate solvate crystals

[0158] Add 0.4 g of cephalaenopsis crystalline form I to 2 mL of methyl acetate solvent to obtain a fourth mixed solution; subject the fourth mixed solution to water bath ultrasound, maintain the power at 100 W, and maintain the temperature at 40°C. After the solid in the fourth mixed solution is completely dissolved, turn off the ultrasonic equipment. Then, place the fourth mixed solution at a low temperature of -20°C for cooling and crystallization for 7 days to precipitate crystals, filter the crystal system, and dry it at 20°C and normal pressure for 4 hours to obtain colorless cephalaenopsis methyl acetate solvate crystals. There are 0.418 g of cephalaenopsis methyl acetate solvate crystals, and the molar yield is 92%. The bulk density of cephalaenopsis methyl acetate solvate crystals is 1.02 g / cm 3 , tap density is 1.04g / cm 3 .

[0159] Example 18: Preparation of Cephalaenopsis methyl acetate solvate crystals

[0160] Add 0.3 g of acetonitrile solvate crystals of celastrol to 2 mL of methyl acetate solvent to obtain a fourth mixed solution; place the fourth mixed solution in a 50°C water bath shaker and shake until the solid is completely dissolved, then place the fourth mixed solution in a low temperature environment of -20°C for cooling and crystallization for 1 day to precipitate crystals, filter the crystal system, and dry at 20°C and normal pressure for 4 hours to obtain colorless methyl acetate solvate crystals of celastrol. There are 0.283 g of methyl acetate solvate crystals of celastrol, and the molar yield is 90%. The bulk density of methyl acetate solvate crystals of celastrol is 0.98 g / cm 3 , tap density is 1.01g / cm 3 .

[0161] Example 19: Preparation of Cephalaenopsis methyl acetate solvate crystals

[0162] Add 0.3 g of cephalaenopsis methanol solvate crystals to 2 mL of methyl acetate solvent to obtain a fourth mixed solution; place the fourth mixed solution in a 50°C water bath shaker and shake until the solid is completely dissolved, then place the fourth mixed solution in a low temperature environment of -10°C for cooling and crystallization for 3 days to precipitate crystals, filter the crystal system, and dry at 20°C and normal pressure for 4 hours to obtain colorless cephalaenopsis methyl acetate solvate crystals. There are 0.296 g of cephalaenopsis methyl acetate solvate crystals, and the molar yield is 91%. The bulk density of cephalaenopsis methyl acetate solvate crystals is 0.96 g / cm 3 , tap density is 0.99g / cm 3 .

[0163] Example 20: Preparation of Cephalaenopsis methyl acetate solvate crystals

[0164] Add 0.3 g of acetonitrile solvate crystals of celastrol to 2 mL of methyl acetate solvent to obtain a fourth mixed solution; subject the fourth mixed solution to water bath ultrasound, maintain the power at 100 W, and maintain the temperature at 40°C. After the solid in the fourth mixed solution is completely dissolved, turn off the ultrasonic equipment. Then, place the fourth mixed solution at room temperature for slow evaporation and crystallization for 3 days to precipitate crystals, filter the crystal system, and dry it at 20°C and normal pressure for 4 hours to obtain colorless methyl acetate solvate crystals of celastrol. There are 0.322 g of methyl acetate solvate crystals of celastrol, and the molar yield is 92%. The bulk density of methyl acetate solvate crystals of celastrol is 0.97 g / cm 3 , tap density is 1.0g / cm 3 .

[0165] Example 21: Preparation of Cephalaenopsis methyl acetate solvate crystals

[0166] Add 0.3 g of cephalaenopsis methanol solvate crystals to 2 mL of methyl acetate solvent to obtain a fourth mixed solution; subject the fourth mixed solution to water bath ultrasound, maintain the power at 100 W, and maintain the temperature at 40°C. After the solid in the fourth mixed solution is completely dissolved, turn off the ultrasonic equipment. Then, place the fourth mixed solution at room temperature for slow evaporation and crystallization for 7 days to precipitate crystals, filter the crystal system, and dry it at 20°C and normal pressure for 4 hours to obtain colorless cephalaenopsis methyl acetate solvate crystals. There are 0.289 g of cephalaenopsis methyl acetate solvate crystals, and the molar yield is 90%. The bulk density of cephalaenopsis methyl acetate solvate crystals is 0.95 g / cm 3 , tap density is 0.99g / cm 3 .

