CN116253742A - Cepharanthine crystal and preparation method thereof - Google Patents
Cepharanthine crystal and preparation method thereof Download PDFInfo
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- 239000013078 crystal Substances 0.000 title claims abstract description 672
- 238000002360 preparation method Methods 0.000 title claims abstract description 65
- VQAWRQZAAIQXHM-UHFFFAOYSA-N Cepharanthine Natural products O1C(C=C2)=CC=C2CC(C=23)N(C)CCC3=CC=3OCOC=3C=2OC(=CC=23)C(OC)=CC=2CCN(C)C3CC2=CC=C(O)C1=C2 VQAWRQZAAIQXHM-UHFFFAOYSA-N 0.000 title claims abstract description 32
- YVPXVXANRNDGTA-WDYNHAJCSA-N cepharanthine Chemical compound C1C(C=C2)=CC=C2OC(=C2)C(OC)=CC=C2C[C@H](C2=C3)N(C)CCC2=CC(OC)=C3OC2=C(OCO3)C3=CC3=C2[C@H]1N(C)CC3 YVPXVXANRNDGTA-WDYNHAJCSA-N 0.000 title claims abstract description 32
- UEAPAHNNFSZHMW-CQSZACIVSA-N stephanine Chemical compound CN([C@@H]1CC2=C(C3=C11)C=CC=C2OC)CCC1=CC1=C3OCO1 UEAPAHNNFSZHMW-CQSZACIVSA-N 0.000 claims abstract description 540
- UEAPAHNNFSZHMW-UHFFFAOYSA-N stepahnine Natural products COC1=CC=CC(C2=C34)=C1CC3N(C)CCC4=CC1=C2OCO1 UEAPAHNNFSZHMW-UHFFFAOYSA-N 0.000 claims abstract description 539
- 239000012453 solvate Substances 0.000 claims abstract description 362
- 239000000843 powder Substances 0.000 claims abstract description 52
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 288
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 279
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- 238000002425 crystallisation Methods 0.000 claims description 94
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- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 83
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- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07C253/00—Preparation of carboxylic acid nitriles
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- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/02—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton
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- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
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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 stephanine powder, the crystal provided by the invention has the advantages of high bulk density, good fluidity, strong stability and convenience in storage and transportation. The stephanine crystal form I crystals and 5 stephanine solvate crystals provided by the invention have better stability, a sample is placed in a dynamic steam adsorption instrument at 40 ℃, the weight when the mass change is less than 0.01g within 3 hours is recorded, the hygroscopicity of the stephanine crystal form I crystals and 5 stephanine solvate crystals is far lower than that of amorphous stephanine powder, and the stability of the stephanine crystals provided by the invention is greatly improved compared with that of the amorphous stephanine powder.
Description
Technical Field
The invention belongs to the technical field of medicine refining, and relates to a cepharanthine crystal and a preparation method thereof.
Background
Cepharanthine (Cepharanthine) is a dibenzyl isoquinoline alkaloid extracted from Fangji family plants. Molecular formula C 37 H 38 N 2 O 6 The relative molecular mass is 606.72g/mol, and the structural formula is shown as follows:
stephanine was first extracted from Japanese climbing fern Ping Sanlang from plants, and at present, research has been focused on the extraction of stephanine, and on the treatment of novel coronavirus, the treatment of leukopenia, anticancer applications, and the like. Patent CN11304632a reports that stephanine has a very good effect against the novel coronavirus SARS-COV2 and that only a small amount of stephanine can inhibit the replication of the novel coronavirus by a factor of about 16000 compared to other drugs. Patent CN102477041B reports that the stephanine has the functions of stimulating reticuloendothelial system, activating hematopoietic tissues, promoting bone marrow tissue proliferation and the like, and can treat leucopenia clinically. Patent CN112516143A discloses that stephanine can effectively inhibit the infection capability of various coronaviruses on cells, and has excellent inhibiting effect on SARS-CoV-2 (S-D614), SARS-CoV-2 (S-G614), SARS-CoV and MERS-CoV coronavirus infection. Patent CN110496225a (B) found for the first time that the anticancer effect of stephanine hydrochloride in vitro was enhanced by using autophagy inhibitors and verified on an in vivo mouse model, provided a novel effective and viable solution for the treatment of solid tumors. Patent CN102477041B shows a preparation method of stephanine hydrochloride, and the prepared stephanine hydrochloride remarkably improves the solubility of stephanine in water and effectively improves a plurality of adverse factors in the preparation. Patent CN114989186a reports a purification method of stephanine, which obviously improves the chemical purity of stephanine by controlling the recrystallization solvent, the dosage, the crystallization temperature and other parameters in the purification process, but the crystallinity of the obtained product is lower.
The solid powder form and structure of the medicine affect the physical and chemical properties of the medicine, such as stability, purity, fluidity, dissolution rate, bioavailability and the like. The amorphous state of cepharanthine has the problems of poor downstream separation operation and stability and the like. Therefore, there is an urgent need to develop a solid form with good fluidity and stability of crystals to improve the production and use requirements.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a stephanine acetonitrile solvate crystal, a stephanine methanol solvate crystal, a stephanine methyl acetate solvate crystal, a stephanine ethyl acetate solvate crystal, a stephanine butyl acetate solvate crystal and a stephanine anhydrous crystal form I crystal.
In order to solve the technical problems, the invention adopts the following technical scheme:
the invention discloses a cepharanthine crystal, which is any one of a cepharanthine acetonitrile solvate crystal, a cepharanthine methanol solvate crystal, a cepharanthine methyl acetate solvate crystal, a cepharanthine ethyl acetate solvate crystal, a cepharanthine butyl acetate solvate crystal and a cepharanthine crystal form I crystal;
The molecular formula of the stephanine acetonitrile solvate crystal is C 37 H 38 N 2 O 6 ·CH 3 CN, the crystal structure of which belongs to an orthorhombic system, P2 1 2 1 2 1 Space group, unit cell parameters are
α=90°, β=90°, γ=90°, unit cell volume +.>
The minimum asymmetric unit number Z=4 in the unit cell, and the minimum asymmetric unit contains 1 stephanine molecule and 1 acetonitrile solvent molecule; with the following angle of 2-diffraction and I/I measured after grinding 0 -an X-ray powder diffraction signature line expressed in relative intensity, measured using Cu-ka radiation:
the molecular formula of the stephanine methanol solvate crystal is C 37 H 38 N 2 O 6 ·0.5CH 3 OH, the crystal structure belongs to a triclinic system, P3 2 Space group, unit cell parameters
α=90°, β=90°, γ=120°, unit cell volume +.>
The minimum asymmetric unit number Z=3 in the unit cell, and the minimum asymmetric unit contains 1 stephanine molecule and 0.5 methanol solvent molecule; with the following angle of 2-diffraction and I/I measured after grinding 0 -an X-ray powder diffraction signature line expressed in relative intensity, measured using Cu-ka radiation:
the stephanine methyl acetate solvate crystalA body of formula C 37 H 38 N 2 O 6 ·C 3 H 6 O 2 The crystal structure belongs to an orthorhombic system, P2 1 2 1 2 1 Space group, unit cell parameters 
α=90°, β=90°, γ=90°, unit cell volume +.>
The minimum asymmetric unit number Z=8 in the unit cell, and the minimum asymmetric unit contains 2 stephanine molecules and 2 methyl acetate solvent molecules, wherein the 2 stephanine molecules are in different conformations, and the 2 methyl acetate solvent molecules are in different conformations; with the following angle of 2-diffraction and I/I measured after grinding 0 -an X-ray powder diffraction signature line expressed in relative intensity, measured using Cu-ka radiation:
the molecular formula of the stephanine ethyl acetate solvate crystal is C 37 H 38 N 2 O 6 ·C 4 H 8 O 2 The crystal structure belongs to monoclinic system, P2 1 Space group, unit cell parameters
α=90°, β= 90.821 (6) °, γ=90°, unit cell volume +.>
The minimum asymmetric unit number Z=4 in the unit cell, and the minimum asymmetric unit contains 2 stephanine molecules and 2 ethyl acetate solvent molecules, wherein 2 stephanine molecules are not usedIsomorphic, 2 ethyl acetate solvent molecules are in different conformations; with the following angle of 2-diffraction and I/I measured after grinding 0 -an X-ray powder diffraction signature line expressed in relative intensity, measured using Cu-ka radiation:
the molecular formula of the stephanine butyl acetate solvate crystal is 2C 37 H 38 N 2 O 6 ·C 6 H 12 O 2 The crystal structure belongs to an orthorhombic system, P2 1 2 1 2 1 Space group, unit cell parameters
α=90°, β=90°, γ=90°, unit cell volume +.>
The minimum asymmetric unit number Z=4 in the unit cell, and the minimum asymmetric unit contains 2 stephanine molecules and 1 butyl acetate solvent molecule, wherein 2 stephanine molecules are in different conformations; with the following angle of 2-diffraction and I/I measured after grinding 0 -an X-ray powder diffraction signature line expressed in relative intensity, measured using Cu-ka radiation: />
The molecular formula of the stephanine crystal form I crystal is C 37 H 38 N 2 O 6 The crystal structure belongs to a triclinic system, P3 1 Space group, unit cell parameters are
α=90°, β=90°, γ=120.00°, unit cell volume +.>
The minimum asymmetric unit number Z=3 in the unit cell, and the minimum asymmetric unit contains 1 stephanin molecule; with the following angle of 2-diffraction and I/I measured after grinding 0 -an X-ray powder diffraction signature line expressed in relative intensity, measured using Cu-ka radiation:
the stephanine acetonitrile solvate crystal, stephanine methanol solvate crystal, stephanine methyl acetate solvate crystal, stephanine ethyl acetate solvate crystal, stephanine butyl acetate solvate crystal and stephanine crystal form I crystal are crystalline powder and colorless.
