CN115010591A - Paeonol eutectic crystal with thermal stability and solubility advantages and preparation method thereof - Google Patents

Paeonol eutectic crystal with thermal stability and solubility advantages and preparation method thereof Download PDF

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CN115010591A
CN115010591A CN202210936285.4A CN202210936285A CN115010591A CN 115010591 A CN115010591 A CN 115010591A CN 202210936285 A CN202210936285 A CN 202210936285A CN 115010591 A CN115010591 A CN 115010591A
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paeonol
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朱彬
任国宾
陈立
苏东明
齐明辉
洪鸣凰
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Changshu Institute Co ltd East China University Of Science And Technology
East China University of Science and Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
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    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
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    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
    • C07C65/05—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring o-Hydroxy carboxylic acids
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    • C07—ORGANIC CHEMISTRY
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    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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Abstract

The invention discloses a paeonol eutectic with thermal stability and solubility advantages and a preparation method thereof, and relates to the technical field of pharmaceutical eutectics. The eutectic formation comprises any one of 2-amino-6-methylbenzothiazole, 2-aminobenzothiazole, 3, 4-dihydroxybenzoic acid, gallic acid, 3, 5-difluorobenzoic acid, urea, 2, 5-dihydroxybenzoic acid and propyl gallate. In addition, compared with easily sublimed paeonol, the paeonol eutectic disclosed by the invention has the advantage of difficult sublimation. In addition, the preferred paeonol co-crystal improves the solubility of paeonol. The paeonol eutectic crystal with the advantages of thermal stability and solubility can better realize the safety of production and storage of paeonol and the effectiveness of clinical application.

Description

Paeonol eutectic crystal with thermal stability and solubility advantages and preparation method thereof
Technical Field
The invention relates to the technical field of pharmaceutical co-crystals, in particular to a paeonol co-crystal with thermal stability and solubility advantages, and a preparation method and application thereof.
Background
Paeonol (Paeonol, Pae) is an effective component extracted from dried root bark of Paeonia suffruticosa Andr of Ranunculaceae, and is a natural phenolic compound with molecular weight: 166.174, the chemical formula is as follows:
Figure 223440DEST_PATH_IMAGE001
many experimental studies show that the structural skeleton of paeonol ketone has wide biological activity. The paeonol has the main pharmacological activity of anti-inflammation and good clinical significance, and has the functions of dilating blood vessels of the heart, relieving neurotoxicity and resisting tumors. As a traditional Chinese medicine extract, paeonol has been successfully applied to the treatment of various inflammatory diseases in China for nearly 50 years, and a good curative effect is achieved.
The paeonol preparation which is commonly used clinically at present can be prepared into ointments, creams, tablets, injections and dropping pills. Chinese patent, granted No.: CN102499913B, which states that paeonol is unstable to heat and easily decomposed and oxidized during purification, it can be heat-treated only for a very short time under specific conditions. In the 10 th year 2010 of Liaoning college of traditional Chinese medicine, Weibin et al published 'Paeonol tablet dissolution influencing factor investigation', which indicates that the dissolution of Paeonol tablet is limited by its lower solubility, and in the production process of Paeonol tablet, attention is paid to the fact that the temperature cannot be controlled to be higher than 40 ℃, otherwise, dissolution and agglomeration of Paeonol raw material are caused, and the disintegration of Paeonol tablet is deteriorated to influence the dissolution. In 2005, wuxuefen et al, published "thermal stability investigation and formation constant determination of paeonol inclusion complex", attempted to improve the stability of paeonol, but these inclusion complexes were complex to prepare and formed unstably.
In conclusion, the paeonol has the problems of poor solubility, thermal instability, easy sublimation and the like, the production and the use of the paeonol preparation are seriously influenced, and the effectiveness, the safety, the quality reliability, the consistency and the like of the paeonol medicament are endangered. Therefore, the paeonol eutectic crystal is developed, the related thermal stability and solubility are researched, and the paeonol eutectic crystal with better thermal stability, higher solubility and lower sublimation rate is developed.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a paeonol eutectic crystal and a preparation method thereof, wherein the paeonol eutectic crystal has good solubility and is not easy to sublimate and can be used for pharmaceutical preparations.
In order to achieve the purpose, the invention adopts the technical scheme that:
the invention provides paeonol eutectic with thermal stability and solubility advantages, which comprises eutectic formed by combining paeonol and eutectic composition; the eutectic formation product is any one of 2-amino-6-methylbenzothiazole, 2-aminobenzothiazole, 3, 4-dihydroxybenzoic acid, gallic acid, 3, 5-difluorobenzoic acid, urea, 2, 5-dihydroxybenzoic acid and propyl gallate.
Preferably, the paeonol and 2-amino-6-methylbenzothiazole eutectic has the following characteristic peaks expressed by an angle 2 theta in an X-ray powder diffraction pattern: 6.67 °, 8.188 °, 10.295 °, 10.884 °, 13.01 °, 15.37 °, 16.177 °, 16.376 °, 17.608 °, 19.575 °, 19.712 °, 20.244 °, 20.821 °, 21.445 °, 21.933 °, 22.292 °, 23.598 °, 23.965 °, 24.9 °, 25.421 °, 26.515 °, 27.086 °, 27.736 °, 27.917 °, 28.861 °, 29.205 °, 30.115 °, 30.352 °, 31.424 °, 31.728 °, 32.174 °, 32.907 °, 33.251 °, 33.741 °, 34.489 °, 34.771 °, 35.582 °, 35.898 °, 36.423 °, 36.85 °, 37.271 °, 38.124 °, 38.628 °, 39.717 °, 40.185 °, 40.844 °, 41.583 °, 42.194 °, 42.608 °, 43.512 °, 43.845 °, 44.27 °, with an error tolerance of ± 0.2 °.
Preferably, the paeonol and 2-aminobenzothiazole eutectic has the following characteristic peaks expressed by an angle 2 theta in an X-ray powder diffraction pattern: 6.077 degrees, 8.584 degrees, 12.163 degrees, 12.873 degrees, 13.725 degrees, 15.387 degrees, 17.016 degrees, 17.324 degrees, 18.272 degrees, 18.99 degrees, 20.88 degrees, 21.25 degrees, 22.041 degrees, 22.687 degrees, 22.986 degrees, 23.727 degrees, 24.441 degrees, 27.461 degrees, 28.619 degrees, 28.896 degrees, 29.797 degrees, 30.268 degrees, 30.594 degrees, 32.254 degrees, 33.209 degrees, 33.694 degrees, 34.251 degrees, 34.737 degrees, 35.029 degrees, 36.064 degrees, 36.395 degrees, 37.021 degrees, 37.871 degrees, 39.114 degrees, 41.035 degrees, 41.291 degrees, 43.494 degrees, and an error tolerance of +/-0.2 degrees exists.