[0167] Example 22: Preparation of Cephalaenopsis ethyl acetate solvate crystals

[0168] Add 0.4 g of amorphous cephalaenopsis powder raw material to 2 mL of ethyl acetate solvent to obtain the fifth mixed solution; subject the fifth mixed solution to water bath ultrasound, maintain the power at 100 W, and maintain the temperature at 30°C. After the solid in the fifth mixed solution is completely dissolved, turn off the ultrasonic equipment. Then place the fifth mixed solution in a low temperature environment of 4°C, cool and crystallize for 3 days, precipitate crystals, filter the crystal system, and dry at 20°C and normal pressure for 4 hours to obtain colorless cephalaenopsis ethyl acetate solvate crystals. There are 0.388 g of cephalaenopsis ethyl acetate solvate crystals, and the molar yield is 86%. The bulk density of cephalaenopsis ethyl acetate solvate crystals is 0.74 g / cm 3 , tap density is 0.77g / cm 3 .

[0169] The X-ray powder diffraction characteristic lines of the ethyl acetate solvate crystals of cephalaenopsis acetochelatin were measured according to the 2θ-diffraction angle and I / I0-relative intensity, using Cu-Kα radiation:

[0170] Table 5 X-ray powder diffraction characteristic spectrum of cephalaenopsis ethyl acetate solvate crystals

[0171]

[0172] The X-ray diffraction pattern of the ethyl acetate solvate crystals of cephalaenopsis is shown in Figure 1 e, the molecular ellipsoid diagram of the minimum asymmetric unit of the ethyl acetate solvate crystal of cepharanthin is shown in Fig.15 The crystal cell packing diagram of the ethyl acetate solvate of cephalaenopsis is shown in Fig.16 The TGA and DSC analysis results of the cepharanthin ethyl acetate solvate crystals are shown in Fig.17 It is shown that there is an endothermic characteristic peak at T = 79.87 ° C on the DSC curve, which corresponds to the starting desolvation point of the ethyl acetate solvate crystal of cephalaenopsis. According to the subsequent hot stage experiment, it can also be proved that the ethyl acetate solvate crystal of cephalaenopsis melts while desolvating during the heating process; there is an obvious weight loss step on the TGA curve, and the weight loss percentage is 11.42%, which is consistent with the weight loss calculated by the theoretical analysis of the single crystal structure. The ethyl acetate solvate crystal of cephalaenopsis, with the molecular formula of C 37 H 38 N2O6·C4H8O2, the crystal structure belongs to the monoclinic system, P21 space group, unit cell parameters α=90°,β=90.821(6)°,γ=90°,the unit cell volume is The minimum asymmetric unit number Z in the unit cell is 4, and the minimum asymmetric unit contains 2 cephalothin molecules and 2 ethyl acetate solvent molecules, wherein the 2 cephalothin molecules are in different conformations, and the 2 ethyl acetate solvent molecules are in different conformations; the specific information related to the crystal structure of cephalothin ethyl acetate solvate is shown in the figure. Fig.25 .

[0173] Example 23: Preparation of Cephalaenopsis ethyl acetate solvate crystals

[0174] Add 0.4 g of cephalaenopsis crystalline form I to 2 mL of ethyl acetate solvent to obtain a fifth mixed solution; place the fifth mixed solution in a 75W, 40°C ultrasonic cleaner for ultrasonication until the solid in the fifth mixed solution is completely dissolved, then place the clarified fifth mixed solution in a low temperature environment of -20°C, cool and crystallize for 7 days, precipitate crystals, filter the crystal system, and dry at 20°C and normal pressure for 4 hours to obtain colorless cephalaenopsis ethyl acetate solvate crystals. There are 0.394 g of cephalaenopsis ethyl acetate solvate crystals, and the molar yield is 88%. The bulk density of cephalaenopsis ethyl acetate solvate crystals is 0.72 g / cm 3 , tap density is 0.74g / cm 3 .