Specifically, the bulk density of the stephanine acetonitrile solvate crystal and crystal powder is more than 0.58g/cm 3 Preferably greater than 0.64g/cm 3 More preferably greater than 0.67g/cm 3 。
Specifically, the stephanine acetonitrile solvate crystal has tap density greater than 0.60g/cm 3 Preferably greater than 0.65g/cm 3 More preferably greater than 0.70g/cm 3 。
Specifically, the bulk density of the stephanine methanol solvate crystal and the crystal powder is more than 0.82g/cm 3 Preferably greater than 0.86g/cm 3 More preferably greater than 0.92g/cm 3 。
Specifically, the stephanine methanol solvate crystal has tap density greater than 0.85g/cm 3 Preferably greater than 0.94g/cm 3 More preferably greater than 1.0g/cm 3 。
Specifically, the bulk density of the stephanine methyl acetate solvate crystal and crystal powder is more than 0.90g/cm 3 Preferably greater than 0.94g/cm 3 More preferably greater than 1.0g/cm 3 。
Specifically, the stephanine methyl acetate solvate crystal and crystal powderTap density of greater than 0.93g/cm 3 Preferably greater than 0.98g/cm 3 More preferably greater than 1.05g/cm 3 。
Specifically, the bulk density of the stephanine ethyl acetate solvate crystal and crystal powder is more than 0.56g/cm 3 Preferably greater than 0.66g/cm 3 More preferably greater than 0.71g/cm 3 。
Specifically, the tap density of the stephanine ethyl acetate solvate crystal and crystal powder is more than 0.59g/cm 3 Preferably greater than 0.67g/cm 3 More preferably greater than 0.73g/cm 3 。
Specifically, the bulk density of the stephanine butyl acetate solvate crystal and crystal powder is more than 0.64g/cm 3 Preferably greater than 0.72g/cm 3 More preferably greater than 0.84g/cm 3 。
Specifically, the tap density of the stephanine butyl acetate solvate crystal and crystal powder is more than 0.69g/cm 3 Preferably greater than 0.78g/cm 3 More preferably greater than 0.88g/cm 3 。
Specifically, the stephanine crystal form I crystal has bulk density greater than 0.80g/cm 3 Preferably greater than 0.86g/cm 3 More preferably greater than 0.95g/cm 3 。
Specifically, the stephanine crystal form I crystal has tap density greater than 0.85g/cm 3 Preferably greater than 0.92g/cm 3 More preferably greater than 1.0g/cm 3 。
Further, the invention discloses a preparation method of the stephanine crystal form I crystal, which comprises the steps of mixing a first raw material with a first solvent, and dissolving the first raw material to obtain a first mixed solution; evaporating and crystallizing the first mixed solution at room temperature to separate out crystals, filtering and drying a crystallization system to obtain stephanine crystal form I crystals;
The first raw material is any one of stephanine, stephanine acetonitrile solvate crystal, stephanine methanol solvate crystal and stephanine ethyl acetate solvate crystal; the first solvent is any one or the combination of a plurality of dimethyl acetamide, N-methyl formamide and isopropanol.
Specifically, in the preparation method of the stephanine crystal form I crystal, the first raw material is any one of amorphous stephanine, stephanine acetonitrile solvate crystal, stephanine methanol solvate crystal and stephanine ethyl acetate solvate crystal; the mass volume ratio of the first raw material to the first solvent is 0.1-0.4 g:2mL, preferably 0.2 to 0.3g:2mL, more preferably 0.2:2mL or 0.3g:2mL; the evaporating crystallization is carried out for 2-8 days, preferably 3-7 days.
In the preparation method of the stephanine crystal form I crystal, the stephanine crystal form I crystal is stephanine non-hydrate crystal form I crystal; the dissolving mode of the first raw material is ultrasonic dissolving or oscillating dissolving; the ultrasonic dissolution is carried out at an ultrasonic power of 50-100W, preferably 50-80W, more preferably 50-60W, most preferably 50W, an ultrasonic temperature of 30-40 ℃, preferably 35-40 ℃, more preferably 40 ℃ and an ultrasonic time of completely dissolving the first raw material solid; the oscillating dissolution is carried out at a temperature of 20-50 ℃, preferably 35-50 ℃, at a rotational speed of 100-300 rpm, preferably 100-150 rpm, more preferably 150 rpm, for a time period of complete dissolution of the first raw material solid; the shaking dissolution is preferably carried out in a shaking table.
Further, the invention discloses a preparation method of the stephanine acetonitrile solvate crystal, which comprises the steps of dissolving a second raw material in a second solvent to obtain a second mixed solution; performing suspension crystal transformation or ultrasonic cooling crystallization on the second mixed solution to separate out crystals, and filtering and drying a crystallization system to obtain stephanine acetonitrile solvate crystals;
the second raw material is stephanine or stephanine crystal form I crystal; the second solvent is acetonitrile or acetonitrile and water with the volume ratio of 3: 1-3.
Specifically, in the preparation method of the stephanine acetonitrile solvate crystal, the second raw material is amorphous stephanine or stephanine crystal form I crystal; the second solvent is acetonitrile or acetonitrile and water with the volume ratio of 3:2, a mixture of two or more of the above-mentioned materials; the mass volume ratio of the second raw material to the second solvent is 0.1-0.4 g:2 to 5mL, preferably 0.2 to 0.3g: 2-5 mL.
In the preparation method of the stephanine acetonitrile solvate crystal, the suspension crystal is transferred, the second mixed solution is stirred for 4 minutes to 4 hours at the temperature of 25 to 40 ℃, preferably 4 minutes or 4 hours, and crystallization is carried out in the stirring process; the ultrasonic cooling crystallization is carried out on the second mixed solution, ultrasonic dissolution is carried out on the second mixed solution, the ultrasonic power is 50-100W, preferably 70-100W, more preferably 70-80W, most preferably 75W, the ultrasonic temperature is 20-40 ℃, preferably 30-40 ℃, more preferably 40 ℃, the ultrasonic time is 5-10 ℃/min, the second mixed solution is cooled to-20-4 ℃, preferably 0-4 ℃, more preferably 0 ℃ after the ultrasonic dissolution is finished, the crystallization system is maintained for 8-24 h at the temperature, preferably 8-12 h, more preferably 10 h.
Further, the invention discloses a preparation method of the stephanine methanol solvate crystal, which comprises the steps of dissolving a third raw material in absolute methanol to obtain a third mixed solution; cooling crystallization or suspension crystal transformation is carried out on the third mixed solution, crystals are separated out, and the crystallization system is filtered and dried to obtain stephanine methanol solvate crystals;
the third raw material is any one of stephanine crystal form I crystal, stephanine acetonitrile solvate crystal, stephanine methyl acetate solvate crystal, stephanine ethyl acetate solvate crystal and stephanine butyl acetate solvate crystal.
Specifically, in the preparation method of the stephanine methanol solvate crystal, the third raw material is any one of stephanine crystal form I crystal, stephanine acetonitrile solvate crystal, stephanine methyl acetate solvate crystal, stephanine ethyl acetate solvate crystal and stephanine butyl acetate solvate crystal; the mass volume ratio of the third raw material to the anhydrous methanol is 0.05-0.25 g:1 to 2mL, preferably 0.1 to 0.2g: 1-2 mL.
In the preparation method of the stephanine methanol solvate crystal, the cooling crystallization is carried out, the third mixed solution is placed at the temperature of-20 ℃ to 6 ℃ for 1 to 5 days for crystallization, preferably the third mixed solution is placed at the temperature of 0 ℃ to 6 ℃ for 1 to 3 days for crystallization, more preferably the third mixed solution is placed at the temperature of 4 ℃ for 1 day for crystallization; and (3) carrying out suspension crystal transformation, and placing the third mixed solution at room temperature for 1-7 days, preferably 3-5 days, to carry out crystallization.
Further, the invention discloses a preparation method of the stephanine methyl acetate solvate crystal, which comprises the steps of dissolving a fourth raw material in methyl acetate to obtain a fourth mixed solution; cooling crystallization or evaporation crystallization is carried out on the fourth mixed solution, crystals are separated out, and the crystallization system is filtered and dried, so that the stephanine methyl acetate solvate crystals are obtained;
the fourth raw material is any one of stephanine, stephanine crystal form I crystals, stephanine acetonitrile solvate crystals and stephanine methanol solvate crystals.
Specifically, in the preparation method of the stephanine methyl acetate solvate crystal, the fourth raw material is any one of amorphous stephanine, stephanine crystal form I crystal, stephanine acetonitrile solvate crystal and stephanine methanol solvate crystal; the mass volume ratio of the fourth raw material to the methyl acetate is 0.2-0.6 g:2mL, preferably 0.3 to 0.4g:2mL, more preferably 0.3:2mL or 0.4g:2mL.
In the preparation method of the stephanine methyl acetate solvate crystal, the fourth raw material is dissolved in an ultrasonic dissolution or oscillation dissolution mode; the ultrasonic dissolution is carried out at an ultrasonic power of 50-100W, preferably 80-100W, more preferably 100W, an ultrasonic temperature of 20-40 ℃, preferably 30-40 ℃, more preferably 40 ℃ and an ultrasonic time of completely dissolving the solid in the fourth mixed solution; the oscillating dissolution is carried out at a temperature of 20-50 ℃, preferably 35-50 ℃, more preferably 50 ℃ for a period of time that the solids in the fourth mixed solution are completely dissolved; the shaking and dissolving are preferably carried out in a shaking table; the cooling crystallization is carried out, the fourth mixed solution is placed at the temperature of minus 20 ℃ to 4 ℃ for 1 to 8 days for crystallization, and preferably, the fourth mixed solution is placed at the temperature of minus 10 ℃ to 4 ℃ for 1 to 7 days for crystallization; the evaporating crystallization is carried out at room temperature for 2-8 days, preferably 3-7 days.
Further, the invention discloses a preparation method of the stephanine ethyl acetate solvate crystal, which comprises the steps of dissolving a fifth raw material in ethyl acetate to obtain a fifth mixed solution; cooling crystallization or evaporative crystallization is carried out on the fifth mixed solution, crystals are separated out, and the crystallization system is filtered and dried to obtain stephanine ethyl acetate solvate crystals;
the fifth raw material is any one of stephanine, stephanine crystal form I crystal, stephanine acetonitrile solvate crystal, stephanine methanol solvate crystal and stephanine methyl acetate solvate crystal.
Specifically, in the preparation method of the stephanine ethyl acetate solvate crystal, the fifth raw material is any one of amorphous stephanine, stephanine crystal form I crystal, stephanine acetonitrile solvate crystal, stephanine methanol solvate crystal and stephanine methyl acetate solvate crystal; the mass volume ratio of the fifth raw material to the ethyl acetate is 0.2-0.7 g:2mL, preferably 0.4 to 0.5g:2mL, more preferably 0.4g:2mL or 0.5g:2mL.
In the preparation method of the stephanine ethyl acetate solvate crystal, the dissolution of the fifth raw material is ultrasonic dissolution or oscillation dissolution; the ultrasonic dissolution is carried out at an ultrasonic power of 50-100W, preferably 70-100W, more preferably 75-100W, even more preferably 75W or 100W, an ultrasonic temperature of 20-40 ℃, preferably 30-40 ℃ and an ultrasonic time of completely dissolving the solid in the fifth mixed solution; the oscillating dissolution is carried out at a temperature of 20-50 ℃, preferably 35-50 ℃, more preferably 50 ℃ for a period of time that the solids in the fifth mixed solution are completely dissolved; the shaking and dissolving are preferably carried out in a shaking table; the cooling crystallization is carried out, the fifth mixed solution is placed at the temperature of minus 20 ℃ to 4 ℃ for 1 to 8 days for crystallization, and preferably, the fifth mixed solution is placed at the temperature of 0 ℃ to 4 ℃ for 3 to 7 days for crystallization; the evaporating crystallization is carried out at room temperature for 2 to 10 days, preferably 6 to 8 days, and more preferably 7 days.
Further, the invention discloses a preparation method of the stephanine butyl acetate solvate crystal, which comprises the steps of dissolving a sixth raw material in butyl acetate to obtain a sixth mixed solution; cooling crystallization or evaporative crystallization is carried out on the sixth mixed solution, crystals are separated out, and the crystallization system is filtered and dried to obtain stephanine butyl acetate solvate crystals;
the sixth raw material is any one of stephanine, stephanine crystal form I crystal, stephanine acetonitrile solvate crystal, stephanine methanol solvate crystal and stephanine methyl acetate solvate crystal.