Preferably, the paeonol and 3, 4-dihydroxy benzoic acid eutectic crystal has the following characteristic peaks expressed by an angle 2 theta in an X-ray powder diffraction pattern: 9.683 degrees, 10.422 degrees, 11.313 degrees, 13.056 degrees, 13.763 degrees, 14.007 degrees, 15.602 degrees, 15.954 degrees, 16.621 degrees, 19.277 degrees, 19.91 degrees, 20.979 degrees, 21.962 degrees, 22.926 degrees, 23.367 degrees, 24.004 degrees, 25.817 degrees, 26.648 degrees, 27.153 degrees, 27.677 degrees, 28.164 degrees, 29.185 degrees, 31.667 degrees, 32.302 degrees, 33.315 degrees, 33.628 degrees, 34.24 degrees, 36.653 degrees, 37.006 degrees, 38.168 degrees, 38.62 degrees, 38.963 degrees, 39.806 degrees, 40.431 degrees, 42.031 degrees, 42.756 degrees, 43.259 degrees, 43.548 degrees and 44.269 degrees, and error tolerance of +/-0.2 degrees exists.
Preferably, the paeonol and gallic acid eutectic has the following characteristic peaks expressed by an angle 2 theta in an X-ray powder diffraction pattern: 7.21 °, 7.982 °, 8.425 °, 9.866 °, 10.613 °, 11.143 °, 11.425 °, 12.259 °, 13.433 °, 13.772 °, 14.59 °, 15.397 °, 16.137 °, 16.938 °, 17.338 °, 18.405 °, 18.923 °, 19.566 °, 20.763 °, 21.14 °, 21.958 °, 22.458 °, 23.165 °, 23.407 °, 24.034 °, 24.802 °, 25.796 °, 26.844 °, 27.934 °, 29.082 °, 29.458 °, 30.344 °, 31.281 °, 31.675 °, 31.947 °, 33.1 °, 33.951 °, 34.448 °, 35.119 °, 37.152 °, 37.94 °, 39.137 °, 40.596 °, 41.604 °, 42.557 °, 43.316 °, 43.897 °, and an error tolerance of ± 0.2 ° exists.
Preferably, the paeonol eutectic crystal with 3, 5-difluorobenzoic acid has the following characteristic peaks expressed by an angle 2 theta in an X-ray powder diffraction pattern: 10.537 degrees, 10.86 degrees, 12.45 degrees, 12.935 degrees, 14.335 degrees, 14.558 degrees, 16.616 degrees, 18.11 degrees, 18.836 degrees, 19.104 degrees, 21.416 degrees, 21.844 degrees, 22.479 degrees, 23.018 degrees, 23.651 degrees, 25.189 degrees, 26.259 degrees, 26.649 degrees, 27.41 degrees, 27.675 degrees, 28.363 degrees, 28.874 degrees, 29.154 degrees, 30.103 degrees, 31.9 degrees, 32.276 degrees, 33.365 degrees, 35.647 degrees, 35.908 degrees, 37.245 degrees, 37.512 degrees, 37.95 degrees, 38.255 degrees, 39.201 degrees, 39.675 degrees, 40.008 degrees, 42.738 degrees, 44.12 degrees, and an error tolerance of +/-0.2 degrees exists.
Preferably, the paeonol and urea eutectic crystal has the following characteristic peaks expressed by an angle 2 theta in an X-ray powder diffraction pattern: 6.106 degrees, 12.27 degrees, 13.038 degrees, 14.128 degrees, 14.399 degrees, 15.697 degrees, 17.693 degrees, 18.483 degrees, 19.635 degrees, 20.012 degrees, 22.488 degrees, 23.336 degrees, 23.705 degrees, 24.015 degrees, 24.619 degrees, 25.136 degrees, 25.694 degrees, 26.336 degrees, 26.686 degrees, 27.248 degrees, 27.544 degrees, 27.948 degrees, 28.473 degrees, 29.245 degrees, 29.971 degrees, 30.789 degrees, 32.134 degrees, 32.623 degrees, 33.733 degrees, 34.51 degrees, 35.099 degrees, 35.567 degrees, 35.893 degrees, 36.796 degrees, 37.776 degrees, 38.268 degrees, 39.33 degrees, 39.917 degrees, 40.754 degrees, 41.975 degrees, 43.004 degrees and 44.111 degrees, and an error tolerance of +/-0.2 degrees exists.
Preferably, the paeonol and 2, 5-dihydroxy benzoic acid eutectic crystal has the following characteristic peaks expressed by an angle 2 theta in an X-ray powder diffraction pattern: 7.514 degrees, 9.24 degrees, 10.94 degrees, 13.338 degrees, 14.501 degrees, 15.001 degrees, 15.82 degrees, 16.363 degrees, 17.521 degrees, 17.78 degrees, 18.939 degrees, 19.483 degrees, 20.379 degrees, 21.161 degrees, 22.056 degrees, 22.901 degrees, 23.22 degrees, 24.332 degrees, 24.74 degrees, 25.36 degrees, 25.963 degrees, 26.999 degrees, 27.44 degrees, 28.576 degrees, 29.299 degrees, 30.478 degrees, 32.857 degrees, 33.241 degrees, 34.262 degrees, 35.481 degrees, 36.139 degrees, 37.458 degrees, 38.6 degrees, 39.781 degrees, 40.94 degrees, 41.461 degrees and 43.761 degrees, and an error tolerance of +/-0.2 degrees exists.
Preferably, the paeonol and propyl gallate eutectic crystal has the following characteristic peaks expressed by an angle 2 theta in an X-ray powder diffraction pattern: 4.441 degrees, 8.938 degrees, 12.623 degrees, 13.223 degrees, 13.46 degrees, 13.738 degrees, 15.101 degrees, 16.263 degrees, 17.617 degrees, 17.943 degrees, 18.34 degrees, 19.141 degrees, 20.801 degrees, 21.14 degrees, 21.958 degrees, 22.616 degrees, 24.193 degrees, 24.444 degrees, 25.4 degrees, 26.022 degrees, 27.056 degrees, 27.876 degrees, 29.643 degrees, 31.8 degrees, 32.418 degrees, 33.152 degrees, 34.597 degrees, 35.814 degrees, 36.45 degrees, 37.305 degrees, 37.901 degrees, 38.702 degrees, 39.154 degrees, 40.061 degrees, 40.639 degrees, 41.244 degrees, 42.343 degrees, 43.218 degrees, 44.454 degrees, and an error tolerance of +/-0.2 degrees exists.