[0175] Example 24: Preparation of Cephalaenopsis ethyl acetate solvate crystals

[0176] Add 0.5 g of acetonitrile solvate crystals of celastrol to 2 mL of ethyl acetate solvent to obtain the fifth mixed solution; subject the fifth mixed solution to water bath ultrasound, maintain the power at 100 W, and maintain the temperature at 30°C. After the solid in the fifth mixed solution is completely dissolved, turn off the ultrasonic equipment. Then place the fifth mixed solution in a low temperature environment of 4°C, cool and crystallize for 7 days, precipitate crystals, filter the crystal system, and dry at 20°C and normal pressure for 4 hours to obtain colorless ethyl acetate solvate crystals of celastrol. There are 0.452 g of ethyl acetate solvate crystals of celastrol, and the molar yield is 87%. The bulk density of ethyl acetate solvate crystals of celastrol is 0.68 g / cm 3 , tap density is 0.71g / cm 3 .

[0177] Example 25: Preparation of Cephalaenopsis ethyl acetate solvate crystals

[0178] Add 0.5 g of acetonitrile solvate crystals of celastrol to 2 mL of ethyl acetate solvent to obtain the fifth mixed solution; place the fifth mixed solution in an ultrasonic cleaner at 75 W and 35 ° C for ultrasonication until the solid in the fifth mixed solution is completely dissolved, then place the clarified fifth mixed solution in a low temperature environment of -20 ° C, cool and crystallize for 3 days, precipitate crystals, filter the crystal system, and dry at 20 ° C and normal pressure for 4 hours to obtain colorless ethyl acetate solvate crystals of celastrol. There are 0.469 g of ethyl acetate solvate crystals of celastrol, and the molar yield is 85%. The bulk density of ethyl acetate solvate crystals of celastrol is 0.69 g / cm 3 , tap density is 0.72g / cm 3 .

[0179] Example 26: Preparation of Cephalaenopsis ethyl acetate solvate crystals

[0180] Add 0.5 g of cephalaenopsis methyl acetate solvate crystals to 2 mL of ethyl acetate solvent to obtain a fifth mixed solution; place the fifth mixed solution in a 50°C water bath shaker and shake until the solid in the fifth mixed solution is completely dissolved, place the clarified fifth mixed solution in a low temperature environment of 4°C, cool and crystallize for 7 days, precipitate crystals, filter the crystal system, and dry at 20°C and normal pressure for 4 hours to obtain colorless cephalaenopsis ethyl acetate solvate crystals. There are 0.443 g of cephalaenopsis ethyl acetate solvate crystals, and the molar yield is 86%. The bulk density of cephalaenopsis ethyl acetate solvate crystals is 0.67 g / cm 3 , tap density is 0.69g / cm 3 .

[0181] Example 27: Preparation of Cephalaenopsis ethyl acetate solvate crystals

[0182] Add 0.5 g of cephalaenopsis methyl acetate solvate crystals to 2 mL of ethyl acetate solvent to obtain a fifth mixed solution; place the fifth mixed solution in a 50°C water bath shaker and shake until the solid in the fifth mixed solution is completely dissolved, place the clarified fifth mixed solution at room temperature and slowly evaporate and crystallize for 7 days to precipitate crystals, filter the crystal system, and dry at 20°C and normal pressure for 4 hours to obtain colorless cephalaenopsis ethyl acetate solvate crystals. There are 0.453 g of cephalaenopsis ethyl acetate solvate crystals, and the molar yield is 88%. The bulk density of cephalaenopsis ethyl acetate solvate crystals is 0.70 g / cm 3 , tap density is 0.72g / cm 3 .

[0183] Example 28: Preparation of Cephalaenopsis ethyl acetate solvate crystals

[0184] Add 0.4 g of cephalaenopsis methanol solvate crystals to 2 mL of ethyl acetate solvent to obtain a fifth mixed solution; place the fifth mixed solution in a 50°C water bath shaker and shake until the solid in the fifth mixed solution is completely dissolved, place the clarified fifth mixed solution in a low temperature environment of 4°C, cool and crystallize for 4 days, precipitate crystals, filter the crystal system, and dry at 20°C and normal pressure for 4 hours to obtain colorless cephalaenopsis ethyl acetate solvate crystals. There are 0.398 g of cephalaenopsis ethyl acetate solvate crystals, and the molar yield is 85%. The bulk density of cephalaenopsis ethyl acetate solvate crystals is 0.71 g / cm 3 , tap density is 0.73g / cm 3 .