Specifically, in the preparation method of the stephanine butyl acetate solvate crystal, the sixth raw material is any one of amorphous stephanine, stephanine crystal form I crystal, stephanine acetonitrile solvate crystal, stephanine methanol solvate crystal and stephanine methyl acetate solvate crystal; the mass volume ratio of the sixth raw material to the butyl acetate is 0.2-0.8 g:2mL, preferably 0.4 to 0.5g:2mL, more preferably 0.4g:2mL or 0.5g:2mL.
In the preparation method of the stephanine butyl acetate solvate crystal, the sixth raw material is dissolved in an ultrasonic dissolution or oscillation dissolution mode; the ultrasonic dissolution is carried out at an ultrasonic power of 50-100W, preferably 60-100W, more preferably 75-100W, further preferably 75W or 100W, an ultrasonic temperature of 20-40 ℃, preferably 30-40 ℃, more preferably 30-35 ℃, further preferably 30-35 ℃ or 35 ℃ for an ultrasonic time of completely dissolving the solid in the sixth mixed solution; the oscillating dissolution is carried out at a temperature of 20-50 ℃, preferably 35-50 ℃, more preferably 50 ℃ for a period of time that the solid in the sixth mixed solution is completely dissolved; the shaking and dissolving are preferably carried out in a shaking table; the cooling crystallization is carried out, the sixth mixed solution is placed at the temperature of minus 20 ℃ to 4 ℃ for 2 days to 8 days for crystallization, and preferably 3 days to 7 days for crystallization; the evaporating crystallization is carried out at room temperature for 5 to 10 days, preferably 6 to 8 days, and more preferably 7 days.
The bulk density and tap density are amounts related to the powder properties. Generally, high bulk density and tap density values are desired. Bulk density refers to the weight per volume of powder under predetermined conditions, expressed as weight per volume unit, typically in g/mL. Tap density also indicates the weight per volume of powder, in the holder of which the powder is subjected to beating or vibration under predetermined conditions. Thus, for the same powder, its tap density is higher than the bulk density.
The crystal with large bulk density and tap density has larger specific gravity, can reflect that the crystal product is thicker and has texture, and has relatively better stability; from another point of view, products with a high bulk density generally have better flowability of the granules and are also easy to store and transport.
Specifically, the method for measuring the bulk density and the tap density of the crystalline powder is as follows:
bulk density of particles was measured according to USP method II (page 1914);
the tap density of the particles was determined by means of an FZS4-4 economical tap densitometer according to GB/T5162-2006. Specifically, the test conditions were: the vibration stroke of the beating device was 3.+ -. 0.1MM and the vibration frequency was 250.+ -.15 times per minute.
The beneficial effects are that:
(1) Compared with amorphous stephanine powder, the crystal provided by the invention has the advantages of high bulk density, good fluidity, strong stability and convenience in storage and transportation.
(2) The stephanine crystal form I crystals and 5 stephanine solvate crystals provided by the invention have better stability, a sample is placed in a dynamic steam adsorption instrument at 40 ℃, the weight when the mass change is less than 0.01g within 3 hours is recorded, the hygroscopicity of the stephanine crystal form I crystals and 5 stephanine solvate crystals is far lower than that of amorphous stephanine powder, and the stability of the stephanine crystals provided by the invention is greatly improved compared with that of the amorphous stephanine powder.
Drawings
The foregoing and/or other advantages of the invention will become more apparent from the following detailed description of the invention when taken in conjunction with the accompanying drawings and detailed description.
FIG. 1 is a powder diffraction pattern of stephanine form I crystals and 5 stephanine solvate crystals.
FIG. 2 is a molecular ellipsoidal diagram of the minimum asymmetric unit of the stephanine crystal form I.
FIG. 3 is a unit cell stacking diagram of the cepharanthine crystal form I crystals.
FIG. 4 is a thermogravimetric/differential scanning analysis of the stephanine form I crystals.
Fig. 5 is a crystal morphology diagram of stephanine crystal form I crystals.
FIG. 6 is a molecular ellipsometry of the smallest unit of crystal asymmetry of the solvate of stephanine acetonitrile.
Fig. 7 is a unit cell stacking diagram of the stephanine acetonitrile solvate crystals.
FIG. 8 is a thermogram/differential scanning analysis of the crystals of the stephanine acetonitrile solvate.
FIG. 9 is a molecular ellipsoidal diagram of the minimum asymmetric unit of a stephanine methanol solvate crystal.
Fig. 10 is a unit cell stacking diagram of cepharanthine methanol solvate crystals.
FIG. 11 is a thermogram/differential scanning analysis of the stephanine methanol solvate crystals.
FIG. 12 is a molecular ellipsometry of the smallest asymmetric unit of the stephanine methyl acetate solvate crystals.
FIG. 13 is a unit cell stacking diagram of the stephanine methyl acetate solvate crystals.
FIG. 14 is a thermogram/differential scanning analysis of the crystals of the methyl cepharanthine acetate solvate.
FIG. 15 is a molecular ellipsometry of the smallest asymmetric unit of the stephanine ethyl acetate solvate crystals.
Fig. 16 is a unit cell stacking diagram of the stephanine ethyl acetate solvate crystals.
FIG. 17 is a thermogram/differential scanning analysis of the crystals of the ethyl acetate solvate of stephanine.
FIG. 18 is a molecular ellipsometry of the smallest asymmetric unit of the crystalline of the solvate of stephanine acetate.
FIG. 19 is a unit cell stacking diagram of the crystalline cepharanthine butyl acetate solvate.
FIG. 20 is a thermogram/differential scanning analysis of the crystalline of the stephanine acetate solvate.
Fig. 21 is a diagram showing information about the crystal structure of stephanine crystal form I.
Fig. 22 is a diagram showing information on crystal structure of the solvate of stephanine acetonitrile.
Fig. 23 is a diagram showing information on the crystal structure of stephanine methanol solvate.
Fig. 24 is a diagram showing information on the crystal structure of the solvate of methyl stephanine acetate.
Fig. 25 is a diagram showing information on the crystal structure of the ethyl acetate solvate of stephanine.
Fig. 26 is a diagram showing information on the crystal structure of the solvate of stephanine butyl acetate.
FIG. 27 is a graph showing the crystal morphology of the product obtained in comparative example 1.
FIG. 28 is a thermogravimetric analysis of the product obtained in comparative example 3.
Detailed Description
The crystalline powder and the preparation form of cepharanthine according to the present invention will be further illustrated by the following non-limiting examples, which are intended to be illustrative only and not limiting, and are not intended to limit the scope of the invention.
X-ray powder diffraction test conditions in the examples of the present invention: rigaku SmartLabSE X-ray powder diffractometer, cu-K alpha radiation, 40KV light pipe voltage, 40mA current, 10 DEG/min scanning speed and 5-40 DEG scanning range.
In the embodiment of the invention, TG/DSC data are obtained by analyzing NETZSCH STA 449F3 type instruments, and the analysis conditions are as follows: placing 5-10 mg of sample in ceramic crucible, using N 2 As a protective gas, the temperature rising rate is 10 ℃/min, and the temperature range is 40-300 ℃ or 40-350 ℃.
The detection method and the instrument for the crystal structure of the stephanine crystal form I crystal and the crystal structures of five stephanine solvates obtained in the embodiment of the invention are as follows:
single crystal X-ray diffraction measurement crystal structure and analytical method: taking out single crystal of Cepharanthine crystal form I and five kinds of Cepharanthine solvate crystals with good quality, cutting into about 0.45X0.30X0.14 mm 3 The size of the block was measured by a BrookAPEX-II CCD diffractometer Mo K alpha radiation source (graphite monochromator,
) Irradiating the sample, collecting diffraction data, recovering diffraction data by SAINT, directly analyzing structure by SHELXL-97 software, and analyzing based on F 2 Is refined by the full matrix least squares method, all non-hydrogen atoms are refined by anisotropism. The final data were plotted by Mercury 3.3 or Materials studio 7.02 software.
The amorphous stephanine powder raw material used in the embodiment of the invention is prepared by an experimental method referring to a patent CN 102146083A, and the bulk density of the obtained amorphous stephanine powder raw material is 0.15g/cm 3 Tap density of 0.17g/cm 3 。
The stephanine crystal form I crystal, the stephanine acetonitrile solvate crystal, the stephanine methanol solvate crystal, the stephanine methyl acetate solvate crystal, the stephanine ethyl acetate solvate crystal and the stephanine butyl acetate solvate crystal used in the embodiment of the invention are all prepared by a laboratory self-made method according to the embodiment of the invention.
The anhydrous methanol used in the embodiment of the invention is purchased from Shanghai Ala Biochemical technology Co., ltd, and the purity is more than or equal to 99.5%.
Example 1: preparation of stephanine crystal form I crystal
Adding 0.2g of amorphous stephanine powder into 2mL of dimethylacetamide solvent to obtain a first mixed solution; and (3) placing the first mixed solution in an ultrasonic cleaning instrument with 50W and 40 ℃ for ultrasonic treatment until all solids in the first mixed solution are dissolved, then placing the clarified first mixed solution at room temperature for slow evaporation and crystallization for 5 days, precipitating crystals, filtering a crystallization system, and drying at 20 ℃ and normal pressure for 4 hours to obtain colorless stephanine crystal form I crystals. The stephanine crystal form I has 0.186g and the molar yield is 93 percent. The bulk density of the obtained stephanine crystal form I crystals is 0.98g/cm 3 Tap density of 1.02g/cm 3 。
Stephanine crystal form I crystal measurement according to 2 theta-diffraction angle and I/I 0 -an X-ray powder diffraction signature line expressed in relative intensity, measured using Cu-ka radiation:
TABLE 1X-ray powder diffraction characteristic lines for Stephanine Crystal form I crystals
The X-ray diffraction diagram of the stephanine crystal form I crystal is shown in figure 1a, the molecular ellipsoidal diagram of the minimum asymmetric unit of the stephanine crystal form I crystal is shown in figure 2, and the unit cell stacking diagram of the stephanine crystal form I crystal is shown in figure 3. The analysis results of TGA and DSC of the stephanine crystal form I are shown in figure 4, wherein an endothermic characteristic peak exists at 184.3 ℃ on a DSC curve, the corresponding characteristic peak exists at 335.3 ℃ and the corresponding characteristic peak exists at the melting point of the stephanine crystal form I, the corresponding characteristic peak exists at the decomposition point of the stephanine crystal form I, no obvious weight loss step exists on the TGA curve, and the stephanine crystal form I crystal is proved to be an anhydrous crystal form. The crystal morphology of the stephanine crystal form I crystal is shown in figure 5. Cepharanthine crystal form I crystal with molecular formula of C 37 H 38 N 2 O 6 The crystal structure belongs to a triclinic system, P3 1 Space group, unit cell parameters are
α=90°, β=90°, γ=120.00°, unit cell volume +.>
The minimum asymmetric unit number Z=3 in the unit cell, and the minimum asymmetric unit contains 1 stephanine molecule, and the specific stephanine crystal form I crystal structure related information is shown in figure 21.
