CN111499651A - Dihydroartemisinin Form A crystal Form and preparation method thereof - Google Patents
Dihydroartemisinin Form A crystal Form and preparation method thereof Download PDFInfo
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- 239000013078 crystal Substances 0.000 title claims abstract description 70
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- BJDCWCLMFKKGEE-HVDUHBCDSA-N dihydroartemisinin group Chemical group C[C@@]12OO[C@]34[C@@H](CC1)[C@@H](CC[C@H]3[C@H](C(O[C@@H]4O2)O)C)C BJDCWCLMFKKGEE-HVDUHBCDSA-N 0.000 title claims description 36
- 229960002521 artenimol Drugs 0.000 claims abstract description 33
- BJDCWCLMFKKGEE-ISOSDAIHSA-N artenimol Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-ISOSDAIHSA-N 0.000 claims abstract description 33
- 229930016266 dihydroartemisinin Natural products 0.000 claims abstract description 33
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 18
- 239000002904 solvent Substances 0.000 claims description 17
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
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- 238000001228 spectrum Methods 0.000 claims description 10
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- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 4
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 4
- 229940057838 polyethylene glycol 4000 Drugs 0.000 claims description 4
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- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 229920003063 hydroxymethyl cellulose Polymers 0.000 claims description 3
- 229940031574 hydroxymethyl cellulose Drugs 0.000 claims description 3
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- 229940069328 povidone Drugs 0.000 claims description 3
- 238000001757 thermogravimetry curve Methods 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 2
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 abstract description 8
- 238000012360 testing method Methods 0.000 abstract description 7
- 238000000227 grinding Methods 0.000 abstract description 6
- 238000013112 stability test Methods 0.000 abstract description 6
- 238000012512 characterization method Methods 0.000 abstract description 5
- 238000011156 evaluation Methods 0.000 abstract description 4
- 229910017488 Cu K Inorganic materials 0.000 abstract description 2
- 229910017541 Cu-K Inorganic materials 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 description 20
- 238000001514 detection method Methods 0.000 description 15
- 239000000843 powder Substances 0.000 description 13
- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical class C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 description 12
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- 239000010949 copper Substances 0.000 description 3
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- 240000000011 Artemisia annua Species 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
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- 239000003430 antimalarial agent Substances 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/20—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/18—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The crystal Form of the dihydroartemisinin is obtained by measuring with Cu-K α rays, and an X-ray powder diffraction spectrogram is shown in figure 1. the dihydroartemisinin is crystallized by adopting a high-molecular template, the preparation process is simple, the purity of the obtained crystal Form is high, and the dihydroartemisinin crystal obtained by the crystal Form A is determined by characterization of XRD, DSC, TGA, DVS and FT-IR and evaluation of crystal Form stability, and the result of stability test and grinding test shows that the crystal has good stability to light, moisture and heat.
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a dihydroartemisinin Form A crystal Form and a preparation method thereof.
Background
Dihydro sweet wormwood herbThe extract is extracted from Herba Artemisiae Annuae (Herba Artemisiae Annuae)]The chemical name of the extracted and separated antimalarial effective monomer, namely the artemisinin derivative is as follows: (3R,5aS,6R,8aS,9R,12S,12aR) -octahydro-3, 6, 9-trimethyl-3, 12-oxo-12H-pyrano [4,3-j ]]-1, 2-benzodiazepine-10 (3H) -ol with molecular formula C15H24O5The molecular weight is 284.35, and the structural formula is shown in formula I.
With the continuous and intensive research on dihydroartemisinin, the biological activity of dihydroartemisinin is found to be diversified. The research shows that the double artemisinin not only has exact antimalarial activity, but also has various pharmacological activities of resisting tumor, inflammation, fibrosis, arrhythmia, fungi, pregnancy, arrhythmia, parasite and radiotherapy sensitization, immunoregulation, overcoming multidrug resistance, or treating diabetes, or treating tuberculosis, etc.
Drug polymorphism is a common phenomenon in drug development and is an important factor affecting drug quality. The crystal form of a drug directly affects the quality of a pharmaceutical formulation of the drug, the absorption behavior in the human body, and ultimately the therapeutic effect and the benefit ratio of side effects produced by the formulation in the human body. With the continuous development of new indications of dihydroartemisinin, the development of the researches on the crystal form, the physicochemical property and the like of dihydroartemisinin has great significance for evaluating the drug effect, the quality and the medication safety of dihydroartemisinin. However, no report is found in the current research on the crystal form of dihydroartemisinin.