Preferably, the differential scanning calorimetry spectrogram of the paeonol eutectic and the 2-amino-6-methylbenzothiazole shows that the Tonset is 88.67 ℃, and the Tpeak is 88.85 ℃;
the differential scanning calorimetry spectrogram of the paeonol and 2-aminobenzothiazole eutectic shows that the Tonset is 59.17 ℃ and the Tpeak is 60.68 ℃;
the differential scanning calorimetry spectrogram of the paeonol and 3, 4-dihydroxy benzoic acid eutectic shows that the Tonset is 126.55 ℃ and 203.10 ℃, and the Tpeak is 128.15 ℃ and 204.13 ℃;
the differential scanning calorimetry spectrogram of the paeonol eutectic crystal with the gallic acid shows that the Tonset is 139.26 ℃ and 238.18 ℃, and the Tpeak is 141.85 ℃ and 248.20 ℃;
the differential scanning calorimetry spectrogram of the paeonol eutectic with the 3, 5-difluorobenzoic acid shows that the Tonset is 91.44 ℃, and the Tpeak is 92.24 ℃;
the differential scanning calorimetry spectrogram of the paeonol and urea eutectic shows that the Tonset is 111.25 ℃ and 131.61 ℃, and the Tpeak is 115.07 ℃ and 132.87 ℃;
the differential scanning calorimetry spectrogram of the paeonol and 2, 5-dihydroxy benzoic acid eutectic shows that the Tonset is 92 ℃ and 200.22 ℃, and the Tpeak is 95.89 ℃ and 202.45 ℃;
a differential scanning calorimetry spectrogram of the paeonol and propyl gallate eutectic crystal shows that the Tonset is 78.36 ℃ and 138.20 ℃, and the Tpeak is 80.55 ℃ and 177.48 ℃.
Preferably, the paeonol and 2-amino-6-methylbenzothiazole eutectic is gradually decomposed and weightless after being melted in the temperature range of 25-200 ℃;
the paeonol and 2-aminobenzothiazole eutectic is gradually decomposed and weightless after being melted in a temperature range of 25-200 ℃;
the paeonol and 3, 4-dihydroxy benzoic acid eutectic has no obvious weight loss in the temperature range of 25-100 ℃; the paeonol and the 3, 4-dihydroxybenzoic acid eutectic have 51.26 percent weight loss within the temperature range of 100-165 ℃; the paeonol and the 3, 4-dihydroxybenzoic acid eutectic have 36.84 percent weight loss within the temperature range of 190-;
the paeonol and gallic acid eutectic has no obvious weight loss within the temperature range of 25-88 ℃; the paeonol and the gallic acid eutectic are subjected to weight loss of 41.21 percent within the temperature range of 88-144 ℃; the paeonol and the gallic acid eutectic have 32.73 percent weight loss within the temperature range of 217 ℃ and 298 ℃;
melting the paeonol and the 3, 5-difluorobenzoic acid eutectic at the temperature of between 25 and 150 ℃ and then gradually decomposing and losing weight;
the paeonol and urea eutectic is 57.23 percent of weight loss in the temperature range of 25-138 ℃; the paeonol and urea eutectic has 35.56 percent weight loss within the temperature range of 138-198 ℃;
the paeonol and the 2, 5-dihydroxybenzoic acid eutectic are subjected to 54.46% weight loss in a temperature range of 25-150 ℃; the paeonol and 2, 5-dihydroxybenzoic acid eutectic has 46.51 percent weight loss within the temperature range of 150-220 ℃;
the paeonol and propyl gallate eutectic crystal is subjected to weight loss of 46.58% within the temperature range of 25-165 ℃; the paeonol and propyl gallate eutectic crystal has 57.13 percent weight loss in the temperature range of 175-257 ℃.
Preferably, in the cocrystal of paeonol and 2-amino-6-methylbenzothiazole, paeonol and 2-amino-6-methylbenzothiazole are present in a 3:2 molar ratio;
in the eutectic of paeonol and 2-aminobenzothiazole, the paeonol and the 2-aminobenzothiazole exist in a molar ratio of 2: 1;
in the eutectic crystal of paeonol and 3, 4-dihydroxybenzoic acid, the paeonol and the 3, 4-dihydroxybenzoic acid exist in a molar ratio of 1: 1;
in the eutectic crystal of paeonol and gallic acid, the paeonol and the gallic acid exist in a molar ratio of 1: 1;
in the eutectic of paeonol and 3, 5-difluorobenzoic acid, the paeonol and the 3, 5-difluorobenzoic acid exist in a molar ratio of 1: 1;
in the eutectic crystal of paeonol and urea, the paeonol and the urea exist in a molar ratio of 1: 2;
in the eutectic crystal of paeonol and 2, 5-dihydroxybenzoic acid, the paeonol and the 2, 5-dihydroxybenzoic acid exist in a molar ratio of 1: 1;
in the co-crystal of paeonol and propyl gallate, paeonol and propyl gallate are present in a 1:1 molar ratio.
The preparation method of the paeonol eutectic crystal comprises the following specific steps: mixing paeonol and an eutectic formation according to a molar ratio of 0.5-2: 1, adding a solvent, heating, and stirring until the paeonol and the eutectic formation are completely dissolved; and standing and volatilizing at room temperature for 1-5 days, separating out crystals, and drying in vacuum at 40 ℃ to obtain the paeonol pharmaceutical co-crystal.
The preparation method of the paeonol eutectic crystal comprises the following specific steps: mixing paeonol and the eutectic formation according to the molar ratio of 0.5-2: 1, adding an organic solvent, heating to 40 ℃, and stirring until the paeonol and the eutectic formation are completely dissolved; and standing at-20 ℃ for cooling for 1-2 days to precipitate crystals, and drying in vacuum at 40 ℃ to obtain the paeonol pharmaceutical co-crystal.
The preparation method of the paeonol eutectic crystal comprises the following specific steps: mixing paeonol and the eutectic formation according to the molar ratio of 0.5-2: 1, adding an organic solvent, stirring, separating, and drying in vacuum at 40 ℃ to obtain the paeonol pharmaceutical eutectic.
A pharmaceutical composition comprising a paeonol co-crystal as an active ingredient and an acceptable carrier; the dosage form of the pharmaceutical composition is selected from the group consisting of: liquid, solid, semi-solid formulations.