Example 2: preparation of stephanine crystal form I crystal
Adding 0.2g of amorphous stephanine powder into 2mL of N-methyl formamide solvent to obtain a first mixed solution; setting the temperature of a shaking table to 25 ℃, oscillating at 150 revolutions per minute, oscillating the first mixed solution in the shaking table until the solid is completely dissolved, slowly evaporating and crystallizing the clarified first mixed solution at room temperature for 5 days to precipitate crystals, filtering a crystallization system, and drying at 20 ℃ under normal pressure for 4 hours to obtain colorless stephanine crystal form I crystals. The stephanine crystal form I has 0.18g and the molar yield is 90%. The bulk density of the obtained stephanine crystal form I crystals is 0.96g/cm 3 Tap density of 1.01g/cm 3 。
Example 3: preparation of stephanine crystal form I crystal
Adding 0.3g of stephanine acetonitrile solvate crystal into 2mL of isopropanol solvent to obtain a first mixed solution; setting the temperature of a shaking table at 35 ℃, oscillating at 150 revolutions per minute, oscillating the first mixed solution in the shaking table until the solid is completely dissolved, slowly evaporating and crystallizing the clarified first mixed solution at room temperature for 3 days to precipitate crystals, filtering a crystallization system, and drying at 20 ℃ under normal pressure for 4 hours to obtain colorless stephanine crystal form I crystals. The stephanine crystal form I has 0.256g and the molar yield is 91%. The bulk density of the obtained stephanine crystal form I crystals is 0.89g/cm 3 Tap density of 0.92g/cm 3 。
Example 4: preparation of stephanine crystal form I crystal
0.3g of stephania root is addedAdding the acetonitrile solvate crystal into 2mL of dimethylacetamide solvent to obtain a first mixed solution; setting the temperature of a shaking table at 45 ℃ and the shaking speed at 150 revolutions per minute, shaking the first mixed solution in the shaking table until the solid is completely dissolved, slowly evaporating and crystallizing the clarified first mixed solution at room temperature for 7 days to precipitate crystals, filtering a crystallization system, and drying at 20 ℃ and normal pressure for 4 hours to obtain colorless stephanine crystal form I crystals. The stephanine crystal form I has 0.259g and the molar yield is 92%. The bulk density of the obtained stephanine crystal form I crystals is 0.90g/cm 3 Tap density of 0.98g/cm 3 。
Example 5: preparation of stephanine crystal form I crystal
Adding 0.3g of stephanine methanol solvate crystals into 2mL of isopropanol solvent to obtain a first mixed solution; setting the temperature of a shaking table at 35 ℃, oscillating at 150 revolutions per minute, oscillating the first mixed solution in the shaking table until the solid is completely dissolved, slowly evaporating and crystallizing the clarified first mixed solution at room temperature for 3 days to precipitate crystals, filtering a crystallization system, and drying at 20 ℃ under normal pressure for 4 hours to obtain colorless stephanine crystal form I crystals. The stephanine crystal form I has 0.263g and the molar yield is 90%. The bulk density of the obtained stephanine crystal form I crystals is 0.88g/cm 3 Tap density of 0.95g/cm 3 。
Example 6: preparation of stephanine crystal form I crystal
Adding 0.3g of stephanine ethyl acetate solvate crystal into 2mL of isopropanol solvent to obtain a first mixed solution; setting the temperature of a shaking table to 35 ℃, oscillating at 150 revolutions per minute, oscillating the first mixed solution in the shaking table until the solid is completely dissolved, slowly evaporating and crystallizing the clarified first mixed solution at room temperature for 3 days to precipitate crystals, filtering a crystallization system, and drying at 20 ℃ under normal pressure for 4 hours to obtain colorless stephanine crystal form I crystals. The stephanine crystal form I has 0.241g and the molar yield is 92%. The bulk density of the obtained stephanine crystal form I crystals is 0.92g/cm 3 Tap density of 0.99g/cm 3 。
Example 7: preparation of stephanine crystal form I crystal
Adding 0.3g of stephanine ethyl acetate solvate crystal into 2mL of isopropanol solvent to obtain a first mixed solution; setting the temperature of a shaking table to 45 ℃, oscillating the first mixed solution in the shaking table at the oscillating speed of 150 revolutions per minute, after oscillating until the solid is completely dissolved, slowly evaporating and crystallizing the clarified first mixed solution at room temperature for 7 days to precipitate crystals, filtering a crystallization system, and drying at 20 ℃ under normal pressure for 4 hours to obtain colorless stephanine crystal form I crystals. The stephanine crystal form I has 0.238g and the molar yield is 90%. The bulk density of the obtained stephanine crystal form I crystals is 0.91g/cm 3 Tap density of 0.98g/cm 3 。
Comparative example 1: preparation method referring to example 1 in patent CN 115260210A, taking 12.0g stephanine, adding 150mL methanol, 10mL acetone, stirring, heating at 55 ℃ for 1h, filtering, standing filtrate, cooling to room temperature, crystallizing at 0 ℃ for 10h, suction filtering, drying at 50 ℃ for 2h to obtain stephanine crystal form I crystal, wherein the mass is 9.3g, and the molar yield is 78%. Tested to have a bulk density of 0.48g/cm 3 Tap density of 0.54g/cm 3 The particles of the whole crystal are finer, the texture is not strong, and a specific crystal morphology diagram is shown in fig. 27.
Example 8: preparation of stephanine acetonitrile solvate crystal
Adding 0.3g of amorphous stephanine powder raw material into 3mL of acetonitrile solvent to obtain a second mixed solution; and (3) placing the second mixed solution at 25 ℃ for stirring for 4 minutes to carry out suspension crystal transformation, carrying out crystallization in the stirring process, filtering a crystallization system after stirring, and drying the crystals at 20 ℃ under normal pressure for 4 hours to obtain colorless stephanine acetonitrile solvate crystals. The acetonitrile solvate was obtained in 0.282g and a molar yield of 88%. Bulk density of stephanine acetonitrile solvate crystal is 0.69g/cm 3 Tap density of 0.72g/cm 3 。
Measured according to 2 theta-diffraction angle and I/I of stephanine acetonitrile solvate crystal 0 X-ray powder diffraction characteristic lines of relative intensity representation, using Cu-K alpha-rayThe amount is as follows:
TABLE 2X-ray powder diffraction characteristic lines of Stephanine acetonitrile solvate crystals
The X-ray diffraction pattern of the stephanine acetonitrile solvate crystal is shown in figure 1b, the molecular ellipsoids of the minimum asymmetric units of the stephanine acetonitrile solvate crystal are shown in figure 6, and the unit cell stacking pattern of the stephanine acetonitrile solvate crystal is shown in figure 7. The TGA and DSC analysis results of the stephanine acetonitrile solvate crystal are shown in figure 8, and the endothermic characteristic peak at 115.88 ℃ on the DSC curve corresponds to the initial desolvation point of the stephanine acetonitrile solvate crystal; an exothermic characteristic peak at t= 323.78 ℃, corresponding to the point of decomposition of the stephanine acetonitrile solvate crystals; the TGA curve has obvious weight loss steps, the numerical value is 5.853 percent, and the weight loss steps are consistent with the theoretical weight loss calculated by single crystal analysis. Cepharanthine acetonitrile solvate crystal with molecular formula of C 37 H 38 N 2 O 6 ·CH 3 CN, the crystal structure of which belongs to an orthorhombic system, P2 1 2 1 2 1 Space group, unit cell parameters are
α=90°, β=90°, γ=90°, unit cell volume 
The minimum asymmetric unit number z=4 in the unit cell, and the minimum asymmetric unit contains 1 stephanine molecule and 1 acetonitrile solvent molecule, and the specific stephanine acetonitrile solvate crystal structure related information is shown in fig. 22.