Disclosure of Invention
In view of the above, the present invention aims to research, discover and provide a crystal form of dihydroartemisinin and a preparation method thereof by a crystallography method.
The invention researches, discovers and provides a Form A crystal Form of dihydroartemisinin crystal Form by a crystallography method.
The present invention employs internationally recognized X-ray powder diffraction (XRPD) to study and characterize the crystalline form of dihydroartemisinin. The measurement conditions and methods: Cu/K-alpha1 (target), 40KV-40mA (Goldman)Voltage and current), i (max) 2244, 2 θ 5-50 (scan range), 0.005/0.06sec (scan speed),
the substantially pure Form A crystal Form provided by the invention has an X-ray powder diffraction pattern as shown in figure 1, and the X-ray powder diffraction pattern has characteristic peaks at 2 theta values of 7.6 +/-0.2 degrees, 9.2 +/-0.2 degrees, 11.1 +/-0.2 degrees, 12.3 +/-0.2 degrees, 13.1 +/-0.2 degrees, 15.2 +/-0.2 degrees, 16.7 +/-0.2 degrees, 17.4 +/-0.2 degrees and 18.7 +/-0.2 degrees. .
Further, the substantially pure Form a crystal Form provided by the invention has the X-ray powder diffraction spectrum characteristics shown in table 1.
Table 1: x-ray powder diffraction spectral characteristics
| 2θ | d-value | I/I0％ |
| 7.678 | 11.5042 | 52.6 |
| 9.242 | 9.5615 | 100.0 |
| 11.121 | 7.9492 | 84.1 |
| 12.321 | 7.1778 | 7.1 |
| 13.180 | 6.7119 | 1.9 |
| 15.262 | 5.8008 | 1.9 |
| 16.745 | 5.2899 | 0.9 |
| 17.402 | 5.0918 | 0.5 |
| 18.681 | 4.7459 | 5.5 |
| 19.201 | 4.6187 | 2.0 |
| 19.681 | 4.5070 | 4.5 |
| 20.824 | 4.2622 | 1.5 |
| 23.345 | 3.8073 | 3.5 |
| 26.544 | 3.3553 | 1.6 |
| 30.103 | 2.9661 | 2.1 |
| 31.344 | 2.8515 | 1.7 |
The invention also adopts a thermogravimetric analysis method to research and characterize the dihydroartemisinin Form A crystal Form. The detection method is high analytic sensitivity of 3.0, step temperature change: heating from 5.00 ℃ to 100.00 ℃ at a rate of 10.00 ℃/min, step temperature: heating to 165 ℃ at the speed of 10.00 ℃/min; control software, Thermal Advantage; analytical software, Universal Analysis.
The thermogravimetric analysis curve of the basically pure dihydroartemisinin Form A crystal Form provided by the invention is shown in figure 2, and the crystal Form has the following characteristics: the thermogravimetric analysis curve thereof has the weight loss of 0.07 percent when being heated to 100 ℃ and the decomposition temperature of 147 ℃. The dihydroartemisinin Form A crystal Form is anhydrous, namely does not contain crystal water.
The invention also adopts a differential scanning calorimetry to research and characterize the dihydroartemisinin Form A crystal Form. The detection method comprises the following steps of setting the equilibrium temperature to be 20 ℃, and raising the temperature gradient: the temperature was raised to 220 ℃ at a rate of 10 ℃/min.
The differential scanning calorimetry analysis curve of the basically pure dihydroartemisinin Form A crystal Form provided by the invention is shown in figure 3, and the crystal Form has the following characteristics: the differential scanning calorimetry analysis curve has no endothermic peak and has exothermic peak at 150 deg.C, which is caused by decomposition.
It is noted that for the X-ray powder diffraction patterns of the above-described crystalline forms, the characteristic peaks of the X-ray powder diffraction patterns may vary slightly between one machine and another and between one sample and another, and may differ in value by about 1 unit, or by about 0.8 unit, or by about 0.5 unit, or by about 0.3 unit, or by about 0.1 unit, and thus the values given are not to be considered absolute. Also the numerical values given in the differential scanning calorimetry diagrams of the above described forms cannot be considered absolute.
The crystalline forms may also be characterized by other analytical techniques well known in the art. Such as Fourier Infrared Spectroscopy (FT-IR) and dynamic moisture sorption (DVS).