An application of paeonol eutectic and its composition in preparing the medicines for treating the inflammation and inflammation of human body and reducing the sublimation loss of paeonol in production and storage is disclosed.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a paeonol eutectic crystal which is used for improving the solubility of paeonol and reducing the sublimation rate of the paeonol. Compared with paeonol bulk drug, the paeonol provided by the invention has good eutectic solubility and low sublimation rate, is beneficial to being used as a pharmaceutical ingredient, improves the clinical application effect, reduces the loss in the production and storage processes, and has higher drug development value.
On the other hand, the paeonol eutectic preparation method is simple, has good repeatability and is suitable for industrial production.
Drawings
FIG. 1 is an X-ray powder diffraction (XRPD) pattern of a paeonol and 2-amino-6-methylbenzothiazole co-crystal prepared in example 1.
FIG. 2 is a Differential Scanning Calorimetry (DSC) spectrum of the paeonol and 2-amino-6-methylbenzothiazole co-crystal prepared in example 1.
FIG. 3 is a thermogravimetric analysis (TGA) spectrum of the paeonol and 2-amino-6-methylbenzothiazole co-crystal prepared in example 1.
FIG. 4 is an X-ray powder diffraction (XRPD) pattern of the paeonol and 2-aminobenzothiazole co-crystal prepared in example 2.
FIG. 5 is a Differential Scanning Calorimetry (DSC) spectrum of the paeonol and 2-aminobenzothiazole co-crystal prepared in example 2.
FIG. 6 is a thermogravimetric analysis (TGA) spectrum of the paeonol and 2-aminobenzothiazole co-crystal prepared in example 2.
FIG. 7 is an X-ray powder diffraction (XRPD) pattern of a cocrystal of paeonol and 3, 4-dihydroxybenzoic acid obtained in example 3.
FIG. 8 is a Differential Scanning Calorimetry (DSC) chart of the co-crystal of paeonol and 3, 4-dihydroxybenzoic acid prepared in example 3.
FIG. 9 is a thermogravimetric analysis (TGA) spectrum of a paeonol and 3, 4-dihydroxybenzoic acid eutectic obtained in example 3.
Fig. 10 is an X-ray powder diffraction (XRPD) pattern of paeonol and gallic acid prepared in example 4.
FIG. 11 is a Differential Scanning Calorimetry (DSC) profile of paeonol and gallic acid obtained in example 4.
FIG. 12 is a thermogravimetric analysis (TGA) profile of paeonol and gallic acid obtained in example 4.
FIG. 13 is an X-ray powder diffraction (XRPD) pattern of paeonol and 3, 5-difluorobenzoic acid obtained in example 5.
FIG. 14 is a Differential Scanning Calorimetry (DSC) profile of paeonol and 3, 5-difluorobenzoic acid obtained in example 5.
FIG. 15 is a thermogravimetric analysis (TGA) profile of paeonol and 3, 5-difluorobenzoic acid obtained in example 5.
Fig. 16 is an X-ray powder diffraction (XRPD) pattern of the paeonol and urea co-crystal prepared in example 6.
FIG. 17 is a Differential Scanning Calorimetry (DSC) spectrum of the paeonol and urea co-crystal obtained in example 6.
Fig. 18 is a thermogravimetric analysis (TGA) profile of the paeonol and urea co-crystal prepared in example 6.
FIG. 19 is an X-ray powder diffraction (XRPD) pattern of a cocrystal of paeonol and 2, 5-dihydroxybenzoic acid obtained in example 7.
FIG. 20 is a Differential Scanning Calorimetry (DSC) spectrum of the cocrystal of paeonol and 2, 5-dihydroxybenzoic acid obtained in example 7.
FIG. 21 is a thermogravimetric analysis (TGA) spectrum of a cocrystal of paeonol and 2, 5-dihydroxybenzoic acid obtained in example 7.
Fig. 22 is an X-ray powder diffraction (XRPD) pattern of the paeonol and propyl gallate co-crystal prepared in example 8.
Fig. 23 is a Differential Scanning Calorimetry (DSC) profile of the paeonol and propyl gallate co-crystal prepared in example 8.
Fig. 24 is a thermogravimetric analysis (TGA) profile of the paeonol and propyl gallate co-crystal prepared in example 8.
FIGS. 25-32 show the structures of single crystal X-ray diffraction patterns of paeonol co-crystals.
FIGS. 33-40 show PXRD patterns of stability experiment results.
FIGS. 41-48 are graphs showing the results of dissolution experiments for a paeonol/paeonol co-crystal.
FIG. 49 shows a sublimation property spectrum of a paeonol and paeonol co-crystal.
FIG. 50 is a graph of sublimation rates of paeonol and paeonol co-crystals.
Detailed Description
In order to facilitate understanding of the present invention, the following embodiments are provided to further illustrate the technical solutions of the present invention, but the present invention is not limited thereto; all the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention. Unless otherwise indicated, the starting materials and reagents used in the examples are all commercially available products; reagents, equipment, or procedures not described herein are routinely determinable by one of ordinary skill in the art.
As shown in the combined drawings of FIGS. 1-50, the invention provides paeonol co-crystals with thermal stability and solubility advantages, including co-crystals formed by the combination of paeonol and a eutectic composition; the eutectic formation product is any one of 2-amino-6-methylbenzothiazole, 2-aminobenzothiazole, 3, 4-dihydroxybenzoic acid, gallic acid, 3, 5-difluorobenzoic acid, urea, 2, 5-dihydroxybenzoic acid and propyl gallate.
Example 1:
with the general scheme of fig. 1-3, the preparation of the paeonol and 2-amino-6-methylbenzothiazole eutectic
240.0mg of paeonol and 158.16mg of 2-amino-6-methylbenzothiazole are weighed in a 10mL glass bottle, 0.5mL of methanol is added, magnetic stirring is carried out, suspension is carried out for 24 hours, supernatant liquid is removed by centrifugation, and the obtained precipitate is paeonol and 2-amino-6-methylbenzothiazole eutectic powder which is named as S1.