Example 9: preparation of stephanine acetonitrile solvate crystal
Adding 0.3g of stephanine crystal form I crystals into 3mL of acetonitrile solvent, and then adding 2mL of water into the system to obtain a second mixed solution; the temperature of the second mixed solution is kept at 40 ℃, and the magnetic stirring is carried out for 4 hours to suspendAnd (3) transferring crystals, filtering a crystallization system after stirring, and drying the crystals at 30 ℃ and normal pressure for 2 hours to obtain colorless stephanine acetonitrile solvate crystals. The stephanine acetonitrile solvate crystals have 0.285g and the molar yield is 88%. Bulk density of stephanine acetonitrile solvate crystal is 0.68g/cm 3 Tap density of 0.71g/cm 3 。
Example 10: preparation of stephanine acetonitrile solvate crystal
Adding 0.2g of stephanine crystal form I crystals into 2mL of acetonitrile solvent to obtain a second mixed solution; and placing the second mixed solution in a 75W ultrasonic cleaner at 40 ℃ for ultrasonic treatment for 5 minutes to obtain a clarified second mixed solution. Cooling the clarified second mixed solution to the temperature of 0 ℃ at the cooling rate of 10 ℃/min, maintaining the solution at the temperature of 0 ℃ for 10 hours for cooling crystallization, separating out crystals, filtering the crystallization system, and drying at the temperature of 20 ℃ and the normal pressure for 4 hours to obtain colorless stephanine acetonitrile solvate crystals. The yield of the stephanine acetonitrile solvate crystal of 0.186g is 87%. Bulk density of stephanine acetonitrile solvate crystal is 0.66g/cm 3 Tap density of 0.69g/cm 3 。
Example 11: preparation of stephanine methanol solvate crystal
Adding 0.1g of stephanine crystal form I crystals into 2mL of absolute methanol solvent to obtain a third mixed solution; setting the temperature of a shaking table to 40 ℃, shaking the shaking table at 150 revolutions per minute, placing the third mixed solution in the shaking table, shaking the third mixed solution until the solid is completely dissolved, placing the clarified third mixed solution in a low-temperature environment of 4 ℃ for cooling and crystallizing for 1 day, precipitating crystals, filtering a crystallization system, and drying the crystals at 20 ℃ under normal pressure for 4 hours to obtain the colorless stephanine methanol solvate crystals. The stephanine methanol solvate crystals had 0.091g and a molar yield of 87%. The bulk density of the stephanine methanol solvate crystal is 0.93g/cm 3 Tap density of 1.02g/cm 3 。
Measured according to 2 theta-diffraction angle and I/I of stephanine methanol solvate crystal 0 -an X-ray powder diffraction signature line expressed in relative intensity, measured using Cu-ka radiation:
TABLE 3X-ray powder diffraction characteristic lines of Stephanine methanol solvate Crystal
The X-ray diffraction pattern of the stephanine methanol solvate crystal is shown in figure 1c, the molecular ellipsoids of the minimum asymmetric units of the stephanine methanol solvate crystal are shown in figure 9, and the unit cell stacking pattern of the stephanine methanol solvate crystal is shown in figure 10. The TGA and DSC analysis results of the stephanine methanol solvate crystal are shown in fig. 11, wherein the DSC curve has an endothermic characteristic peak at t=112.5 ℃, the initial desolvation point of the stephanine methanol solvate crystal corresponds to the starting desolvation point, and the stephanine methanol solvate crystal corresponds to the liberation point at t= 328.94 ℃; there are two obvious weight loss steps on the TGA curve, the first section weight loss is 7.252% (which is methanol solvent on the crystal surface), the second section weight loss is 2.869%, and the result is basically consistent with the calculation of single crystal analysis theory. Cepharanthine methanol solvate crystal with molecular formula of C 37 H 38 N 2 O 6 ·0.5CH 3 OH, the crystal structure belongs to a triclinic system, P3 2 Space group, unit cell parameters
Example 12: preparation of stephanine methanol solvate crystal
Adding 0.15g of stephanine acetonitrile solvate crystal into 2mL of absolute methanol solvent to obtain a third mixed solution;and (3) placing the third mixed solution at room temperature for 4 days for suspension crystal transformation, separating out crystals, filtering a crystallization system, and drying for 4 hours at 20 ℃ under normal pressure to obtain colorless stephanine methanol solvate crystals. The stephanine methanol solvate crystals have 0.14g and the molar yield is 90%. The bulk density of the stephanine methanol solvate crystals was 0.94g/cm 3 Tap density of 1.03g/cm 3 。
Example 13: preparation of stephanine methanol solvate crystal
Adding 0.2g of stephanine methyl acetate solvate crystal into 2mL of absolute methanol solvent to obtain a third mixed solution; and (3) placing the third mixed solution at room temperature for 3 days for suspension crystal transformation, separating out crystals, filtering a crystallization system, and drying for 4 hours at 20 ℃ and normal pressure to obtain colorless stephanine methanol solvate crystals. The stephanine methanol solvate crystals have 0.157g and the molar yield is 88%. The bulk density of the stephanine methanol solvate crystals is 0.95g/cm 3 Tap density of 1.04g/cm 3 。
Example 14: preparation of stephanine methanol solvate crystal
Adding 0.1g of the stephanine ethyl acetate solvate crystal into 2mL of absolute methanol solvent to obtain a third mixed solution; and (3) placing the third mixed solution at room temperature for 5 days for suspension crystal transformation, separating out crystals, filtering a crystallization system, and drying for 4 hours at 20 ℃ and normal pressure to obtain colorless stephanine methanol solvate crystals. The stephanine methanol solvate crystals have 0.072g and the molar yield is 86%. The bulk density of the stephanine methanol solvate crystals is 0.89g/cm 3 Tap density of 0.96g/cm 3 。
Example 15: preparation of stephanine methanol solvate crystal
Adding 0.1g of stephanine butyl acetate solvate crystal into 1mL of absolute methanol solvent to obtain a third mixed solution; and (3) placing the third mixed solution at normal temperature for 4 days to carry out suspension crystal transformation, separating out crystals, filtering a crystallization system, and drying for 4 hours at 20 ℃ and normal pressure to obtain colorless stephanine methanol solvate crystals. Methanol solvation of stephanineThe crystals had a molar yield of 89% and a content of 0.072 g. The bulk density of the stephanine methanol solvate crystals is 0.88g/cm 3 Tap density of 0.95g/cm 3 。
Comparative example 2: the preparation method is the same as in example 11, except that anhydrous methanol is replaced with 75% MeOH, 85% MeOH or 95% MeOH to give amorphous cepharanthine powder with bulk density of 0.16-0.18 g/cm 3 The tap density is 0.20-0.23 g/cm 3 。
Comparative example 3: the preparation method is the same as in test example 1 of patent CN 114989186A, 20g of stephanine benzene adduct crude product A and absolute methanol are mixed (the solid-to-liquid ratio of the stephanine benzene adduct crude product to the absolute methanol is 1:1), the mixture is heated to 70 ℃ until the solid is completely dissolved, stirred and cooled to 25 ℃, stirred and crystallized for 1h, filtered and dried to obtain stephanine product, and the bulk density of the stephanine product is 0.27g/cm 3 Tap density of 0.33g/cm 3 . The product was subjected to thermogravimetric analysis as shown in figure 28 with no significant weight loss on the TGA curve of the product, indicating that the product was not a stephanine methanol solvate crystal.
Example 16: preparation of stephanine methyl acetate solvate crystal
Adding 0.4g of amorphous stephanine powder raw material into 2mL of methyl acetate solvent to obtain a fourth mixed solution; and carrying out water bath ultrasonic treatment on the fourth mixed solution, keeping the power at 100W, keeping the temperature at 40 ℃, and closing the ultrasonic equipment after the solid in the fourth mixed solution is completely dissolved. And then cooling and crystallizing the fourth mixed solution at a low temperature of 4 ℃ for 2 days, precipitating crystals, filtering a crystallization system, and drying at 20 ℃ under normal pressure for 4 hours to obtain colorless stephanine methyl acetate solvate crystals. The stephanine methyl acetate solvate crystals have 0.432g and the molar yield is 93%. The bulk density of the stephanine methyl acetate solvate crystal is 1.05g/cm 3 Tap density of 1.08g/cm 3 。
Measured according to 2 theta-diffraction angle and I/I of stephanine methyl acetate solvate crystal 0 -an X-ray powder diffraction signature line expressed in relative intensity, measured using Cu-ka radiation:
TABLE 4X-ray powder diffraction characteristic lines for the crystals of the methyl Cepharanthine acetate solvate
The X-ray diffraction pattern of the stephanine methyl acetate solvate crystal is shown in figure 1d, the molecular ellipsoids of the minimum asymmetric units of the stephanine methyl acetate solvate crystal are shown in figure 12, and the unit cell stacking pattern of the stephanine methyl acetate solvate crystal is shown in figure 13. The TGA and DSC analysis results of the stephanine methyl acetate solvate crystal are shown in fig. 14, and the DSC curve has an endothermic characteristic peak at t= 83.84 ℃, which corresponds to the initial desolvation point of the stephanine methyl acetate solvate crystal, and the subsequent hot bench experiment can prove that the stephanine methyl acetate solvate crystal is melted while desolvation in the heating process; there are two obvious weightlessness steps on the TGA curve, the first section weightlessness is 8.9%, the second section weightlessness is 0.3%, and the result completely coincides with the theoretical weightlessness calculated by single crystal analysis. Stephanine methyl acetate solvate crystal with molecular formula of C 37 H 38 N 2 O 6 ·C 3 H 6 O 2 The crystal structure belongs to an orthorhombic system, P2 1 2 1 2 1 Space group, unit cell parameters
α=90°, β=90°, γ=90°, unit cell volume
The minimum asymmetric unit number Z=8 in the unit cell, and the minimum asymmetric unit contains 2 stephanine molecules and 2 methyl acetate solvent molecules, wherein the 2 stephanine molecules are in different conformations, and the 2 methyl acetate solvent moleculesIs in different constellations; the specific information diagram of the crystal structure of the stephanine methyl acetate solvate is shown in figure 24.
Example 17: preparation of stephanine methyl acetate solvate crystal
Adding 0.4g of stephanine crystal form I crystals into 2mL of methyl acetate solvent to obtain a fourth mixed solution; and carrying out water bath ultrasonic treatment on the fourth mixed solution, keeping the power at 100W, keeping the temperature at 40 ℃, and closing the ultrasonic equipment after the solid in the fourth mixed solution is completely dissolved. And then cooling and crystallizing the fourth mixed solution at the low temperature of minus 20 ℃ for 7 days, precipitating crystals, filtering a crystallization system, and drying for 4 hours at the normal pressure at the temperature of 20 ℃ to obtain colorless stephanine methyl acetate solvate crystals. The stephanine methyl acetate solvate crystals have 0.418g and the molar yield is 92%. The bulk density of the stephanine methyl acetate solvate crystal is 1.02g/cm 3 Tap density of 1.04g/cm 3 。
Example 18: preparation of stephanine methyl acetate solvate crystal
Adding 0.3g of stephanine acetonitrile solvate crystal into 2mL of methyl acetate solvent to obtain a fourth mixed solution; and (3) placing the fourth mixed solution in a water bath shaking table at 50 ℃ to completely dissolve the solid, then placing the fourth mixed solution in a low-temperature environment at-20 ℃ to cool and crystallize for 1 day, separating out crystals, filtering a crystallization system, and drying for 4 hours at 20 ℃ under normal pressure to obtain colorless stephanine methyl acetate solvate crystals. The stephanine methyl acetate solvate crystals have 0.283g and the molar yield is 90%. The bulk density of the stephanine methyl acetate solvate crystal is 0.98g/cm 3 Tap density of 1.01g/cm 3 。
Example 19: preparation of stephanine methyl acetate solvate crystal
Adding 0.3g of stephanine methanol solvate crystal into 2mL of methyl acetate solvent to obtain a fourth mixed solution; placing the fourth mixed solution in a 50 deg.C water bath shaker, oscillating until the solid is completely dissolved, cooling and crystallizing at-10deg.C for 3 days to separate out crystals, and collecting the crystal systemFiltering, and drying at 20deg.C under normal pressure for 4 hr to obtain colorless stephanine methyl acetate solvate crystal. The stephanine methyl acetate solvate crystals have 0.296g and the molar yield is 91%. The bulk density of the stephanine methyl acetate solvate crystals is 0.96g/cm 3 Tap density of 0.99g/cm 3 。
Example 20: preparation of stephanine methyl acetate solvate crystal
Adding 0.3g of stephanine acetonitrile solvate crystal into 2mL of methyl acetate solvent to obtain a fourth mixed solution; and carrying out water bath ultrasonic treatment on the fourth mixed solution, keeping the power at 100W, keeping the temperature at 40 ℃, and closing the ultrasonic equipment after the solid in the fourth mixed solution is completely dissolved. And then the fourth mixed solution is slowly evaporated and crystallized for 3 days at room temperature, crystals are separated out, the crystallization system is filtered, and the crystallization system is dried for 4 hours at 20 ℃ and normal pressure, thus obtaining colorless stephanine methyl acetate solvate crystals. The stephanine methyl acetate solvate crystals have 0.322g and the molar yield is 92%. The bulk density of the stephanine methyl acetate solvate crystal is 0.97g/cm 3 Tap density of 1.0g/cm 3 。
Example 21: preparation of stephanine methyl acetate solvate crystal
Adding 0.3g of stephanine methanol solvate crystal into 2mL of methyl acetate solvent to obtain a fourth mixed solution; and carrying out water bath ultrasonic treatment on the fourth mixed solution, keeping the power at 100W, keeping the temperature at 40 ℃, and closing the ultrasonic equipment after the solid in the fourth mixed solution is completely dissolved. And then the fourth mixed solution is slowly evaporated and crystallized for 7 days at room temperature, crystals are separated out, the crystallization system is filtered, and the crystallization system is dried for 4 hours at 20 ℃ and normal pressure, thus obtaining colorless stephanine methyl acetate solvate crystals. The stephanine methyl acetate solvate crystals have 0.289g and the molar yield is 90%. The bulk density of the stephanine methyl acetate solvate crystal is 0.95g/cm 3 Tap density of 0.99g/cm 3 。
Example 22: preparation of stephanine ethyl acetate solvate crystal
0.4g of amorphous stephania japonicaAdding the raw material of the plain powder into 2mL of ethyl acetate solvent to obtain a fifth mixed solution; and carrying out water bath ultrasonic treatment on the fifth mixed solution, keeping the power at 100W, keeping the temperature at 30 ℃, and closing the ultrasonic equipment after the solid in the fifth mixed solution is completely dissolved. And then placing the fifth mixed solution in a low-temperature environment at 4 ℃, cooling and crystallizing for 3 days, precipitating crystals, filtering a crystallization system, and drying for 4 hours at 20 ℃ and normal pressure to obtain colorless stephanine ethyl acetate solvate crystals. The stephanine ethyl acetate solvate crystals have 0.388g and a molar yield of 86%. The bulk density of the stephanine ethyl acetate solvate crystals is 0.74g/cm 3 Tap density of 0.77g/cm 3 。
Measured according to 2 theta-diffraction angle and I/I of stephanine ethyl acetate solvate crystal 0 -an X-ray powder diffraction signature line expressed in relative intensity, measured using Cu-ka radiation:
TABLE 5X-ray powder diffraction characteristic lines for Stephanine ethyl acetate solvate crystals
The X-ray diffraction pattern of the stephanine ethyl acetate solvate crystal is shown in figure 1e, the molecular ellipsoids of the minimum asymmetric units of the stephanine ethyl acetate solvate crystal are shown in figure 15, and the unit cell stacking pattern of the stephanine ethyl acetate solvate crystal is shown in figure 16. The TGA and DSC analysis results of the stephanine ethyl acetate solvate crystal are shown in fig. 17, and the DSC curve has an endothermic characteristic peak at t=79.87 ℃, which corresponds to the initial desolvation point of the stephanine ethyl acetate solvate crystal, and the subsequent hot bench experiment can prove that the stephanine ethyl acetate solvate crystal is melted while desolvation in the heating process; the TGA curve has obvious weight loss steps, the weight loss percentage is 11.42 percent, and the weight loss steps are consistent with the weight loss calculated by the analyzed monocrystal structure theory. Cepharanthine ethyl acetate solvate crystal with molecular formula of C 37 H 38 N 2 O 6 ·C 4 H 8 O 2 The crystal structure belongs to monoclinic system, P2 1 Space group, unit cell parameters
α=90°, β= 90.821 (6) °, γ=90°, unit cell volume +.>
The minimum asymmetric unit number Z=4 in the unit cell, wherein the minimum asymmetric unit contains 2 stephanine molecules and 2 ethyl acetate solvent molecules, wherein the 2 stephanine molecules are in different constellations, and the 2 ethyl acetate solvent molecules are in different constellations; the specific information diagram of the crystal structure of the ethyl acetate solvate of stephanine is shown in figure 25.