The Fourier infrared spectrogram of the basically pure dihydroartemisinin Form A crystal Form provided by the invention is shown in figure 4, and the basically pure dihydroartemisinin Form A crystal Form has the following characteristics: the Fourier infrared spectrum has characteristic absorption peaks at wave numbers of 3373 +/-2, 2923 +/-2, 2852 +/-2, 1443 +/-2, 1377 +/-2, 1188 +/-2, 1176 +/-2, 1159 +/-2, 1134 +/-2, 1092 +/-2, 1061 +/-2, 1022 +/-2, 984 +/-2, 969 +/-2, 957 +/-2, 932 +/-2, 895 +/-2, 875 +/-2, 846 +/-2, 824 +/-2, 690 +/-2 and 657 +/-2 cm < -1 >.
The dynamic moisture adsorption curve of the basically pure dihydroartemisinin Form A crystal Form provided by the invention is shown in figure 5, and the basically pure dihydroartemisinin Form A crystal Form has the following characteristics: the dynamic moisture adsorption curve has a weight change of less than 0.1% in the humidity range of 0% RH to 80% RH, i.e. no moisture absorption.
The invention also provides a preparation method of the dihydroartemisinin Form A crystal Form, which has high purity and does not contain residual solvent.
The preparation method of the dihydroartemisinin Form A crystal Form provided by the invention is high-molecular template crystallization. The specific operation is that dihydroartemisinin is dissolved in organic solvent, then polymer material is added, and the solvent is recovered to obtain the dihydroartemisinin.
Preferably, the organic solvent is at least one of methanol, ethanol, trifluoroethanol, acetone, butanone, ethyl acetate, tetrahydrofuran, 1, 4-dioxane, dichloromethane, or chloroform.
Preferably, the polymer material is at least one of sodium hydroxymethyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol 4000, povidone (polyvinylpyrrolidone), copovidone, crospovidone, polyethylene oxide (polyethylene oxide), and polyvinyl chloride.
Further, preferably, the mass volume ratio of the polymer material to the organic solvent is 1:10 to 1:100000 in g/ml.
Preferably, the temperature of the recovered solvent is less than or equal to 50 ℃, and the drying weight loss of the obtained dihydrosouthernwood Form A crystal Form is less than or equal to 3%. In some embodiments, the solvent is recovered under vacuum at 40 ℃. In some embodiments, the solvent is recovered under vacuum at 45 ℃. In some embodiments, the solvent is recovered under vacuum at 35 ℃.
The dihydro southernwood Form A crystal Form prepared by the preparation method has the advantages of crystal Form content of more than 99 percent, high purity, consistent X-ray powder diffraction spectrum characteristics and DCS characteristic spectrum, stable property and good stability to light, moisture and heat.
According to the technical scheme, the crystal Form of the dihydroartemisinin is an X-ray powder diffraction spectrogram obtained by measuring Cu-K α rays and shown in figure 1, the dihydroartemisinin is crystallized by adopting a high-molecular template, the preparation process is simple, the obtained crystal Form is high in purity, the dihydroartemisinin crystal is determined to be the dihydroartemisinin crystal obtained by the crystal Form A through characterization of XRD, DSC, TGA, DVS and FT-IR and evaluation of crystal Form stability, and the stability test and grinding test show that the crystal has good stability to light, moisture and heat.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below.
FIG. 1 shows an X-ray powder diffractogram of the crystalline Form A of dihydroartemisinin Form, obtained by irradiation with copper K α radiation, in which the ordinate represents the diffraction intensity in counts per second (cps) and the abscissa represents the diffraction angle 2 θ in degrees;
FIG. 2 shows a TGA analysis of the crystalline Form of dihydroartemisinin Form A; the ordinate is the weight retention percentage and the abscissa is the temperature in units of ℃;
FIG. 3 shows a Differential Scanning Calorimetry (DSC) plot of a crystalline Form A of dihydroartemisinin Form, with heat flow rate on the ordinate in calories/sec; the abscissa is temperature in units of;
FIG. 4 shows a Fourier infrared spectrum of a crystalline Form A of dihydroartemisinin Form;
FIG. 5 shows a DVS analysis of dihydroartemisinin Form A crystal Form;
FIG. 6 shows XRD contrast patterns of dihydroartemisinin Form A crystal Form under different stability conditions;
FIG. 7 shows DSC comparison spectra of dihydroartemisinin Form A crystal Form under different stability conditions;
figure 8 shows the XRD pattern of a ground 30 second sample of dihydroartemisinin Form a.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
For a further understanding of the invention, reference will now be made in detail to the following examples. In the examples described below, unless otherwise indicated, the test procedures described are generally carried out according to conventional conditions or conditions recommended by the manufacturer.