In this example, the paeonol and 2-amino-6-methylbenzothiazole eutectic has the following characteristic peaks expressed by an angle 2 theta in an X-ray powder diffraction pattern of Cu-K alpha rays: 6.67 °, 8.188 °, 10.295 °, 10.884 °, 13.01 °, 15.37 °, 16.177 °, 16.376 °, 17.608 °, 19.575 °, 19.712 °, 20.244 °, 20.821 °, 21.445 °, 21.933 °, 22.292 °, 23.598 °, 23.965 °, 24.9 °, 25.421 °, 26.515 °, 27.086 °, 27.736 °, 27.917 °, 28.861 °, 29.205 °, 30.115 °, 30.352 °, 31.424 °, 31.728 °, 32.174 °, 32.907 °, 33.251 °, 33.741 °, 34.489 °, 34.771 °, 35.582 °, 35.898 °, 36.423 °, 36.85 °, 37.271 °, 38.124 °, 38.628 °, 39.717 °, 40.185 °, 40.844 °, 41.583 °, 42.194 °, 42.608 °, 43.512 °, 43.845 °, 44.27 °, with an error tolerance of ± 0.2 °.
In this example, in the DSC chart of the eutectic of paeonol and 2-amino-6-methylbenzothiazole, the differential scanning calorimetry of the eutectic of paeonol and 2-amino-6-methylbenzothiazole showed that Tonset was 88.67 ℃ and Tpeak was 88.85 ℃. In a TGA spectrogram of the paeonol and 2-amino-6-methylbenzothiazole eutectic, the paeonol and the 2-amino-6-methylbenzothiazole eutectic are gradually decomposed and weightlessness after being melted in a temperature range of 25-200 ℃.
Example 2:
as shown in the comprehensive diagrams of 4-6, the preparation of the cocrystal of paeonol and 2-aminobenzothiazole
400.0mg of paeonol and 180.8mg of 2-aminobenzothiazole were weighed into a 10mL glass bottle, and 1mL of ethyl acetate was added and stirred to dissolve the paeonol and the 2-aminobenzothiazole, and the mixture was cooled and crystallized at-20 ℃ to obtain a paeonol and 2-aminobenzothiazole eutectic sample, which was named S2.
In this example, the paeonol and 2-aminobenzothiazole eutectic has the following characteristic peaks expressed by an angle 2 theta in an X-ray powder diffraction pattern of Cu-K alpha rays: 6.077 degrees, 8.584 degrees, 12.163 degrees, 12.873 degrees, 13.725 degrees, 15.387 degrees, 17.016 degrees, 17.324 degrees, 18.272 degrees, 18.99 degrees, 20.88 degrees, 21.25 degrees, 22.041 degrees, 22.687 degrees, 22.986 degrees, 23.727 degrees, 24.441 degrees, 27.461 degrees, 28.619 degrees, 28.896 degrees, 29.797 degrees, 30.268 degrees, 30.594 degrees, 32.254 degrees, 33.209 degrees, 33.694 degrees, 34.251 degrees, 34.737 degrees, 35.029 degrees, 36.064 degrees, 36.395 degrees, 37.021 degrees, 37.871 degrees, 39.114 degrees, 41.035 degrees, 41.291 degrees, 43.494 degrees, and an error tolerance of +/-0.2 degrees exists.
In the embodiment, in a DSC spectrogram of the paeonol and 2-aminobenzothiazole eutectic, the differential scanning calorimetry spectrogram of the paeonol and 2-aminobenzothiazole eutectic shows that the Tonset is 59.17 ℃ and the Tpeak is 60.68 ℃; in a TGA spectrogram of the paeonol and 2-aminobenzothiazole eutectic, the paeonol and 2-aminobenzothiazole eutectic is gradually decomposed and weightless after being melted in a temperature range of 25-200 ℃.
Example 3:
as shown in the general diagrams of FIGS. 7 to 9, the preparation of the cocrystal of paeonol and 3, 4-dihydroxybenzoic acid
200.0mg of paeonol and 185.5mg of 3, 4-dihydroxybenzoic acid were weighed into a 10mL glass bottle, dissolved by adding 1mL of methanol, and crystallized by cooling at-20 ℃ to obtain a pure eutectic sample, which was designated as S3.
In this example, the eutectic of paeonol and 3, 4-dihydroxybenzoic acid has the following characteristic peaks expressed by an angle 2 θ in an X-ray powder diffraction pattern of Cu-K α radiation: 9.683 degrees, 10.422 degrees, 11.313 degrees, 13.056 degrees, 13.763 degrees, 14.007 degrees, 15.602 degrees, 15.954 degrees, 16.621 degrees, 19.277 degrees, 19.91 degrees, 20.979 degrees, 21.962 degrees, 22.926 degrees, 23.367 degrees, 24.004 degrees, 25.817 degrees, 26.648 degrees, 27.153 degrees, 27.677 degrees, 28.164 degrees, 29.185 degrees, 31.667 degrees, 32.302 degrees, 33.315 degrees, 33.628 degrees, 34.24 degrees, 36.653 degrees, 37.006 degrees, 38.168 degrees, 38.62 degrees, 38.963 degrees, 39.806 degrees, 40.431 degrees, 42.031 degrees, 42.756 degrees, 43.259 degrees, 43.548 degrees and 44.269 degrees, and error tolerance of +/-0.2 degrees exists.
In this example, in the DSC chart of the eutectic of paeonol and 3, 4-dihydroxybenzoic acid, the differential scanning calorimetry of the eutectic of paeonol and 3, 4-dihydroxybenzoic acid showed Tonset at 126.55 ℃ and 203.10 ℃ and Tpeak at 128.15 ℃ and 204.13 ℃. In a TGA spectrogram of the paeonol and 3, 4-dihydroxybenzoic acid eutectic, the paeonol and 3, 4-dihydroxybenzoic acid eutectic has no obvious weight loss within the temperature range of 25-100 ℃; the paeonol and the 3, 4-dihydroxybenzoic acid eutectic have 51.26 percent weight loss within the temperature range of 100-165 ℃; the paeonol and the 3, 4-dihydroxybenzoic acid eutectic have 36.84 percent weight loss within the temperature range of 190-; the first endothermic peak is the endothermic melting of 3, 4-dihydroxybenzoic acid, and the second endothermic peak is the endothermic sublimation of paeonol from the eutectic powder alone.
Example 4:
as shown in the comprehensive figure 10-12, the preparation of paeonol and gallic acid
Weighing 200.0mg of paeonol and 204.7mg of gallic acid in a 10mL glass bottle, adding 0.5mL of methanol, magnetically stirring and suspending for 24h, centrifuging to remove supernatant, and obtaining precipitate, namely paeonol and gallic acid eutectic powder, which is named as S4.