Example 23: preparation of stephanine ethyl acetate solvate crystal
Adding 0.4g of stephanine crystal form I crystals into 2mL of ethyl acetate solvent to obtain a fifth mixed solution; placing the fifth mixed solution into an ultrasonic cleaning instrument with the temperature of 75W and 40 ℃ for ultrasonic treatment, placing the clarified fifth mixed solution into a low-temperature environment with the temperature of-20 ℃ after the solid in the fifth mixed solution is completely dissolved, cooling and crystallizing for 7 days, separating out crystals, filtering a crystallization system, and drying for 4 hours at the temperature of 20 ℃ and the normal pressure to obtain colorless stephanine ethyl acetate solvate crystals. The stephanine ethyl acetate solvate crystals have 0.394g and the molar yield is 88%. The bulk density of the stephanine ethyl acetate solvate crystals is 0.72g/cm 3 Tap density of 0.74g/cm 3 。
Example 24: preparation of stephanine ethyl acetate solvate crystal
Adding 0.5g of stephanine acetonitrile solvate crystal into 2mL of ethyl acetate solvent to obtain a fifth mixed solution; and carrying out water bath ultrasonic treatment on the fifth mixed solution, keeping the power at 100W, keeping the temperature at 30 ℃, and closing the ultrasonic equipment after the solid in the fifth mixed solution is completely dissolved. Then placing the fifth mixed solution in a low temperature environment of 4deg.C, cooling and crystallizing for 7 days to separate out crystals, filtering the crystallization system, and drying at 20deg.C under normal pressure for 4 hr to obtain colorless herba Euphorbiae HumifusaeCrystalline ethyl acetate solvate of rattan. The stephanine ethyl acetate solvate crystals have 0.452g and the molar yield is 87%. The bulk density of the stephanine ethyl acetate solvate crystals is 0.68g/cm 3 Tap density of 0.71g/cm 3 。
Example 25: preparation of stephanine ethyl acetate solvate crystal
Adding 0.5g of stephanine acetonitrile solvate crystal into 2mL of ethyl acetate solvent to obtain a fifth mixed solution; placing the fifth mixed solution in 75W ultrasonic cleaner at 35 ℃, after the solid in the fifth mixed solution is completely dissolved by ultrasonic, placing the clarified fifth mixed solution in a low-temperature environment at-20 ℃, cooling and crystallizing for 3 days, precipitating crystals, filtering a crystallization system, and drying for 4 hours at 20 ℃ and normal pressure to obtain colorless stephanine ethyl acetate solvate crystals. The stephanine ethyl acetate solvate crystals have 0.469g and a molar yield of 85%. The bulk density of the stephanine ethyl acetate solvate crystals is 0.69g/cm 3 Tap density of 0.72g/cm 3 。
Example 26: preparation of stephanine ethyl acetate solvate crystal
Adding 0.5g of stephanine methyl acetate solvate crystal into 2mL of ethyl acetate solvent to obtain a fifth mixed solution; and (3) placing the fifth mixed solution in a water bath shaking table at 50 ℃ to completely dissolve solids in the fifth mixed solution, placing the clarified fifth mixed solution in a low-temperature environment at 4 ℃, cooling and crystallizing for 7 days, separating out crystals, filtering a crystallization system, and drying for 4 hours at 20 ℃ and normal pressure to obtain colorless stephanine ethyl acetate solvate crystals. The stephanine ethyl acetate solvate crystals had 0.443g and a molar yield of 86%. The bulk density of the stephanine ethyl acetate solvate crystals is 0.67g/cm 3 Tap density of 0.69g/cm 3 。
Example 27: preparation of stephanine ethyl acetate solvate crystal
Adding 0.5g of stephanine methyl acetate solvate crystal into 2mL of ethyl acetate solvent to obtain a fifth mixed solution; shaking the fifth mixed solution in a water bath at 50deg.CAnd (3) oscillating in the bed until the solid in the fifth mixed solution is completely dissolved, slowly evaporating and crystallizing the clarified fifth mixed solution at room temperature for 7 days to separate out crystals, filtering a crystallization system, and drying at 20 ℃ and normal pressure for 4 hours to obtain colorless stephanine ethyl acetate solvate crystals. The stephanine ethyl acetate solvate crystals have 0.453g and 88% molar yield. The bulk density of the stephanine ethyl acetate solvate crystals is 0.70g/cm 3 Tap density of 0.72g/cm 3 。
Example 28: preparation of stephanine ethyl acetate solvate crystal
Adding 0.4g of stephanine methanol solvate crystal into 2mL of ethyl acetate solvent to obtain a fifth mixed solution; and (3) placing the fifth mixed solution in a water bath shaking table at 50 ℃ to completely dissolve solids in the fifth mixed solution, placing the clarified fifth mixed solution in a low-temperature environment at 4 ℃, cooling and crystallizing for 4 days, separating out crystals, filtering a crystallization system, and drying for 4 hours at 20 ℃ and normal pressure to obtain colorless stephanine ethyl acetate solvate crystals. The stephanine ethyl acetate solvate crystals have 0.398g and a molar yield of 85%. The bulk density of the stephanine ethyl acetate solvate crystals is 0.71g/cm 3 Tap density of 0.73g/cm 3 。
Example 29: preparation of stephanine ethyl acetate solvate crystal
Adding 0.4g of stephanine methanol solvate crystal into 2mL of ethyl acetate solvent to obtain a fifth mixed solution; and carrying out water bath ultrasonic treatment on the fifth mixed solution, keeping the power at 100W, keeping the temperature at 30 ℃, and closing the ultrasonic equipment after the solid in the fifth mixed solution is completely dissolved. And then the fifth mixed solution is slowly evaporated and crystallized for 7 days at room temperature, crystals are separated out, the crystallization system is filtered, and the crystallization system is dried for 4 hours at 20 ℃ and normal pressure, thus obtaining colorless stephanine ethyl acetate solvate crystals. The stephanine ethyl acetate solvate crystals had 0.404g and a molar yield of 87%. The bulk density of the stephanine ethyl acetate solvate crystals is 0.68g/cm 3 Tap density of 0.71g/cm 3 。
Example 30: preparation of stephanine butyl acetate solvate crystal
Adding 0.4g of amorphous stephanine powder raw material into 2mL of butyl acetate solvent to obtain a sixth mixed solution; and carrying out water bath ultrasonic treatment on the sixth mixed solution, keeping the power at 100W, keeping the temperature at 35 ℃, and closing the ultrasonic equipment after the solid in the sixth mixed solution is completely dissolved. And then placing the sixth mixed solution in a low-temperature environment at 4 ℃, cooling and crystallizing for 6 days, precipitating crystals, filtering a crystallization system, and drying for 4 hours at 20 ℃ and normal pressure to obtain colorless stephanine butyl acetate solvate crystals. The stephanine butyl acetate solvate crystals have 0.394g and the molar yield is 90%. The bulk density of the stephanine butyl acetate solvate crystal is 0.86g/cm 3 Tap density of 0.90g/cm 3 。
Measured according to 2 theta-diffraction angle and I/I of stephanine butyl acetate solvate crystal 0 -an X-ray powder diffraction signature line expressed in relative intensity, measured using Cu-ka radiation:
TABLE 6X-ray powder diffraction characteristic lines for crystalline Cepharanthine butyl acetate solvate
The X-ray diffraction diagram of the stephanine butyl acetate solvate crystal is shown in figure 1f, the molecular ellipsoids of the minimum asymmetric units of the stephanine butyl acetate solvate crystal are shown in figure 18, and the unit cell stacking diagram of the stephanine butyl acetate solvate crystal is shown in figure 19. The TGA and DSC analysis results of the stephanine butyl acetate solvate crystal are shown in fig. 20, wherein the DSC curve has an endothermic characteristic peak at t= 111.08 ℃, corresponding to the initial desolvation point of the stephanine butyl acetate solvate crystal, and has an exothermic characteristic peak at t= 331.92 ℃, corresponding to the decomposition point of the stephanine butyl acetate solvate crystal; the TGA curve has obvious two steps of weightlessness, wherein the first step of weightlessness is 2.724%, and the second step of weightlessness is 6.028%, which are consistent with the theoretical calculation of the resolved single crystal. Cepharanthine butyl acetate solvent A compound crystal with a molecular formula of 2C 37 H 38 N 2 O 6 ·C 6 H 12 O 2 The crystal structure belongs to an orthorhombic system, P2 1 2 1 2 1 Space group, unit cell parameters
α=90°, β=90°, γ=90°, unit cell volume
The minimum asymmetric unit number Z=4 in the unit cell, and the minimum asymmetric unit contains 2 stephanine molecules and 1 butyl acetate solvent molecule, wherein 2 stephanine molecules are in different conformations; the specific information diagram of the crystal structure of the stephanine butyl acetate solvate is shown in figure 26.
