CN118084906A - Dehydroevodiamine fumarate crystal form and preparation method thereof - Google Patents
Dehydroevodiamine fumarate crystal form and preparation method thereof Download PDFInfo
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- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 title claims abstract description 102
- VXHNSVKJHXSKKM-UHFFFAOYSA-N dehydroevodiamine Natural products C1CN2C(=O)C3=CC=CC=C3N(C)C2=C2C1=C1C=CC=CC1=N2 VXHNSVKJHXSKKM-UHFFFAOYSA-N 0.000 title claims abstract description 92
- VXHNSVKJHXSKKM-UHFFFAOYSA-O dehydroevidiamine Chemical compound O=C1C2=CC=CC=C2[N+](C)=C2N1CCC1=C2NC2=CC=CC=C21 VXHNSVKJHXSKKM-UHFFFAOYSA-O 0.000 title claims abstract description 89
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 title claims abstract description 88
- 239000013078 crystal Substances 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 8
- -1 dehydroevodiamine fumarate Chemical class 0.000 claims abstract description 3
- 239000001530 fumaric acid Substances 0.000 claims description 15
- 239000002994 raw material Substances 0.000 claims description 12
- 238000012360 testing method Methods 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 9
- 239000000843 powder Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 238000002329 infrared spectrum Methods 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000002441 X-ray diffraction Methods 0.000 claims 1
- 150000001450 anions Chemical class 0.000 claims 1
- SVOMSEHNGXLQRU-UHFFFAOYSA-N dehydroevodiamine chloride Chemical compound [Cl-].O=C1C2=CC=CC=C2N(C)C2=[N+]1CCC1=C2NC2=CC=CC=C21 SVOMSEHNGXLQRU-UHFFFAOYSA-N 0.000 abstract description 8
- 239000007787 solid Substances 0.000 abstract description 8
- 238000011161 development Methods 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000003814 drug Substances 0.000 description 9
- 229940079593 drug Drugs 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- 238000012512 characterization method Methods 0.000 description 5
- 238000010586 diagram Methods 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000005286 illumination Methods 0.000 description 4
- 238000000634 powder X-ray diffraction Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 241001078983 Tetradium ruticarpum Species 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000000643 oven drying Methods 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000002076 thermal analysis method Methods 0.000 description 2
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 206010061459 Gastrointestinal ulcer Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 238000002083 X-ray spectrum Methods 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- WYTGDNHDOZPMIW-RCBQFDQVSA-N alstonine Chemical compound C1=CC2=C3C=CC=CC3=NC2=C2N1C[C@H]1[C@H](C)OC=C(C(=O)OC)[C@H]1C2 WYTGDNHDOZPMIW-RCBQFDQVSA-N 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 238000005102 attenuated total reflection Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229930005303 indole alkaloid Natural products 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000001144 powder X-ray diffraction data Methods 0.000 description 1
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/13—Dicarboxylic acids
- C07C57/15—Fumaric acid
-
- 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 invention discloses a dehydroevodiamine fumarate crystal form and a preparation method thereof. Specifically, the invention discloses a solid form of a dehydroevodiamine fumarate crystal form; a preparation method of dehydroevodiamine fumarate crystal form. The crystal form of the dehydroevodiamine fumarate formed by the invention can solve the problem of poor solubility of the commercial dehydroevodiamine hydrochloride, and has good stability; in addition, the method has the advantages of simple reaction conditions, good reproducibility, easy industrial production and good application and development prospect.
Description
Technical Field
The invention discloses a dehydroevodiamine fumarate crystal form and a preparation method thereof; specifically, the invention discloses a solid form of a dehydroevodiamine fumarate crystal form; a preparation method of dehydroevodiamine fumarate crystal form solid form.
Background
The dehydroevodiamine hydrochloride (formula 1) is an indole alkaloid extracted from fruits of traditional Chinese medicine evodia rutaecarpa, is one of main components of evodia rutaecarpa for exerting efficacy, and has important pharmacological effects. In recent years, the dehydroevodiamine has good activity of resisting arrhythmia, reducing blood pressure, treating gastrointestinal ulcers, improving dysmnesia and the like, and has good development and application prospects. Accordingly, researchers have been working on developing dehydroevodiamine. However, the commercial form of dehydroevodiamine, dehydroevodiamine hydrochloride, has poor water solubility, resulting in lower bioavailability, which inhibits further development.