[0185] Example 29: Preparation of Cephalaenopsis ethyl acetate solvate crystals

[0186] Add 0.4 g of cephalaenopsis methanol solvate crystals to 2 mL of ethyl acetate solvent to obtain the fifth mixed solution; subject the fifth mixed solution to water bath ultrasound, maintain the power at 100 W, and maintain the temperature at 30°C. After the solid in the fifth mixed solution is completely dissolved, turn off the ultrasonic equipment. Then, place the fifth mixed solution at room temperature for slow evaporation and crystallization for 7 days to precipitate crystals, filter the crystal system, and dry at 20°C and normal pressure for 4 hours to obtain colorless cephalaenopsis ethyl acetate solvate crystals. There are 0.404 g of cephalaenopsis ethyl acetate solvate crystals, and the molar yield is 87%. The bulk density of cephalaenopsis ethyl acetate solvate crystals is 0.68 g / cm 3 , tap density is 0.71g / cm 3 .

[0187] Example 30: Preparation of Cephalaenopsis butyl acetate solvate crystals

[0188] Add 0.4 g of amorphous cephalaenopsis powder raw material to 2 mL of butyl acetate solvent to obtain the sixth mixed solution; subject the sixth mixed solution to water bath ultrasound, maintain the power at 100 W, and maintain the temperature at 35°C. After the solid in the sixth mixed solution is completely dissolved, turn off the ultrasonic equipment. Then place the sixth mixed solution in a low temperature environment of 4°C, cool and crystallize for 6 days, precipitate crystals, filter the crystal system, and dry at 20°C and normal pressure for 4 hours to obtain colorless cephalaenopsis butyl acetate solvate crystals. There are 0.394 g of cephalaenopsis butyl acetate solvate crystals, and the molar yield is 90%. The bulk density of cephalaenopsis butyl acetate solvate crystals is 0.86 g / cm 3 , tap density is 0.90g / cm 3 .

[0189] X-ray powder diffraction characteristic lines of the measured cephalaenopsis butyl acetate solvate crystals expressed in terms of 2θ-diffraction angle and I / I0-relative intensity, measured using Cu-Kα radiation:

[0190] Table 6 X-ray powder diffraction characteristic spectrum of cephalaenopsis butyl acetate solvate crystals

[0191]

[0192] The X-ray diffraction pattern of the crystalline of cephalaenopsis butyl acetate solvate is shown in Figure 1 f, the molecular ellipsoid diagram of the minimum asymmetric unit of the crystalline form of cephalaenoic acid butyl ester solvate is shown in Fig.18 The unit cell packing diagram of the cephalaenoic acid butyl ester solvate crystal is shown in Fig.19 The TGA and DSC analysis results of the cepharanthin butyl acetate solvate crystals are shown in Fig. 20 It is shown that there is an endothermic characteristic peak at T = 111.08 ° C on the DSC curve, which corresponds to the starting desolvation point of the cephalothin butyl acetate solvate crystal, and an exothermic characteristic peak at T = 331.92 ° C, which corresponds to the decomposition point of the cephalothin butyl acetate solvate crystal; there are obvious two-step weight loss steps on the TGA curve, the first step weight loss is 2.724%, and the second step weight loss is 6.028%, which is consistent with the single crystal theoretical calculation. The cephalothin butyl acetate solvate crystal has a molecular formula of 2C 37 H 38 N2O6·C6H 12 O2, the crystal structure belongs to the orthorhombic system, the space group is P212121, the unit cell parameters α=90°,β=90°,γ=90°,unit cell volume The minimum asymmetric unit number Z in the unit cell is 4, and the minimum asymmetric unit contains 2 cephalothin molecules and 1 butyl acetate solvent molecule, wherein the 2 cephalothin molecules are in different conformations; the specific information related to the crystal structure of cephalothin butyl acetate solvate is shown in the figure Fig.26 .

[0193] Example 31: Preparation of Cephalaenopsis butyl acetate solvate crystals

[0194] Add 0.4 g of cephalaenopsis crystalline form I to 2 mL of butyl acetate solvent to obtain a sixth mixed solution; place the sixth mixed solution in a 75W, 35°C ultrasonic cleaner for ultrasonication until the solid in the sixth mixed solution is completely dissolved, place the clarified sixth mixed solution in a low temperature environment of -20°C, cool and crystallize for 6 days, precipitate crystals, filter the crystal system, and dry at 20°C and normal pressure for 4 hours to obtain colorless cephalaenopsis butyl acetate solvate crystals. There are 0.398 g of cephalaenopsis butyl acetate solvate crystals, and the molar yield is 92%. The bulk density of cephalaenopsis butyl acetate solvate crystals is 0.85 g / cm 3 , tap density is 0.89g / cm 3 .