In this example, in the X-ray powder diffraction pattern of Cu-ka radiation, paeonol and gallic acid have the following characteristic peaks expressed by an angle 2 θ: 7.21 °, 7.982 °, 8.425 °, 9.866 °, 10.613 °, 11.143 °, 11.425 °, 12.259 °, 13.433 °, 13.772 °, 14.59 °, 15.397 °, 16.137 °, 16.938 °, 17.338 °, 18.405 °, 18.923 °, 19.566 °, 20.763 °, 21.14 °, 21.958 °, 22.458 °, 23.165 °, 23.407 °, 24.034 °, 24.802 °, 25.796 °, 26.844 °, 27.934 °, 29.082 °, 29.458 °, 30.344 °, 31.281 °, 31.675 °, 31.947 °, 33.1 °, 33.951 °, 34.448 °, 35.119 °, 37.152 °, 37.94 °, 39.137 °, 40.596 °, 41.604 °, 42.557 °, 43.316 °, 43.897 °, and an error tolerance of ± 0.2 ° exists.
In the embodiment, in the DSC spectrogram of the paeonol and the gallic acid eutectic, the DSC spectrogram of the paeonol and the gallic acid eutectic shows that the Tonset is 139.26 ℃ and 238.18 ℃, and the Tpeak is 141.85 ℃ and 248.20 ℃; in a TGA spectrogram of the paeonol and the gallic acid eutectic, the paeonol and the gallic acid eutectic have no obvious weight loss within the temperature range of 25-88 ℃; the paeonol and gallic acid eutectic has weight loss of 41.21% in the temperature range of 88-144 ℃, corresponding to the first endothermic peak of DSC, and paeonol is completely sublimated from the eutectic powder independently; the paeonol and gallic acid eutectic have 32.73% weight loss in the temperature range of 217-298 ℃, and the second endothermic peak is the endothermic melting of gallic acid.
Example 5:
as shown in the comprehensive diagrams 13-15, the preparation of paeonol and 3, 5-difluorobenzoic acid
200.0mg of paeonol and 190.3mg of 3, 5-difluorobenzoic acid are weighed into a 10mL glass bottle, 0.5mL of acetone is added, and the mixture is rapidly volatilized through opening to obtain eutectic powder of paeonol and 3, 5-difluorobenzoic acid, which is named as S5.
In this example, paeonol and 3, 5-difluorobenzoic acid have the following characteristic peaks expressed in terms of angle 2 θ in an X-ray powder diffraction pattern of Cu — K α radiation: 10.537 degrees, 10.86 degrees, 12.45 degrees, 12.935 degrees, 14.335 degrees, 14.558 degrees, 16.616 degrees, 18.11 degrees, 18.836 degrees, 19.104 degrees, 21.416 degrees, 21.844 degrees, 22.479 degrees, 23.018 degrees, 23.651 degrees, 25.189 degrees, 26.259 degrees, 26.649 degrees, 27.41 degrees, 27.675 degrees, 28.363 degrees, 28.874 degrees, 29.154 degrees, 30.103 degrees, 31.9 degrees, 32.276 degrees, 33.365 degrees, 35.647 degrees, 35.908 degrees, 37.245 degrees, 37.512 degrees, 37.95 degrees, 38.255 degrees, 39.201 degrees, 39.675 degrees, 40.008 degrees, 42.738 degrees, 44.12 degrees, and an error tolerance of +/-0.2 degrees exists.
In the example, in a DSC spectrum of the eutectic of paeonol and 3, 5-difluorobenzoic acid, a differential scanning calorimetry spectrum of the eutectic of paeonol and 3, 5-difluorobenzoic acid shows that the Tonset is 91.44 ℃ and the Tpeak is 92.24 ℃; in a TGA spectrogram of the paeonol and 3, 5-difluorobenzoic acid eutectic, the paeonol and the 3, 5-difluorobenzoic acid eutectic are gradually decomposed and weightlessness after being melted in a temperature range of 25-150 ℃.
Example 6:
as shown in the comprehensive diagrams 16-18, the preparation of paeonol and urea
200.0mg of paeonol and 144.6mg of urea are weighed into a 10mL glass bottle, 0.5mL of methanol is added, magnetic stirring and suspension are carried out for 24 hours, the supernatant fluid is removed by centrifugation, and the obtained precipitate is pure eutectic powder which is named as S6.
In this example, paeonol and urea have the following characteristic peaks expressed by an angle 2 θ in an X-ray powder diffraction pattern of Cu-K α radiation: 6.106 degrees, 12.27 degrees, 13.038 degrees, 14.128 degrees, 14.399 degrees, 15.697 degrees, 17.693 degrees, 18.483 degrees, 19.635 degrees, 20.012 degrees, 22.488 degrees, 23.336 degrees, 23.705 degrees, 24.015 degrees, 24.619 degrees, 25.136 degrees, 25.694 degrees, 26.336 degrees, 26.686 degrees, 27.248 degrees, 27.544 degrees, 27.948 degrees, 28.473 degrees, 29.245 degrees, 29.971 degrees, 30.789 degrees, 32.134 degrees, 32.623 degrees, 33.733 degrees, 34.51 degrees, 35.099 degrees, 35.567 degrees, 35.893 degrees, 36.796 degrees, 37.776 degrees, 38.268 degrees, 39.33 degrees, 39.917 degrees, 40.754 degrees, 41.975 degrees, 43.004 degrees and 44.111 degrees, and an error tolerance of +/-0.2 degrees exists.
In the embodiment, in a DSC spectrogram of the paeonol and urea eutectic, the DSC spectrogram of the paeonol and urea eutectic shows that the Tonset is 111.25 ℃ and 131.61 ℃, and the Tpeak is 115.07 ℃ and 132.87 ℃; in a TGA spectrogram of the paeonol and urea eutectic, the paeonol and urea eutectic is subjected to weight loss of 57.23% within a temperature range of 25-138 ℃, and the paeonol is independently sublimated from eutectic powder corresponding to a first endothermic peak of DSC; the paeonol and urea eutectic has 35.56 percent weight loss in the temperature range of 138-198 ℃, and is endothermic melting of urea corresponding to a second endothermic peak.
Example 7:
as shown in FIGS. 19-21, the preparation of paeonol and 2, 5-dihydroxybenzoic acid
200.0mg of paeonol and 185.5mg of 2, 5-dihydroxybenzoic acid were weighed into a 10mL glass bottle, dissolved by adding 1mL of methanol, and crystallized by cooling at-20 ℃ to obtain a pure eutectic sample, which was named S7.