The drug salification refers to the process that acidic or alkaline drugs are subjected to ion exchange with counter ions after ionization to form ionic bonds, and finally are separated out in a salt form. Because salification can improve physicochemical properties of the drug such as stability, solubility, bioavailability and the like, most of clinically used drugs are salts. In view of the different physicochemical properties of different salt forms of the drug, it is expected to improve its water solubility by changing the salt form.
Formula 1: molecular structure of dehydroevodiamine hydrochloride
The invention adopts fumaric acid as a counter ion (formula 2) to synthesize dehydroevodiamine fumarate to solve the problem of poor solubility of the commercial form by changing the physical and chemical properties of the dehydroevodiamine fumarate; through document retrieval, no report of the dehydroevodiamine fumarate crystal form exists at present, so that the development of the dehydroevodiamine fumarate crystal form has important significance and good application prospect.
Formula 2: molecular structure of fumaric acid
Disclosure of Invention
One of the objects of the present invention is: provides the existence state and the characterization mode of the dehydroevodiamine fumarate crystal form.
The second object of the invention is: provides a preparation method of dehydroevodiamine fumarate crystal form.
The third object of the present invention is: provides a dehydroevodiamine fumarate crystal form substance which is obviously superior to dehydroevodiamine hydrochloride in solubility.
The fourth object of the invention is: provides a dehydroevodiamine fumarate crystal form substance which has good stability.
In order to achieve the above purpose, the invention adopts the following technical scheme:
1. Morphological characteristics of dehydroevodiamine fumarate crystalline sample:
1.1 the crystal form of dehydroevodiamine fumarate provided by the invention is a salt formed by non-covalent bonds of dehydroevodiamine and fumaric acid according to a molar ratio of 1:1.
1.2 The crystalline form of dehydroevodiamine fumarate according to the present invention, when analyzed using single crystal X-ray diffraction at 297K, exhibits monoclinic system, space group P21/n, unit cell parameters a/a= 7.396 (1), b/a= 22.130 (2), c/a= 12.310 (2), α/° =γ/° =90, β/° = 103.35 (1), v= 1960.6 (3)/a 3, z=2, molecular formula: 2 (C 19H16N3O)·2(C4H3O4)·H2 O).
1.3 The dehydroevodiamine fumarate Crystal form according to the present invention, when powder X-ray diffraction analysis was used to employ MoK alpha radiation experimental conditions, the diffraction peak positions were mainly located 7.9±0.2º, 8.3±0.2º, 10.8±0.2º, 12.8±0.2º, 13.4±0.2º,14.0±0.2º, 15.3±0.2º, 15.9±0.2º, 16.2±0.2º, 17.6±0.2º, 19.0±0.2º, 19.8±0.2º, 20.5±0.2º, 23.5±0.2º, 24.4±0.2º, 24.7±0.2º, 24.9±0.2º, 25.2±0.2º, 26.0±0.2º, 27.5±0.2º, 28.6±0.2º.
1.4 The crystalline form of dehydroevodiamine fumarate according to the invention has an infrared spectrum characteristic peak mainly at 3563±5、3037±5、3008±5、2928±5、2868±5、2825±5、2771±5、1703±5、1650±5、1609±5、1548±5、1516±5、1427±5、1386±5、1342±5、1322±5、1273±5、1217±5、1158±5、1132±5、1098±5、1047±5、983±5、965±5、913±5、886±5、759±5、637±5cm-1 when analyzed by attenuated total reflection Fourier infrared spectroscopy.
1.5 The crystalline form of dehydroevodiamine fumarate according to the present invention, when analyzed using differential scanning calorimetry, shows 1 endothermic peak at 214 ± 5 ℃ in a DSC profile with a heating rate of 10 ℃ per minute.
2. The preparation method of the dehydroevodiamine fumarate crystal form is characterized in that:
The invention relates to a dehydroevodiamine fumarate crystal form, which is prepared by taking free dehydroevodiamine (formula 3) and fumaric acid as raw materials, placing the raw materials in a mixed solvent of water and an organic solvent according to a molar ratio of 1:0.5-1:3, stirring or dissolving the raw materials at 20-70 ℃, volatilizing or dissolving the raw materials by the solvent, cooling and recrystallizing the raw materials, and finally filtering and drying the raw materials. The organic solvent is acetone, acetonitrile, tetrahydrofuran, methanol, ethanol, N-propanol, isopropanol, N-butanol, ethylene glycol, dimethyl sulfoxide, N-dimethylacetamide or N, N-dimethylformamide; the ratio of the total mass of the free dehydroevodiamine and the fumaric acid to the solvent is 1g: (1-200 ml).