[0195] Example 32: Preparation of Cephalaenopsis butyl acetate solvate crystals

[0196] Add 0.5 g of acetonitrile solvate crystals of celastrol to 2 mL of butyl acetate solvent to obtain the sixth mixed solution; subject the sixth mixed solution to water bath ultrasound, maintain the power at 100 W, and maintain the temperature at 30°C. After the solid in the sixth mixed solution is completely dissolved, turn off the ultrasonic equipment. Then place the sixth mixed solution at a low temperature of 4°C, cool and crystallize for 7 days, precipitate crystals, filter the crystal system, and dry at 20°C and normal pressure for 4 hours to obtain colorless celastrol butyl acetate solvate crystals. There are 0.471 g of butyl acetate solvate crystals of celastrol, and the molar yield is 91%. The bulk density of butyl acetate solvate crystals of celastrol is 0.88 g / cm 3 , tap density is 0.92g / cm 3 .

[0197] Example 33: Preparation of Cephalaenopsis butyl acetate solvate crystals

[0198] Add 0.4 g of cephalaenopsis methanol solvate crystals to 2 mL of butyl acetate solvent to obtain a sixth mixed solution; shake the sixth mixed solution in a 50°C water bath shaker until the solid in the sixth mixed solution is completely dissolved, place the clarified sixth mixed solution in a low temperature environment of 4°C, cool and crystallize for 3 days, precipitate crystals, filter the crystal system, and dry at 20°C and normal pressure for 4 hours to obtain colorless cephalaenopsis butyl acetate solvate crystals. There are 0.39 g of cephalaenopsis butyl acetate solvate crystals, and the molar yield is 89%. The bulk density of cephalaenopsis butyl acetate solvate crystals is 0.83 g / cm 3 , tap density is 0.87g / cm 3 .

[0199] Example 34: Preparation of Cephalaenopsis butyl acetate solvate crystals

[0200] Add 0.5 g of acetonitrile solvate crystals of celastrol to 2 mL of butyl acetate solvent to obtain the sixth mixed solution; subject the sixth mixed solution to water bath ultrasound, maintain the power at 100 W, and maintain the temperature at 30°C. After the solid in the sixth mixed solution is completely dissolved, turn off the ultrasonic equipment. Then place the sixth mixed solution at a low temperature of -20°C, cool and crystallize for 3 days, precipitate crystals, filter the crystal system, and dry at 20°C and normal pressure for 4 hours to obtain colorless butyl acetate solvate crystals of celastrol. There are 0.452 g of butyl acetate solvate crystals of celastrol, and the molar yield is 88%. The bulk density of butyl acetate solvate crystals of celastrol is 0.76 g / cm 3 , tap density is 0.82g / cm 3 .

[0201] Example 35: Preparation of Cephalaenopsis butyl acetate solvate crystals

[0202] Add 0.5 g of cephalaenopsis methyl acetate solvate crystals to 2 mL of butyl acetate solvent to obtain a sixth mixed solution; shake the sixth mixed solution in a 50°C water bath shaker until the solid in the sixth mixed solution is completely dissolved, place the clarified sixth mixed solution in a low temperature environment of 4°C, cool and crystallize for 7 days, precipitate crystals, filter the crystal system, and dry at 20°C and normal pressure for 4 hours to obtain colorless cephalaenopsis butyl acetate solvate crystals. 0.46 g of cephalaenopsis butyl acetate solvate was obtained, and the molar yield was 90%. The bulk density of the cephalaenopsis butyl acetate solvate crystals is 0.78 g / cm 3 , tap density is 0.86g / cm 3 .

[0203] Example 36: Preparation of Cephalaenopsis butyl acetate solvate crystals

[0204] Add 0.4 g of cephalaenopsis methanol solvate crystals to 2 mL of ethyl acetate solvent to obtain a sixth mixed solution; subject the sixth mixed solution to water bath ultrasound, maintain the power at 100 W, and maintain the temperature at 30°C. After the solid in the sixth mixed solution is completely dissolved, turn off the ultrasonic equipment. Then, place the sixth mixed solution at room temperature for slow evaporation and crystallization for 7 days to precipitate crystals, filter the crystal system, and dry it at 20°C and normal pressure for 4 hours to obtain colorless cephalaenopsis butyl acetate solvate crystals. There are 0.39 g of cephalaenopsis butyl acetate solvate crystals, and the molar yield is 89%. The bulk density of cephalaenopsis butyl acetate solvate crystals is 0.80 g / cm 3 , tap density is 0.88g / cm 3 .