In this example, paeonol and 2, 5-dihydroxybenzoic acid have the following characteristic peaks expressed by an angle 2 θ in an X-ray powder diffraction pattern of Cu-K α radiation: 7.514 degrees, 9.24 degrees, 10.94 degrees, 13.338 degrees, 14.501 degrees, 15.001 degrees, 15.82 degrees, 16.363 degrees, 17.521 degrees, 17.78 degrees, 18.939 degrees, 19.483 degrees, 20.379 degrees, 21.161 degrees, 22.056 degrees, 22.901 degrees, 23.22 degrees, 24.332 degrees, 24.74 degrees, 25.36 degrees, 25.963 degrees, 26.999 degrees, 27.44 degrees, 28.576 degrees, 29.299 degrees, 30.478 degrees, 32.857 degrees, 33.241 degrees, 34.262 degrees, 35.481 degrees, 36.139 degrees, 37.458 degrees, 38.6 degrees, 39.781 degrees, 40.94 degrees, 41.461 degrees and 43.761 degrees, and an error tolerance of +/-0.2 degrees exists.
In the example, the differential scanning calorimetry of the paeonol and the eutectic of 2, 5-dihydroxy benzoic acid shows that Tonset is 92 ℃ and 200.22 ℃, and Tpeak is 95.89 ℃ and 202.45 ℃; the paeonol and the 2, 5-dihydroxybenzoic acid eutectic are subjected to 54.46 percent weight loss in a temperature range of 25-150 ℃, and the paeonol single melting is at a first endothermic peak corresponding to DSC; the paeonol and 2, 5-dihydroxybenzoic acid eutectic has 46.51% weight loss in the temperature range of 150-220 ℃, and is endothermic melting of 2, 5-dihydroxybenzoic acid corresponding to the second endothermic peak.
Example 8:
as shown in the general diagrams of 22-24, the preparation of paeonol and propyl gallate
200.0mg of paeonol and 255.4mg of propyl gallate are weighed into a 10mL glass bottle, 1mL of acetone is added for dissolution, and the solution is rapidly volatilized through opening to obtain a paeonol and propyl gallate eutectic sample which is named as S8.
In this example, paeonol and propyl gallate have the following characteristic peaks expressed by an angle 2 θ in an X-ray powder diffraction pattern of Cu — K α radiation: 4.441 °, 8.938 °, 12.623 °, 13.223 °, 13.46 °, 13.738 °, 15.101 °, 16.263 °, 17.617 °, 17.943 °, 18.34 °, 19.141 °, 20.801 °, 21.14 °, 21.958 °, 22.616 °, 24.193 °, 24.444 °, 25.4 °, 26.022 °, 27.056 °, 27.876 °, 29.643 °, 31.8 °, 32.418 °, 33.152 °, 34.597 °, 35.814 °, 36.45 °, 37.305 °, 37.901 °, 38.702 °, 39.154 °, 40.061 °, 40.639 °, 41.244 °, 42.343 °, 43.218 °, 44.454 °, with an error tolerance of ± 0.2 °.
In the present example, the differential scanning calorimetry of the paeonol and propyl gallate eutectic shows Tonset at 78.36 ℃ and 138.20 ℃, Tpeak at 80.55 ℃ and 177.48 ℃; the paeonol and propyl gallate eutectic crystal has weight loss of 46.58% in the temperature range of 25-165 ℃, and is single melting of paeonol corresponding to the first endothermic peak of DSC; the paeonol and propyl gallate eutectic crystal has 57.13% weight loss in the temperature range of 175-257 ℃, which corresponds to the second endothermic peak and is endothermic melting of propyl gallate.
Example 9:
as shown in the comprehensive figures 25-32, the paeonol eutectic crystal has single crystal X-ray diffraction structure
Single crystal X-ray diffraction (SCXRD) structures of paeonol and 2-amino-6-methylbenzothiazole have the following parameters:
Figure 224894DEST_PATH_IMAGE002
the paeonol and 2-amino-6-methylbenzothiazole crystals belong to a triclinic system, P-1 space group, and the minimum asymmetric unit of the paeonol and 2-amino-benzothiazole crystals consists of 3 paeonol molecules and 2 amino-benzothiazole molecules.
The single crystal X-ray diffraction (SCXRD) structure of paeonol and 2-aminobenzothiazole has the following parameters:
Figure 141903DEST_PATH_IMAGE003
the paeonol and 2-aminobenzothiazole crystals belong to a triclinic crystal system, a P-1 space group, and the minimum asymmetric unit of the paeonol and 2-aminobenzothiazole crystals consists of 2 paeonol molecules and 1 2-aminobenzothiazole molecule.
The single crystal X-ray diffraction (SCXRD) structure of paeonol and 3, 4-dihydroxy benzoic acid has the following parameters:
Figure 279624DEST_PATH_IMAGE004
the paeonol and 3, 4-dihydroxy benzoic acid crystal belong to monoclinic system, P21/c space group, and the minimum asymmetric unit of the crystal consists of 1 paeonol molecule and 13, 4-dihydroxy benzoic acid molecule.
The single crystal X-ray diffraction (SCXRD) structure of paeonol and gallic acid has the following parameters:
Figure 741829DEST_PATH_IMAGE005
the paeonol and the gallic acid crystal belong to monoclinic system, C2/C space group, and the minimum asymmetric unit of the paeonol and gallic acid crystal consists of 1 paeonol molecule and 1 gallic acid molecule.
The single crystal X-ray diffraction (SCXRD) structure of paeonol and 3, 5-difluorobenzoic acid has the following parameters:
Figure 965000DEST_PATH_IMAGE006
the paeonol and 3, 5-difluorobenzoic acid crystal belong to a triclinic system, P-1 space group, and the minimum asymmetric unit of the paeonol and 3, 5-difluorobenzoic acid crystal is composed of 1 paeonol molecule and 13, 5-difluorobenzoic acid molecule.
The single crystal X-ray diffraction (SCXRD) structure of paeonol and urea has the following parameters:
Figure 436433DEST_PATH_IMAGE007
the paeonol and urea crystals belong to a triclinic system, P-1 space group, and the minimum asymmetric unit of the paeonol and urea crystals consists of 1 paeonol molecule and 2 urea molecules.
The single crystal X-ray diffraction (SCXRD) structure of paeonol and 2, 5-dihydroxy benzoic acid has the following parameters:
Figure 677927DEST_PATH_IMAGE008
the paeonol and 2, 5-dihydroxy benzoic acid crystal belong to a triclinic system, P-1 space group, and the minimum asymmetric unit of the paeonol and 2, 5-dihydroxy benzoic acid crystal consists of 1 paeonol molecule and 12, 5-dihydroxy benzoic acid molecule.