Example 31: preparation of stephanine butyl acetate solvate crystal
Adding 0.4g of stephanine crystal form I crystals into 2mL of butyl acetate solvent to obtain a sixth mixed solution; placing the sixth mixed solution into an ultrasonic cleaning instrument with the temperature of 75W and 35 ℃ for ultrasonic treatment, placing the clarified sixth mixed solution into a low-temperature environment with the temperature of-20 ℃ after the solid in the sixth mixed solution is completely dissolved, cooling and crystallizing for 6 days, precipitating crystals, filtering a crystallization system, and drying for 4 hours at the temperature of 20 ℃ and the normal pressure to obtain colorless stephanine butyl acetate solvate crystals. The stephanine butyl acetate solvate crystals have 0.398g and the molar yield is 92%. The bulk density of the stephanine butyl acetate solvate crystal is 0.85g/cm 3 Tap density of 0.89g/cm 3 。
Example 32: preparation of stephanine butyl acetate solvate crystal
Adding 0.5g of stephanine acetonitrile solvate crystal into 2mL of butyl acetate solvent to obtain a sixth mixed solution; and carrying out water bath ultrasonic treatment on the sixth mixed solution, keeping the power at 100W, keeping the temperature at 30 ℃, and closing the ultrasonic equipment after the solid in the sixth mixed solution is completely dissolved. Then the sixth mixed solution is placed in a low temperature environment of 4 ℃ for cooling and crystallization for 7 days, and crystals are separated out, and thenFiltering the crystallization system, and drying for 4 hours at 20 ℃ and normal pressure to obtain colorless stephanine butyl acetate solvate crystals. The stephanine butyl acetate solvate crystals had 0.471g and a molar yield of 91%. The bulk density of the stephanine butyl acetate solvate crystal is 0.88g/cm 3 Tap density of 0.92g/cm 3 。
Example 33: preparation of stephanine butyl acetate solvate crystal
Adding 0.4g of stephanine methanol solvate crystal into 2mL of butyl acetate solvent to obtain a sixth mixed solution; oscillating the sixth mixed solution in a water bath shaking table at 50 ℃ until the solid in the sixth mixed solution is completely dissolved, placing the clarified sixth mixed solution in a low-temperature environment at 4 ℃, cooling and crystallizing for 3 days, precipitating crystals, filtering a crystallization system, and drying for 4 hours at 20 ℃ and normal pressure to obtain colorless stephanine butyl acetate solvate crystals. The stephanine butyl acetate solvate crystals had 0.39g and a molar yield of 89%. Bulk density of the Cepharanthine butyl acetate solvate crystals was 0.83g/cm 3 Tap density of 0.87g/cm 3 。
Example 34: preparation of stephanine butyl acetate solvate crystal
Adding 0.5g of stephanine acetonitrile solvate crystal into 2mL of butyl acetate solvent to obtain a sixth mixed solution; and carrying out water bath ultrasonic treatment on the sixth mixed solution, keeping the power at 100W, keeping the temperature at 30 ℃, and closing the ultrasonic equipment after the solid in the sixth mixed solution is completely dissolved. And then placing the sixth mixed solution in a low-temperature environment of-20 ℃, cooling and crystallizing for 3 days, precipitating crystals, filtering a crystallization system, and drying for 4 hours at 20 ℃ and normal pressure to obtain colorless stephanine butyl acetate solvate crystals. The stephanine butyl acetate solvate crystals have 0.452g and the molar yield is 88%. The bulk density of the stephanine butyl acetate solvate crystal is 0.76g/cm 3 Tap density of 0.82g/cm 3 。
Example 35: preparation of stephanine butyl acetate solvate crystal
Crystalline methyl stephanine acetate solvate in 0.5gAdding the mixture into 2mL of butyl acetate solvent to obtain a sixth mixed solution; oscillating the sixth mixed solution in a water bath shaking table at 50 ℃ until the solid in the sixth mixed solution is completely dissolved, placing the clarified sixth mixed solution in a low-temperature environment at 4 ℃, cooling and crystallizing for 7 days, separating out crystals, filtering a crystallization system, and drying for 4 hours at 20 ℃ and normal pressure to obtain colorless stephanine butyl acetate solvate crystals. The obtained stephanine butyl acetate solvate has 0.46g and the molar yield is 90%. The bulk density of the stephanine butyl acetate solvate crystal is 0.78g/cm 3 Tap density of 0.86g/cm 3 。
Example 36: preparation of stephanine butyl acetate solvate crystal
Adding 0.4g of stephanine methanol solvate crystal into 2mL of ethyl acetate solvent to obtain a sixth mixed solution; and carrying out water bath ultrasonic treatment on the sixth mixed solution, keeping the power at 100W, keeping the temperature at 30 ℃, and closing the ultrasonic equipment after the solid in the sixth mixed solution is completely dissolved. And then the sixth mixed solution is placed at normal temperature to slowly evaporate and crystallize for 7 days, crystals are separated out, the crystallization system is filtered, and the crystallization system is dried for 4 hours at 20 ℃ and normal pressure, thus obtaining colorless stephanine butyl acetate solvate crystals. The stephanine butyl acetate solvate crystals had 0.39g and a molar yield of 89%. The bulk density of the stephanine butyl acetate solvate crystal is 0.80g/cm 3 Tap density of 0.88g/cm 3 。
TABLE 7 hygroscopicity comparison of Stephanine Crystal and Stephanine amorphous raw Material at 40℃
As can be seen from table 7, the hygroscopicity of the stephanine crystal form I crystals (prepared in example 1) and the 5 stephanine solvate crystals (prepared in example 8, example 11, example 16, example 22 and example 30 respectively) of the present invention is far lower than that of stephanine amorphous powder, indicating that the stability of the stephanine crystals provided in the present invention is greatly improved compared with that of the amorphous stephanine powder.
The invention provides stephanine crystal and the thought and method of preparing the same, and the method and the way of realizing the technical scheme are a plurality of methods, the above is only the preferred embodiment of the invention, it should be pointed out that, for the person skilled in the art, a plurality of improvements and modifications can be made without departing from the principle of the invention, and the improvements and modifications should be regarded as the protection scope of the invention. The components not explicitly described in this embodiment can be implemented by using the prior art.
Claims (25)
1. The stephanine crystal is characterized in that the stephanine crystal is any one of stephanine acetonitrile solvate crystal, stephanine methanol solvate crystal, stephanine methyl acetate solvate crystal, stephanine ethyl acetate solvate crystal, stephanine butyl acetate solvate crystal and stephanine crystal form I crystal;
the molecular formula of the stephanine acetonitrile solvate crystal is C 37 H 38 N 2 O 6 ·CH 3 CN, the crystal structure of which belongs to an orthorhombic system, P2 1 2 1 2 1 Space group, unit cell parameters are
α=90°, β=90°, γ=90°, unit cell volume +.>
The minimum asymmetric unit number Z=4 in the unit cell, and the minimum asymmetric unit contains 1 stephanine molecule and 1 acetonitrile solvent molecule; with the following angle of 2-diffraction and I/I measured after grinding 0 -an X-ray powder diffraction signature line expressed in relative intensity, measured using Cu-ka radiation:
the molecular formula of the stephanine methanol solvate crystal is C 37 H 38 N 2 O 6 ·0.5CH 3 OH, the crystal structure belongs to a triclinic system, P3 2 Space group, unit cell parameters
α=90°, β=90°, γ=120°, unit cell volume +.>
The minimum asymmetric unit number Z=3 in the unit cell, and the minimum asymmetric unit contains 1 stephanine molecule and 0.5 methanol solvent molecule; with the following angle of 2-diffraction and I/I measured after grinding 0 -an X-ray powder diffraction signature line expressed in relative intensity, measured using Cu-ka radiation:
the molecular formula of the stephanine methyl acetate solvate crystal is C 37 H 38 N 2 O 6 ·C 3 H 6 O 2 The crystal structure belongs to an orthorhombic system, P2 1 2 1 2 1 Space group, unit cell parameters
α=90°, β=90°, γ=90°, unit cell volume +.>
The minimum asymmetric unit number Z=8 in the unit cell, and the minimum asymmetric unit contains 2 stephanine molecules and 2 methyl acetate solvent molecules, wherein the 2 stephanine molecules are in different conformations, and the 2 methyl acetate solvent molecules are in different conformations; the following post-grinding measurements were carried outIn terms of 2-theta diffraction angle and I/I of quantity 0 -an X-ray powder diffraction signature line expressed in relative intensity, measured using Cu-ka radiation: / >
The molecular formula of the stephanine ethyl acetate solvate crystal is C 37 H 38 N 2 O 6 ·C 4 H 8 O 2 The crystal structure belongs to monoclinic system, P2 1 Space group, unit cell parameters
α=90°, β= 90.821 (6) °, γ=90°, unit cell volume +.>
The minimum asymmetric unit number Z=4 in the unit cell, wherein the minimum asymmetric unit contains 2 stephanine molecules and 2 ethyl acetate solvent molecules, wherein the 2 stephanine molecules are in different constellations, and the 2 ethyl acetate solvent molecules are in different constellations; with the following angle of 2-diffraction and I/I measured after grinding 0 -an X-ray powder diffraction signature line expressed in relative intensity, measured using Cu-ka radiation:
the molecular formula of the stephanine butyl acetate solvate crystal is 2C 37 H 38 N 2 O 6 ·C 6 H 12 O 2 The crystal structure belongs to an orthorhombic system, P2 1 2 1 2 1 Space group, unit cell parameters
α=90°, β=90°, γ=90°, unit cell volume +.>
The minimum asymmetric unit number Z=4 in the unit cell, and the minimum asymmetric unit contains 2 stephanine molecules and 1 butyl acetate solvent molecule, wherein 2 stephanine molecules are in different conformations; with the following angle of 2-diffraction and I/I measured after grinding 0 -an X-ray powder diffraction signature line expressed in relative intensity, measured using Cu-ka radiation: / >
The molecular formula of the stephanine crystal form I crystal is C 37 H 38 N 2 O 6 The crystal structure belongs to a triclinic system, P3 1 Space group, unit cell parameters are
α=90°, β=90°, γ=120.00°, unit cell volume +.>
The minimum asymmetric unit number Z=3 in the unit cell, and the minimum asymmetric unit contains 1 stephanin molecule; with the following angle of 2-diffraction and I/I measured after grinding 0 -an X-ray powder diffraction signature line expressed in relative intensity, measured using Cu-ka radiation:
the stephanine acetonitrile solvate crystal, stephanine methanol solvate crystal, stephanine methyl acetate solvate crystal, stephanine ethyl acetate solvate crystal, stephanine butyl acetate solvate crystal and stephanine crystal form I crystal are crystal powder.