[0205] Table 7 Comparison of hygroscopicity of cephalaenoside crystals and cephalaenoside amorphous raw materials at 40°C

[0206]

[0207] The sample was placed in a dynamic vapor adsorption instrument at 40°C, and the weight was recorded when the mass change was less than 0.01g within 3 hours. It can be seen from Table 7 that the hygroscopicity of the cephalothin form I crystals (prepared in Example 1) and 5 cephalothin solvate crystals (prepared in Example 8, Example 11, Example 16, Example 22 and Example 30, respectively) of the present invention is much lower than that of the cephalothin amorphous powder, indicating that the stability of the cephalothin crystals provided by the present invention is greatly improved compared with the amorphous cephalothin powder.

[0208] The present invention provides ideas and methods for preparing cephalaenopsis crystals and methods thereof. There are many methods and approaches to realize the technical solution. The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention. All components not specified in this embodiment can be realized by existing technologies.

Claims

1. A cephalaenopsis crystal, characterized in that: The cephalaenoside crystals are any one of cephalaenoside acetonitrile solvate crystals, cephalaenoside methanol solvate crystals, cephalaenoside methyl acetate solvate crystals, cephalaenoside ethyl acetate solvate crystals and cephalaenoside butyl acetate solvate crystals; The cephalaenopsis acetonitrile solvate crystal has a molecular formula of C 37 H 38 N2O6·CH3CN, the crystal structure belongs to the orthorhombic system, P212121 space group, the unit cell parameters are α=90°,β=90°,γ=90°,unit cell volume The minimum number of asymmetric units in the unit cell is Z=4, and the minimum asymmetric unit contains 1 cepharanthin molecule and 1 acetonitrile solvent molecule; there are the following X-ray powder diffraction characteristic lines measured after grinding according to 2θ-diffraction angle and I / I0-relative intensity, measured using Cu-Kα rays: The methanol solvate crystal of cephalaenopsis has the molecular formula C 37 H 38 N2O6·0.5CH3OH, the crystal structure belongs to the triclinic system, P32 space group, unit cell parameters α=90°,β=90°,γ=120°,unit cell volume The minimum number of asymmetric units in the unit cell is Z=3, and the minimum asymmetric unit contains 1 cepharanthin molecule and 0.5 methanol solvent molecule; there are the following X-ray powder diffraction characteristic lines measured after grinding according to 2θ-diffraction angle and I / I0-relative intensity, measured using Cu-Kα rays: The cephalaenopsis methyl acetate solvate crystal has a molecular formula of C 37 H 38 N2O6·C3H6O2, the crystal structure belongs to the orthorhombic system, P212121 space group, unit cell parameters α=90°,β=90°,γ=90°,unit cell volume The minimum asymmetric unit number Z in the unit cell is 8, and the minimum asymmetric unit contains 2 cephalothin molecules and 2 methyl acetate solvent molecules, wherein the 2 cephalothin molecules are in different conformations, and the 2 methyl acetate solvent molecules are in different conformations; there are the following X-ray powder diffraction characteristic lines measured after grinding according to 2θ-diffraction angle and I / I0-relative intensity, measured using Cu-Kα rays: The cephalaenopsis ethyl acetate solvate crystal has a molecular formula of C 37 H 38 N2O6·C4H8O2, the crystal structure belongs to the monoclinic system, P21 space group, unit cell parameters α=90°,β=90.821(6)°,γ=90°,the unit cell volume is The minimum asymmetric unit number Z in the unit cell is 4, and the minimum asymmetric unit contains 2 cephalothin molecules and 2 ethyl acetate solvent molecules, wherein the 2 cephalothin molecules are in different conformations, and the 2 ethyl acetate solvent molecules are in different conformations; there are the following X-ray powder diffraction characteristic lines measured after grinding according to 2θ-diffraction angle and I / I0-relative intensity, measured using Cu-Kα rays: The cephalaenopsis butyl acetate solvate crystal has a molecular formula of 2C 37 H 38 N2O6·C6H 12 O2, the crystal structure belongs to the orthorhombic system, the space group is P212121, the unit cell parameters α=90°,β=90°,γ=90°,unit cell volume The minimum asymmetric unit number Z in the unit cell is 4, and the minimum asymmetric unit contains 2 cephalothin molecules and 1 butyl acetate solvent molecule, wherein the 2 cephalothin molecules are in different conformations; and there are the following X-ray powder diffraction characteristic lines measured after grinding according to 2θ-diffraction angle and I / I0-relative intensity, measured using Cu-Kα rays: The cepharanthin acetonitrile solvate crystals, cepharanthin methanol solvate crystals, cepharanthin methyl acetate solvate crystals, cepharanthin ethyl acetate solvate crystals and cepharanthin butyl acetate solvate crystals are crystalline powders.