Formula 3: molecular structure of free dehydroevodiamine
The beneficial technical effects of the invention are as follows:
1. The crystal form of the dehydroevodiamine fumarate obtained by the invention obviously improves the solubility of the dehydroevodiamine and can better exert the treatment effect;
2. The dehydroevodiamine fumarate crystal form has good stability, does not generate phase change under the conditions of high temperature, high humidity and illumination, and is more stable as a medicine raw material in the preparation production and storage processes.
3. The dehydroevodiamine fumarate crystal form does not contain any organic crystallization solvent, and has the advantage of good safety patent medicine.
4. The preparation condition of the dehydroevodiamine fumarate crystal form is mild, the control is easy, the method is simple and easy to implement, the repeatability is good, the large-scale industrial production is easy, the production cost is low, and the method has a large commercial application value.
Drawings
FIG. 1 is a powder X-ray diffraction pattern of the crystalline form of dehydroevodiamine fumarate;
FIG. 2 is a crystal structure diagram of the crystalline form of dehydroevodiamine fumarate;
FIG. 3 is a unit cell stacking diagram of the crystalline form of dehydroevodiamine fumarate;
FIG. 4 is a thermal analysis (TG-DSC) plot of the crystalline form of dehydroevodiamine fumarate;
FIG. 5 is an Infrared (IR) spectrum of the crystalline form of dehydroevodiamine fumarate;
FIG. 6 is a graph of a factor-affected test of the crystalline form of dehydroevodiamine fumarate;
fig. 7 is a graph showing the dissolution of the crystalline form of dehydroevodiamine fumarate.
Detailed Description
The technical features of the present application will be further illustrated by the following specific examples and the accompanying drawings, in order to enable those skilled in the relevant study to understand the present application and implement it accordingly, but not to limit the scope of the present application. Further, it is understood that various changes and modifications may be made by those skilled in the art after reading the teachings of the application, but such equivalents are intended to fall within the scope of the application as defined in the appended claims.
The instrument and the method for detecting the crystal structure and the property of the dehydroevodiamine fumarate are as follows:
Single crystal diffraction characterization: bruker APEX-II D8X-ray single crystal diffractometer, structure analysis and correction were performed with SHELXTL and OLEX; the block diagram was obtained using Mercury and OLEX software.
Powder X-ray diffraction (PXRD) characterization: instrument: bruker D8 advanced, cuK alpha radiation, 40kV power, 40mA; detection conditions: the scanning range 2 theta is 5-50 degrees, the scanning speed is 4 degrees/min, and the testing temperature is 20 ℃.
Thermal analysis (TG-DSC) characterization: instrument: ZCT-B DSC/TGA of Beijing instrument Gaokou instrument Co., ltd., detection conditions: sample was placed in an open crucible, and the temperature was raised at a rate of: 10 ℃/min, temperature range: 40-300 ℃.
Fourier Infrared (IR) characterization: instrument: fourier transform infrared spectrometer (Thermo Fisher, nicolet Nexus IS5 model, ATR method); detection conditions: the scanning wave band is 4000-500 cm -1 resolution ratio: 5 cm -1.
Influence factor experiment: the dehydroevodiamine fumarate crystal form sample was placed in an open clean surface dish and sampled by IR at 60℃for 10 days in an environment of 90% + -5% (25 ℃) or 4500 lx+ -500 lx (25 ℃), respectively.
Drug dissolution: the instrument is an SHZ-A water bath constant temperature oscillator (Shanghai Bosch Co., ltd medical equipment factory); a detector: l8 ultraviolet spectrophotometer (Shanghai precision analytical instruments Co., ltd.); the dissolution medium was a dilute hydrochloric acid solution (ph=1.2); weighing excessive sample into 30mL of medium; rate of shaking: 100 rpm; temperature: 37 ℃; sampling time: 5. 10, 20, 30, 45, 60, 90, 120, and 180 minutes; sampling 0.5 mL, filtering, diluting and testing dehydroevodiamine hydrochloride and dehydroevodia fumarate crystal forms respectively by 160 times.
Example 1
Preparation method of dehydroevodiamine fumarate crystal form sample 1:
Weighing free dehydroevodiamine and fumaric acid with a molar ratio of 1:1, adding into acetone-water (volume ratio of 4:1), performing ultrasonic treatment, heating to 45 ℃, clarifying the solution, filtering, taking out, standing at normal temperature, filtering after 72 h is completely separated out, and drying to obtain yellow solid powder which is dehydroevodiamine fumarate crystal form; wherein the mass-volume ratio of the total mass of the free dehydroevodiamine and the fumaric acid to the solvent is 1:60 g/ml.