2. The stephanine crystals of claim 1, wherein the stephanine acetonitrile solvate crystals have a bulk density of crystalline powder greater than 0.58g/cm 3 Preferably greater than 0.64g/cm 3 More preferably greater than 0.67g/cm 3 。
3. The stephanine crystal according to claim 1, wherein the stephanine acetonitrile solvate crystal has a tap density of more than 0.60g/cm 3 Preferably greater than 0.65g/cm 3 More preferably greater than 0.70g/cm 3 。
4. The stephanine crystals of claim 1, wherein the stephanine methanol solvate crystals have a bulk density of crystalline powder greater than 0.82g/cm 3 Preferably greater than 0.86g/cm 3 More preferably greater than 0.92g/cm 3 。
5. The stephanine crystal according to claim 1, wherein the stephanine methanol solvate crystal has a tap density of more than 0.85g/cm 3 Preferably greater than 0.94g/cm 3 More preferably greater than 1.0g/cm 3 。
6. The stephanine crystals of claim 1, wherein the stephanine methyl acetate solvate crystals have a bulk density of the crystalline powder of greater than 0.90g/cm 3 Preferably greater than 0.94g/cm 3 More preferably greater than 1.0g/cm 3 。
7. The stephanine crystal according to claim 1, wherein the stephanine methyl acetate solvate crystalBulk, tap density of crystalline powder is greater than 0.93g/cm 3 Preferably greater than 0.98g/cm 3 More preferably greater than 1.05g/cm 3 。
8. The stephanine crystals of claim 1, wherein the stephanine ethyl acetate solvate crystals have a bulk density of crystalline powder greater than 0.56g/cm 3 Preferably greater than 0.66g/cm 3 More preferably greater than 0.71g/cm 3 。
9. The stephanine crystals of claim 1, wherein the stephanine ethyl acetate solvate crystals have a tap density of the crystalline powder of greater than 0.59g/cm 3 Preferably greater than 0.67g/cm 3 More preferably greater than 0.73g/cm 3 。
10. The stephanine crystals of claim 1, wherein the stephanine butyl acetate solvate crystals have a bulk density of crystalline powder greater than 0.64g/cm 3 Preferably greater than 0.72g/cm 3 More preferably greater than 0.84g/cm 3 。
11. The stephanine crystal according to claim 1, wherein the stephanine butyl acetate solvate crystal has a tap density of more than 0.69g/cm 3 Preferably greater than 0.78g/cm 3 More preferably greater than 0.88g/cm 3 。
12. The stephanine crystals of claim 1, wherein the stephanine crystals of form I have a bulk density of the crystalline powder of greater than 0.80g/cm 3 Preferably greater than 0.86g/cm 3 More preferably greater than 0.95g/cm 3 。
13. The stephanine crystal according to claim 1, wherein the stephanine crystal form I crystal, crystal powder The tap density of the powder is more than 0.85g/cm 3 Preferably greater than 0.92g/cm 3 More preferably greater than 1.0g/cm 3 。
14. The process for producing a cepharanthine crystal according to claim 1, wherein the first raw material is mixed with a first solvent to dissolve the first raw material, thereby obtaining a first mixed solution; evaporating and crystallizing the first mixed solution at room temperature to separate out crystals, filtering and drying a crystallization system to obtain stephanine crystal form I crystals;
the first raw material is any one of stephanine, stephanine acetonitrile solvate crystal, stephanine methanol solvate crystal and stephanine ethyl acetate solvate crystal; the first solvent is any one or the combination of a plurality of dimethyl acetamide, N-methyl formamide and isopropanol.
15. The method according to claim 14, wherein the first raw material is any one of amorphous stephanine, stephanine acetonitrile solvate crystals, stephanine methanol solvate crystals and stephanine ethyl acetate solvate crystals; the mass volume ratio of the first raw material to the first solvent is 0.1-0.4 g:2mL, preferably 0.2 to 0.3g:2mL, more preferably 0.2:2mL or 0.3g:2mL; the evaporating crystallization is carried out for 2-8 days, preferably 3-7 days.
16. The method for preparing stephanine crystals as claimed in claim 1, wherein the second raw material is dissolved in a second solvent to obtain a second mixed solution; performing suspension crystal transformation or ultrasonic cooling crystallization on the second mixed solution to separate out crystals, and filtering and drying a crystallization system to obtain stephanine acetonitrile solvate crystals;
the second raw material is stephanine or stephanine crystal form I crystal; the second solvent is acetonitrile or acetonitrile and water with the volume ratio of 3: 1-3.
17. The method of claim 16, wherein the second material is amorphous stephanine or stephanine form I crystals; the second solvent is acetonitrile or acetonitrile and water with the volume ratio of 3:2, a mixture of two or more of the above-mentioned materials; the mass volume ratio of the second raw material to the second solvent is 0.1-0.4 g:2 to 5mL, preferably 0.2 to 0.3g: 2-5 mL.
18. The method for preparing stephanine crystals as claimed in claim 1, wherein the third raw material is dissolved in absolute methanol to obtain a third mixed solution; cooling crystallization or suspension crystal transformation is carried out on the third mixed solution, crystals are separated out, and the crystallization system is filtered and dried to obtain stephanine methanol solvate crystals;
The third raw material is any one of stephanine crystal form I crystal, stephanine acetonitrile solvate crystal, stephanine methyl acetate solvate crystal, stephanine ethyl acetate solvate crystal and stephanine butyl acetate solvate crystal.
19. The preparation method of claim 18, wherein the third raw material is any one of stephanine crystal form I crystals, stephanine acetonitrile solvate crystals, stephanine methyl acetate solvate crystals, stephanine ethyl acetate solvate crystals and stephanine butyl acetate solvate crystals; the mass volume ratio of the third raw material to the anhydrous methanol is 0.05-0.25 g:1 to 2mL, preferably 0.1 to 0.2g: 1-2 mL.
20. The method for preparing stephanine crystals as claimed in claim 1, wherein the fourth raw material is dissolved in methyl acetate to obtain a fourth mixed solution; cooling crystallization or evaporation crystallization is carried out on the fourth mixed solution, crystals are separated out, and the crystallization system is filtered and dried, so that the stephanine methyl acetate solvate crystals are obtained;
the fourth raw material is any one of stephanine, stephanine crystal form I crystals, stephanine acetonitrile solvate crystals and stephanine methanol solvate crystals.
21. The method according to claim 20, wherein the fourth raw material is any one of amorphous stephanine, stephanine crystal form I crystals, stephanine acetonitrile solvate crystals and stephanine methanol solvate crystals; the mass volume ratio of the fourth raw material to the methyl acetate is 0.2-0.6 g:2mL, preferably 0.3 to 0.4g:2mL, more preferably 0.3:2mL or 0.4g:2mL.
22. The method for preparing stephanine crystals as claimed in claim 1, wherein the fifth raw material is dissolved in ethyl acetate to obtain a fifth mixed solution; cooling crystallization or evaporative crystallization is carried out on the fifth mixed solution, crystals are separated out, and the crystallization system is filtered and dried to obtain stephanine ethyl acetate solvate crystals;
the fifth raw material is any one of stephanine, stephanine crystal form I crystal, stephanine acetonitrile solvate crystal, stephanine methanol solvate crystal and stephanine methyl acetate solvate crystal.
23. The method according to claim 22, wherein the fifth raw material is any one of amorphous stephanine, stephanine crystal form I crystals, stephanine acetonitrile solvate crystals, stephanine methanol solvate crystals and stephanine methyl acetate solvate crystals; the mass volume ratio of the fifth raw material to the ethyl acetate is 0.2-0.7 g:2mL, preferably 0.4 to 0.5g:2mL, more preferably 0.4g:2mL or 0.5g:2mL.
24. The process for producing a cepharanthine crystal according to claim 1, wherein a sixth raw material is dissolved in butyl acetate to obtain a sixth mixed solution; cooling crystallization or evaporative crystallization is carried out on the sixth mixed solution, crystals are separated out, and the crystallization system is filtered and dried to obtain stephanine butyl acetate solvate crystals;
the sixth raw material is any one of stephanine, stephanine crystal form I crystal, stephanine acetonitrile solvate crystal, stephanine methanol solvate crystal and stephanine methyl acetate solvate crystal.
25. The method according to claim 24, wherein the sixth raw material is any one of amorphous stephanine, stephanine crystal form I crystals, stephanine acetonitrile solvate crystals, stephanine methanol solvate crystals and stephanine methyl acetate solvate crystals; the mass volume ratio of the sixth raw material to the butyl acetate is 0.2-0.8 g:2mL, preferably 0.4 to 0.5g:2mL, more preferably 0.4g:2mL or 0.5g:2mL.
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| US6123943A (en) * | 1997-12-22 | 2000-09-26 | Kaken Shoyaku Co., Ltd. | NF-KB activity inhibitor |
| CN106380472A (en) * | 2016-08-30 | 2017-02-08 | 云南中医学院 | Brominated crebanine compound and preparation method and application thereof |
| CN111228330A (en) * | 2020-03-13 | 2020-06-05 | 广州暨南生物医药研究开发基地有限公司 | Stephanine-containing anti-inflammatory pharmaceutical composition and preparation method thereof |
| CN114989185A (en) * | 2022-07-06 | 2022-09-02 | 四川健腾药业有限公司 | Extraction and preparation method of cepharanthine |
| CN115197235A (en) * | 2022-07-15 | 2022-10-18 | 四川健腾药业有限公司 | Method for preparing cepharanthine by enzymolysis and extraction |
| CN115260210A (en) * | 2022-08-19 | 2022-11-01 | 四川健腾药业有限公司 | Cepharanthine crystal form and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US6123943A (en) * | 1997-12-22 | 2000-09-26 | Kaken Shoyaku Co., Ltd. | NF-KB activity inhibitor |
| CN106380472A (en) * | 2016-08-30 | 2017-02-08 | 云南中医学院 | Brominated crebanine compound and preparation method and application thereof |
| CN111228330A (en) * | 2020-03-13 | 2020-06-05 | 广州暨南生物医药研究开发基地有限公司 | Stephanine-containing anti-inflammatory pharmaceutical composition and preparation method thereof |
| CN114989185A (en) * | 2022-07-06 | 2022-09-02 | 四川健腾药业有限公司 | Extraction and preparation method of cepharanthine |
| CN115197235A (en) * | 2022-07-15 | 2022-10-18 | 四川健腾药业有限公司 | Method for preparing cepharanthine by enzymolysis and extraction |
| CN115260210A (en) * | 2022-08-19 | 2022-11-01 | 四川健腾药业有限公司 | Cepharanthine crystal form and preparation method thereof |
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