2. The cephalaenopsis crystal according to claim 1, characterized in that The bulk density of the cephalaenopsis acetonitrile solvate crystal is greater than 0.58 g / cm 3 , preferably greater than 0.64 g / cm 3 , more preferably greater than 0.67 g / cm 3 .

3. The cephalaenopsis crystal according to claim 1, characterized in that The tap density of the cephalaenopsis acetonitrile solvate crystal is greater than 0.60 g / cm 3 , preferably greater than 0.65 g / cm 3 , more preferably greater than 0.70 g / cm 3 .

4. The cephalaenopsis crystal according to claim 1, characterized in that The bulk density of the crystalline powder of the methanol solvate of Stephania tetrandra is greater than 0.82 g / cm 3 , preferably greater than 0.86 g / cm 3 , more preferably greater than 0.92 g / cm 3 .

5. The cephalaenopsis crystal according to claim 1, characterized in that The tap density of the crystalline powder of the methanol solvate of Stephania tetrandra is greater than 0.85 g / cm 3 , preferably greater than 0.94 g / cm 3 , more preferably greater than 1.0 g / cm 3 .

6. The cephalaenopsis crystal according to claim 1, characterized in that The bulk density of the cepharanthin methyl acetate solvate crystals is greater than 0.90 g / cm 3 , preferably greater than 0.94 g / cm 3 , more preferably greater than 1.0 g / cm 3 .

7. The cephalaenopsis crystal according to claim 1, characterized in that The tap density of the cephalaenopsis methyl acetate solvate crystal is greater than 0.93 g / cm 3 , preferably greater than 0.98 g / cm 3 , more preferably greater than 1.05 g / cm 3 .

8. The cephalaenopsis crystal according to claim 1, characterized in that The bulk density of the cephalaenopsis ethyl acetate solvate crystals is greater than 0.56 g / cm 3 , preferably greater than 0.66 g / cm 3 , more preferably greater than 0.71 g / cm 3 .

9. The cephalaenopsis crystal according to claim 1, characterized in that The tap density of the cephalaenopsis ethyl acetate solvate crystal is greater than 0.59 g / cm 3 , preferably greater than 0.67 g / cm 3 , more preferably greater than 0.73 g / cm 3 .

10. The cephalaenopsis crystal according to claim 1, characterized in that The bulk density of the crystalline powder of the cephalaenopsis butyl acetate solvate crystal is greater than 0.64 g / cm 3 , preferably greater than 0.72 g / cm 3 , more preferably greater than 0.84 g / cm 3 .

11. The cephalaenopsis crystal according to claim 1, characterized in that The tap density of the cephalaenopsis butyl acetate solvate crystal is greater than 0.69 g / cm 3 , preferably greater than 0.78 g / cm 3 , more preferably greater than 0.88 g / cm 3 .

12. The method for preparing the cepharanthin crystals according to claim 1, characterized in that: dissolving the second raw material in the second solvent to obtain a second mixed solution; subjecting the second mixed solution to suspension crystallization or ultrasonic cooling crystallization to precipitate crystals, filtering and drying the crystal system to obtain cetonitrile solvate crystals of cetonitrile; The second raw material is cephalanthrin or cephalanthrin crystal form I; the second solvent is acetonitrile or a mixture of acetonitrile and water in a volume ratio of 3:1 to 3.

13. The preparation method according to claim 12, characterized in that: The second raw material is amorphous cephalaenopsis or cephalaenopsis crystal form I; the second solvent is acetonitrile or a mixture of acetonitrile and water in a volume ratio of 3:2; the mass volume ratio of the second raw material to the second solvent is 0.1-0.4g:2-5mL, preferably 0.2-0.3g:2-5mL.