The main reagent and instrument used in the invention are as follows:
reagent: dihydroartemisinin, Kunzi group, Inc.; methanol, ethanol, trifluoroethanol, acetone, butanone, ethyl acetate, tetrahydrofuran, 1, 4-dioxane, dichloromethane, chloroform, chemical reagents of national medicine group limited; carboxymethyl starch sodium, ethyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol 4000, produced by lazhou expecting pharmaceutical industry limited; polyvinylpyrrolidone, copovidone, crospovidone, manufactured by BASF SE.
The instrument equipment comprises: x-ray powder diffractometer (D8), Bruker; temperature-changing thermal table XRD, Shanghai micrographs Instrument science and technology development Co., Ltd; differential thermal analysis scanner (Q200) TA; thermogravimetric analyzer (Q500) TA; fourier infrared spectrometer (Tensor27), Bruker; analytical balance (BT125D), sydows scientific instruments ltd; a constant temperature and humidity chamber (SHH-250SD), a perpetual instrument; high temperature oven (DHG-9053A), Shanghai sperm macro laboratory Equipment Co., Ltd.
Example 1: preparation of dihydroartemisinin Form A crystal Form
Adding 10g of artemisinin into a round-bottom flask containing 2000ml of methanol, stirring to dissolve, adding 0.2g of sodium hydroxymethyl cellulose, and stirring for 20 minutes; recovering solvent under vacuum reduced pressure at 40 deg.C to obtain white crystalline powder.
Example 2: preparation of dihydroartemisinin Form A crystal Form
Adding 10g of artemisinin into a round-bottom flask containing 2000ml of ethanol, stirring to dissolve, adding 2g of ethyl cellulose, and stirring for 20 minutes; recovering solvent under vacuum at 45 deg.C under reduced pressure to obtain white crystalline powder.
Example 3: preparation of dihydroartemisinin Form A crystal Form
Adding 20g of artemisinin into a round-bottom flask containing 2000ml of trifluoroethanol, stirring to dissolve, adding 20g of hydroxypropyl cellulose, and stirring for 20 minutes; recovering solvent under vacuum at 45 deg.C under reduced pressure to obtain white crystalline powder.
Example 4: preparation of dihydroartemisinin Form A crystal Form
Adding 15g of artemisinin into a round-bottom flask containing 2000ml of acetone, stirring to dissolve, adding 10g of hydroxypropyl methyl cellulose, and stirring for 20 minutes; recovering solvent under vacuum at 45 deg.C under reduced pressure to obtain white crystalline powder.
Example 5: preparation of dihydroartemisinin Form A crystal Form
Adding 15g of artemisinin into a round-bottom flask containing 2000ml of butanone, stirring to dissolve, adding 3g of polyethylene glycol 4000, and stirring for 20 minutes; recovering solvent under vacuum at 45 deg.C under reduced pressure to obtain white crystalline powder.
Example 6: preparation of dihydroartemisinin Form A crystal Form
Adding 15g of artemisinin into a round-bottom flask containing 2000ml of ethyl acetate, stirring to dissolve, adding 1g of povidone (polyvinylpyrrolidone), and stirring for 20 minutes; recovering solvent under vacuum at 35 deg.C under reduced pressure to obtain white crystalline powder.
Example 7: preparation of dihydroartemisinin Form A crystal Form
Adding 30g of artemisinin into a round-bottom flask containing 2000ml of tetrahydrofuran, stirring to dissolve, adding 0.02g of copovidone, and stirring for 20 minutes; recovering solvent under vacuum at 35 deg.C under reduced pressure to obtain white crystalline powder.
Example 8: preparation of dihydroartemisinin Form A crystal Form
Adding 20g of artemisinin into a round-bottom flask containing 2000ml of 1, 4-dioxane, stirring to dissolve, adding 0.02g of crospovidone, and stirring for 20 minutes; recovering solvent under vacuum at 35 deg.C under reduced pressure to obtain white crystalline powder.