Preparation method of dehydroevodiamine fumarate crystal form sample 2:
Weighing free dehydroevodiamine and fumaric acid with a molar ratio of 1:1, adding into ethanol-water (volume ratio of 1:1), heating to 50deg.C, clarifying the solution, filtering, standing at normal temperature, filtering after 48 hr precipitation, and oven drying to obtain yellow solid powder which is dehydroevodiamine fumarate crystal form; wherein the mass-volume ratio of the total mass of the free dehydroevodiamine and the fumaric acid to the solvent is 1:40g/ml.
Preparation method of dehydroevodiamine fumarate crystal form sample 3:
Weighing free dehydroevodiamine and fumaric acid with a molar ratio of 1:1.5, adding into acetonitrile-water (volume ratio of 2:1), heating to 50 ℃, clarifying the solution, filtering, standing at normal temperature, filtering after 72h precipitation is completed, and drying to obtain yellow solid powder which is the crystal form of dehydroevodiamine fumarate; wherein the mass-volume ratio of the total mass of the free dehydroevodiamine and the fumaric acid to the solvent is 1:50g/ml.
Preparation method of dehydroevodiamine fumarate crystal form sample 4:
Weighing free dehydroevodiamine and fumaric acid with a molar ratio of 1:2, adding into acetone-water (volume ratio of 2:1), stirring at 30deg.C for 10 h, filtering, and oven drying the obtained solid at 40deg.C to obtain yellow solid powder which is dehydroevodiamine fumarate crystal form; wherein the mass-volume ratio of the total mass of the free dehydroevodiamine and the fumaric acid to the solvent is 1:10g/ml.
The dehydroevodiamine fumarate crystals prepared in preparation methods 1 to 4 belong to a monoclinic system when tested at 297K, have a space group of P21/n, a unit cell parameter of a/a= 7.396 (1), b/a= 22.130 (2), c/a= 12.310 (2), α/° = γ/° = 90, β/° = 103.35 (1), v= 1960.6 (3)/a 3, z=2, and have a molecular formula of: 2 (C 19H16N3O)·2(C4H3O4)·H2 O).
Powder X-ray spectrum positions show a main diffraction peak at 7.9±0.2º, 8.3±0.2º, 10.8±0.2º, 12.8±0.2º, 13.4±0.2º,14.0±0.2º, 15.3±0.2º, 15.9±0.2º, 16.2±0.2º, 17.6±0.2º, 19.0±0.2º, 19.8±0.2º, 20.5±0.2º, 23.5±0.2º, 24.4±0.2º, 24.7±0.2º, 24.9±0.2º, 25.2±0.2º, 26.0±0.2º, 27.5±0.2º, 28.6±0.2º as expressed in terms of 2θ.
The dehydroevodiamine fumarate crystal form prepared by the preparation method 1 is tested, and the test results are shown in figures 1-5. Fig. 1 is a PXRD pattern of crystalline form of dehydroevodiamine fumarate. FIG. 2 is a crystal structure diagram of the crystalline form of dehydroevodiamine fumarate; fig. 3 is a unit cell stacking diagram of the crystalline form of dehydroevodiamine fumarate. The crystallographic parameters are shown in table 1.
Table 1: crystal parameters of dehydroevodiamine fumarate crystal form
FIG. 4 is a TG and DSC spectra of crystalline form of dehydroevodiamine fumarate; TG profile shows a mass loss of 20.6±2.0% in the temperature range of 200 ℃ to 270 ℃, with 1 endothermic peak present at 214±5 ℃ in combination with DSC curve.
FIG. 5 is a crystalline form of dehydroevodiamine fumarate, with an infrared spectrum characteristic peak at 3563±5、3037±5、3008±5、2928±5、2868±5、2825±5、2771±5、1703±5、1650±5、1609±5、1548±5、1516±5、1427±5、1386±5、1342±5、1322±5、1273±5、1217±5、1158±5、1132±5、1098±5、1047±5、983±5、965±5、913±5、886±5、759±5、637±5cm-1 at the position of the infrared spectrum characteristic peak (cm -1).
Example 2
Stability characteristics of the dehydroevodiamine fumarate crystalline form are shown in figure 6.
High temperature test: the sample of the dehydroevodiamine fumarate crystal form is placed in an open clean surface dish, and after being placed at the temperature of 60 ℃ for 10 days, the sample is sampled for IR analysis, the graph is consistent with that of FIG. 5, and the result shows that the dehydroevodiamine fumarate crystal form is stable under a high-temperature influence factor test.