14. The method for preparing the cepharanthin crystals according to claim 1, characterized in that: dissolving the third raw material in anhydrous methanol to obtain a third mixed solution; cooling the third mixed solution for crystallization or suspension crystallization to precipitate crystals, filtering and drying the crystal system to obtain cephalaenopsis methanol solvate crystals; The third raw material is any one of cephalaenopsis crystalline form I crystals, cephalaenopsis acetonitrile solvate crystals, cephalaenopsis methyl acetate solvate crystals, cephalaenopsis ethyl acetate solvate crystals and cephalaenopsis butyl acetate solvate crystals.

15. The preparation method according to claim 14, characterized in that: The third raw material is any one of cephalaenopsis crystalline form I crystals, cephalaenopsis acetonitrile solvate crystals, cephalaenopsis methyl acetate solvate crystals, cephalaenopsis ethyl acetate solvate crystals and cephalaenopsis butyl acetate solvate crystals; the mass volume ratio of the third raw material to anhydrous methanol is 0.05-0.25 g:1-2 mL, preferably 0.1-0.2 g:1-2 mL.

16. The method for preparing the cepharanthin crystals according to claim 1, characterized in that: The fourth raw material is dissolved in methyl acetate to obtain a fourth mixed solution; the fourth mixed solution is cooled and crystallized or evaporated and crystallized to precipitate crystals, and the crystal system is filtered and dried to obtain cephalaenopsis methyl acetate solvate crystals; The fourth raw material is any one of cephalaenopsis, cephalaenopsis crystal form I crystals, cephalaenopsis acetonitrile solvate crystals and cephalaenopsis methanol solvate crystals.

17. The preparation method according to claim 16, characterized in that: The fourth raw material is any one of amorphous cephalothin, cephalothin form I crystals, cephalothin acetonitrile solvate crystals and cephalothin methanol solvate crystals; the mass volume ratio of the fourth raw material to methyl acetate is 0.2-0.6 g:2 mL, preferably 0.3-0.4 g:2 mL, and more preferably 0.3:2 mL or 0.4 g:2 mL.

18. The method for preparing the cepharanthin crystals according to claim 1, characterized in that: The fifth raw material is dissolved in ethyl acetate to obtain a fifth mixed solution; the fifth mixed solution is cooled and crystallized or evaporated and crystallized to precipitate crystals; the crystal system is filtered and dried to obtain cephalaenopsis ethyl acetate solvate crystals; The fifth raw material is any one of cephalaenopsis, cephalaenopsis crystal form I crystals, cephalaenopsis acetonitrile solvate crystals, cephalaenopsis methanol solvate crystals and cephalaenopsis methyl acetate solvate crystals.

19. The preparation method according to claim 18, characterized in that: The fifth raw material is any one of amorphous cephalothin, cephalothin crystal form I crystals, cephalothin acetonitrile solvate crystals, cephalothin methanol solvate crystals and cephalothin methyl acetate solvate crystals; the mass volume ratio of the fifth raw material to ethyl acetate is 0.2-0.7g:2mL, preferably 0.4-0.5g:2mL, more preferably 0.4g:2mL or 0.5g:2mL.

20. The method for preparing the cephalaenopsis crystal according to claim 1, characterized in that: The sixth raw material is dissolved in butyl acetate to obtain a sixth mixed solution; the sixth mixed solution is cooled and crystallized or evaporated and crystallized to precipitate crystals; the crystal system is filtered and dried to obtain cephalaenopsis butyl acetate solvate crystals; The sixth raw material is any one of cephalaenopsis, cephalaenopsis crystal form I crystals, cephalaenopsis acetonitrile solvate crystals, cephalaenopsis methanol solvate crystals and cephalaenopsis methyl acetate solvate crystals.

21. The preparation method according to claim 20, characterized in that: The sixth raw material is any one of amorphous cephalothin, cephalothin crystal form I crystals, cephalothin acetonitrile solvate crystals, cephalothin methanol solvate crystals and cephalothin methyl acetate solvate crystals; the mass volume ratio of the sixth raw material to butyl acetate is 0.2-0.8g:2mL, preferably 0.4-0.5g:2mL, more preferably 0.4g:2mL or 0.5g:2mL.

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