Example 9: preparation of dihydroartemisinin Form A crystal Form
Adding 200g of artemisinin into a round-bottom flask containing 2000ml of dichloromethane, stirring to dissolve, adding 0.2g of polyethylene oxide (polyoxyethylene), and stirring for 20 minutes; recovering solvent under vacuum at 35 deg.C under reduced pressure to obtain white crystalline powder.
Example 10: preparation of dihydroartemisinin Form A crystal Form
Adding 40g of artemisinin into a round-bottom flask containing 2000ml of trichloromethane, stirring to dissolve, adding 12g of polyvinyl chloride, and stirring for 20 minutes; recovering solvent under vacuum at 35 deg.C under reduced pressure to obtain white crystalline powder.
Example 11: crystal form characterization test
The samples obtained in examples 1 to 10 were subjected to XRD, TGA, DSC, FT-IR and DVS tests under the following conditions:
x-ray powder diffractometer (XRD) detection: Cu/K-alpha1 (target), 40KV-200mA (working voltage and current), I (max) 2244, 2 theta 5-50 (scanning range),0.005/0.06sec (scan speed),
the amount of the detected sample is 4 mg; collecting software, namely Diffrac Plus XRD Commander; analytical software, MDI Jade, EVA.
The thermogravimetric analyzer (TGA) comprises a sample plate, a platinum crucible, a detection sample amount of 6mg, protective gas, nitrogen, a gas flow rate of 40m L/min, a detection method with high analytic sensitivity of 3.0, a step temperature change of heating from 5.00 ℃ to 100.00 ℃ at 10.00 ℃/min, a step temperature of heating to 165 ℃ at 10.00 ℃/min, control software, Thermal Advantage and Analysis software, Universal Analysis.
Differential Thermal analysis scanner (DSC) comprises a sample tray, an aluminum crucible (covered without holes), a detection sample amount of 3mg, protective gas, nitrogen, a gas flow rate of 40m L/min, control software, Thermal Advantage, analysis software, Universal analysis, wherein the detection method is a common method, the equilibrium temperature is 20 ℃, and the temperature rise gradient is that the temperature rises to 220 ℃ at the speed of 10 ℃/min.
Fourier Infrared Spectroscopy (FT-IR): detection method, ATR method; collection wavelength range of 600-4000cm-1(ii) a Scan time, 32 seconds; resolution, 4cm-1. Control software/analytical software, OPUS.
Dynamic moisture adsorption apparatus (DVS) comprises a sample plate, a platinum crucible, a detection sample amount of 6mg, protective gas, nitrogen, a gas flow rate of 10m L/min, a detection method, a balance temperature of 25 ℃, a humidity of 0 percent, a fixed temperature of 90min, and a next operation stopping if the weight (%) of 15.00min is less than 0.0100, wherein the humidity is increased by 10 percent every 90min to 80.00 percent, control software, ThermalAdvantage, analysis software, Universal analysis.
And (3) detection results: XRD, crystalline, numbered Form A. DSC, no endothermic melting peak is observed in the sample, a wide exothermic peak appears at about 150 ℃, and the exothermic peak is determined by combining with the decomposition temperature of TGA; TGA, a sample having a slow weight loss of about 0.07% before 100 ℃ is anhydrous and has a decomposition temperature of about 147 ℃. DVS/isothermal adsorption curve, weight change less than 0.1% from 0% RH to 80% RH, no moisture absorption. The patterns are respectively shown in an X-ray powder diffraction pattern of the dihydroartemisinin crystal form of figure 1, a TGA analysis pattern of the dihydroartemisinin crystal form of figure 2, a DSC analysis pattern of the dihydroartemisinin crystal form of figure 3, a Fourier infrared spectrum pattern of the dihydroartemisinin crystal form of figure 4 and a DVS analysis pattern of the dihydroartemisinin crystal form of figure 5. The XRD, TGA, DSC, FT-IR, and DVS patterns of the prepared samples of the respective examples were consistent.
And (4) conclusion: the crystal Form A is determined by characterization of XRD, DSC, TGA, DVS and FT-IR and evaluation of crystal Form stability.