High humidity test: the sample of the dehydroevodiamine fumarate crystal form is placed in an open clean surface dish, and after being placed for 10 days under the condition of 90% +/-5% humidity (25 ℃), the sample is sampled for IR analysis, the graph is consistent with that of FIG. 5, and the result shows that the dehydroevodiamine fumarate crystal form is stable under the high-humidity influence factor test.
Illumination test: the sample of the dehydroevodiamine fumarate crystal form is placed in an open clean surface dish, and after being placed for 10 days under the condition of illumination 4500 lx+/-500 lx (25 ℃), the sample is sampled for IR analysis, the graph is consistent with that of FIG. 5, and the result shows that the dehydroevodiamine fumarate crystal form is stable under the illumination influence factor test.
FIG. 7 is a graph showing the dissolution of powders of dehydroevodiamine fumarate and commercially available dehydroevodiamine hydrochloride in example 1; the dissolution rate of dehydroevodiamine fumarate and commercial dehydroevodiamine hydrochloride is 4.5 mg/mL and 1.3 mg/mL respectively at 3 h.
The crystal form of the dehydroevodiamine fumarate has obviously higher solubility than the commercial form, good stability and better development and application prospects.
Claims (7)
1. The dehydroevodiamine fumarate crystal form is characterized in that the dehydroevodiamine and fumaric acid form a salt crystal form in a molar ratio of 1:1.
2. The crystalline form of dehydroevodiamine fumarate according to claim 1, characterized in that the basic structural unit consists of 2 dehydroevodiamine cations, 2 fumaric anions and 1 water molecule, and that under the test conditions of 297K the crystalline form of dehydroevodiamine fumarate belongs to the monoclinic system, the space group is P21/n, the unit cell parameters are a/a= 7.396 (1), b/a= 22.130 (2), c/a= 12.310 (2), α/° = γ/° = 90, β/° = 103.35 (1), v= 1960.6 (3)/a 3, z=2, the molecular formula is: 2 (C 19H16N3O)·2(C4H3O4)·H2 O).
3. The crystalline form of dehydroevodiamine fumarate according to claim 1, characterized in that the powder X-ray pattern position exhibits a main diffraction peak at 7.9±0.2º, 8.3±0.2º, 10.8±0.2º, 12.8±0.2º, 13.4±0.2º,14.0±0.2º, 15.3±0.2º, 15.9±0.2º, 16.2±0.2º, 17.6±0.2º, 19.0±0.2º, 19.8±0.2º, 20.5±0.2º, 23.5±0.2º, 24.4±0.2º, 24.7±0.2º, 24.9±0.2º, 25.2±0.2º, 26.0±0.2º, 27.5±0.2º, 28.6±0.2º as expressed in terms of 2Θ angle.
4. The crystalline form of dehydroevodiamine fumarate according to claim 1, characterized by the presence of an infrared spectrum characteristic peak at 3563±5、3037±5、3008±5、2928±5、2868±5、2825±5、2771±5、1703±5、1650±5、1609±5、1548±5、1516±5、1427±5、1386±5、1342±5、1322±5、1273±5、1217±5、1158±5、1132±5、1098±5、1047±5、983±5、965±5、913±5、886±5、759±5、637±5cm-1 when analyzed using infrared spectrum.
5. The crystalline form of dehydroevodiamine fumarate according to claim 1, characterized by the presence of 1 endothermic peak at 214 ± 5 ℃ in a DSC profile at a rate of temperature rise of 10 ℃ per minute when analyzed using differential scanning calorimetric techniques.
6. The crystalline form of dehydroevodiamine fumarate according to any one of claims 1 to 5, characterized in that free dehydroevodiamine and fumaric acid are used as raw materials, and the crystalline form is obtained by placing the raw materials in a mixed solvent of water and an organic solvent in a molar ratio of 1:0.5 to 1:3, and under the condition of 20 to 70 ℃, volatilizing or dissolving the raw materials by the solvent, cooling and recrystallizing the raw materials, and finally filtering and drying the raw materials.
7. The preparation method of the dehydroevodiamine fumarate crystal form is characterized in that the organic solvent is acetone, acetonitrile, tetrahydrofuran, methanol, ethanol, N-propanol, isopropanol, N-butanol, ethylene glycol, dimethyl sulfoxide, N-dimethylacetamide or N, N-dimethylformamide; the ratio of the total mass of the free dehydroevodiamine and the fumaric acid to the solvent is 1g: (1-200 ml).
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