Example 12: stability test
The experiment is carried out according to the guidelines of stability test of the XC bulk drug and the pharmaceutical preparation XI in the second part of the Chinese pharmacopoeia 2015 edition, and the dihydroartemisinin prepared in the example 1 is placed in: the test is carried out for 10 days under the conditions of 60 ℃/75% RH opening, 60 ℃/75% RH closing, 40 ℃/75% RH opening, 40 ℃/75% RH closing, 25 ℃/60% RH opening and 25 ℃/60% RH closing, and the content of the sample and the detection results of related substances under each condition are shown in table 2. The X-ray powder diffraction spectrum is shown in FIG. 6, and the DCS characteristic analysis spectrum is shown in FIG. 7.
Table 2: content of dihydroartemisinin under different stability conditions and detection result of related substances
The stability test result shows that the content of the dihydroartemisinin and related substances have no significant change, the X-ray powder diffraction spectrum characteristics and the DCS characteristic spectrum are consistent, and the properties are stable.
Example 13: grinding test
The dihydroartemisinin prepared in example 1 was ground in a mortar, and the content and the related substances of the ground sample were detected and identified by X-ray powder diffraction. The content of the ground sample and the detection results of related substances are shown in Table 3, and the X-ray powder diffraction spectrogram is shown in FIG. 8.
Table 3: content before and after grinding of dihydroartemisinin and detection result of related substances
The result shows that the content of the dihydroartemisinin and related substances after grinding has no significant change, the X-ray powder diffraction spectrum characteristics are consistent, and the properties are stable.
In conclusion, the dihydroartemisinin is crystallized by adopting a high molecular template, and is determined to be a crystal Form A through characterization of XRD, DSC, TGA, DVS and FT-IR and crystal Form stability evaluation. The stability test and the grinding test show that the obtained dihydroartemisinin crystal has good stability to light, moisture and heat.
Claims (10)
1. The dihydroartemisinin Form A crystal Form is characterized in that an X-ray powder diffraction pattern of the dihydroartemisinin Form A crystal Form has characteristic peaks at 2 theta values of 7.6 +/-0.2 degrees, 9.2 +/-0.2 degrees, 11.1 +/-0.2 degrees, 12.3 +/-0.2 degrees, 13.1 +/-0.2 degrees, 15.2 +/-0.2 degrees, 16.7 +/-0.2 degrees, 17.4 +/-0.2 degrees and 18.7 +/-0.2 degrees.
2. The crystalline form of claim 1, having a thermogravimetric analysis curve with a weight loss of 0.07% when heated to 100 ℃ and a decomposition temperature of 147 ℃.
3. The crystalline form of claim 1, which has a differential scanning calorimetry trace without an endothermic peak and an exothermic peak at 150 ℃.
4. The crystalline form of claim 1, characterized by a fourier spectrum having characteristic absorption peaks at wavenumbers of 3373 ± 2, 2923 ± 2, 2852 ± 2, 1443 ± 2, 1377 ± 2, 1188 ± 2, 1176 ± 2, 1159 ± 2, 1134 ± 2, 1092 ± 2, 1061 ± 2, 1022 ± 2, 984 ± 2, 969 ± 2, 957 ± 2, 932 ± 2, 895 ± 2, 875 ± 2, 846 ± 2, 824 ± 2, 690 ± 2, 657 ± 2cm "1.
5. The crystalline form of claim 1, having a dynamic moisture sorption profile with a weight change of less than 0.1% over the humidity range of 0% RH to 80% RH.
6. The method for preparing dihydroartemisinin Form A crystal Form of claim 1, characterized in that dihydroartemisinin is dissolved in organic solvent, then polymer material is added, and solvent is recovered to obtain the dihydroartemisinin Form A crystal Form.
7. The method according to claim 6, wherein the organic solvent is at least one of methanol, ethanol, trifluoroethanol, acetone, methyl ethyl ketone, ethyl acetate, tetrahydrofuran, 1, 4-dioxane, dichloromethane, and chloroform.
8. The preparation method according to claim 6, wherein the polymer material is at least one of sodium hydroxymethyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol 4000, povidone, copovidone, crospovidone, polyethylene oxide, and polyvinyl chloride.
9. The preparation method according to claim 6, wherein the mass-to-volume ratio of the polymer material to the organic solvent is 1:10 to 1:100000 in g/ml.
10. The preparation method according to claim 6, wherein the temperature of the recovered solvent is less than or equal to 50 ℃, and the drying weight loss of the obtained dihydroartemisia apiacea Form A crystal Form is less than or equal to 3%.
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| CN1106011A (en) * | 1994-01-28 | 1995-08-02 | 中信技术公司 | Method for recovery of alpha-isomer of dihydroartemisin ether derivant |
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