The single crystal X-ray diffraction (SCXRD) structure of paeonol and propyl gallate has the following parameters:
Figure 576613DEST_PATH_IMAGE009
the paeonol and propyl gallate crystal belong to monoclinic system, P21/c space group, and the minimum asymmetric unit of the paeonol and propyl gallate crystal consists of 1 paeonol molecule and 1 propyl gallate molecule.
Example 10:
with the synthesis of the attached figures 33-40, stability experiment of paeonol eutectic crystal
In order to determine whether the prepared eutectic can exist stably, stability tests need to be carried out on the prepared eutectic samples, and the stability of the eutectic samples is examined under four experimental conditions, namely acceleration (A), high humidity (H), illumination (L) and high temperature (T). The specific experimental conditions were as follows: a: the accelerated experiment is carried out under the supernormal condition, the stability of the medicine is inspected by accelerating the change speed of the physical and chemical properties of the medicine, the accelerated experiment condition of the experiment is 40 ℃, 75% RH, the sample is placed in the accelerated experiment, and the sample is sampled and detected on the 5 th day and the 10 th day; h: a high humidity test, which examines the stability of the drug under 92.5% RH, and places the sample therein, and samples are taken and tested on the 5 th and 10 th days; l: in the illumination experiment, a sample is placed in an illumination box, the illumination intensity is 4500Lx under the experiment condition, and sampling detection is carried out on the 5 th day and the 10 th day; t: high temperature test, placing the sample in a constant temperature stability box at 60 ℃, sampling and detecting on 5 th day and 10 th day, wherein the experimental results of paeonol eutectic crystal stability are as follows:
Figure 287080DEST_PATH_IMAGE010
according to the stability test result of 10 days, S3, S4, S5 and S7 have good stability under the conditions of acceleration, high humidity, illumination and high temperature; s1 and S2 are unstable at high temperatures, S6 is unstable at accelerated conditions, and S8 is unstable at both high temperatures and accelerated conditions; whereas for Pae it melts directly at high temperature, sublimation occurs under other conditions; in general, most paeonol co-crystals have good stability.
Example 11:
as shown in FIGS. 41-48, the solubility test method is as follows.
The eutectics of examples 1-8 were analyzed for dissolution by the following procedure and analysis: adopting Agilent1260 series high performance liquid chromatograph, adopting pH =2.0 glycine-hydrochloric acid buffer solution as dissolution medium, respectively performing dissolution analysis on paeonol and eutectic thereof, wherein the operation and analysis steps are as follows: the dissolution rates of paeonol eutectic at 10 time points of 5min, 10min, 15min, 30min, 45min, 60min, 90min, 120min, 180min and 24h are measured by adopting an Agilent1260 series high performance liquid chromatograph.
From the above results, it can be seen that: in a buffer dissolution medium with pH =2.0, the maximum solubility of paeonol is 0.9 mg/mL, compared with paeonol, eutectic samples S2, S3, S4, S6, S7 and S8 have better solubility, and the maximum solubilities of S2, S3, S4, S6, S7 and S8 are respectively 1.12 mg/mL, 1.36 mg/mL, 1.39 mg/mL, 1.19 mg/mL, 1.13 mg/mL and 1.14 mg/mL; s1 and S5 have lower solubility.
Example 12
Comparison of sublimation rates
Referring to FIGS. 49-50, the specific experimental procedure was as follows: instruments used in the experiment are all DVS, the test time is 24h, the diameter of a sample evaporation disc adopted in the experiment is 10mm, sieved sample powder is fully paved at the bottom, the test conditions are 40 ℃ and 10% RH, a fitting trend line is drawn according to a sublimation weight loss curve tested by the DVS, the sublimation weight loss rate of the sample is calculated according to the slope of the fitting trend line and the bottom area of the evaporation disc, and the sublimation weight loss rate is expressed as VSub (mg/(min. mm 2).
The results of the experiments are shown in the following table
Figure 31045DEST_PATH_IMAGE011
The sublimation weight loss rate sequence of paeonol and eutectic samples under the condition of 40 ℃ and 10% RH is Pae > S5> S2> S7= S8= S1> S6> S3> S4, and compared with paeonol, the sublimation rate of all the eutectic is reduced by at least one order of magnitude, wherein the sublimation rate of S3 and S4 eutectic samples with solubility advantages is reduced particularly obviously and is respectively reduced by 333 times and 167 times, the safety of production and storage of the paeonol can be obviously improved, the environmental pollution caused by sublimation loss of the paeonol or the loss of effective content in the preparation in the production or storage process is avoided, and the effectiveness, safety and quality consistency of the paeonol preparation are ensured.
It should be noted that: unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs; all patents and publications referred to herein are incorporated by reference. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are described herein.
Paeonol co-crystals can be identified by a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point methods, Differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance methods, raman spectroscopy, X-ray single crystal diffraction, and the like.
X-ray powder diffraction (XRPD) can detect information such as change, crystallinity, crystal structure state and the like of a crystal form, and is a common means for identifying the crystal form. The peak positions of the XRPD patterns depend primarily on the structure of the crystalline form, being relatively insensitive to experimental details, while their relative peak heights depend on a number of factors related to sample preparation and instrument geometry. Accordingly, in some embodiments, the crystalline form of the present invention is characterized by an XRPD pattern having certain peak positions, substantially as shown in the XRPD patterns provided in the figures of the present invention. Meanwhile, the 2 θ measurement of the XRPD pattern may have experimental error, and the 2 θ measurement of the XRPD pattern may be slightly different between different instruments and different samples, so the 2 θ value cannot be regarded as absolute; the diffraction peaks have a tolerance of ± 0.2 ° according to the conditions of the instrument used in the test.
Differential Scanning Calorimetry (DSC) is a technique that measures the change in energy difference between a sample and an inert reference (commonly α -Al2O3) with temperature by continuously heating or cooling under program control. The endothermic peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Thus, in some embodiments, the crystalline form of the present invention is characterized by a DSC profile with characteristic peak positions substantially as shown in the DSC profiles provided in the figures of the present invention. Meanwhile, the DSC profile may have experimental errors, and the peak position and peak value of the DSC profile may slightly differ between different instruments and different samples, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute; the endothermic peak has a tolerance of + -3 deg.C depending on the instrument used in the experiment.
Thermogravimetric analysis (TGA) is a technique for measuring the change in mass of a substance with temperature under program control, and is suitable for examining the loss of a solvent in a crystal or the sublimation and decomposition of a sample, and it can be presumed that the crystal contains crystal water or a crystal solvent. The change in mass shown by the TGA profile depends on many factors such as sample preparation and instrumentation; the mass change of the TGA detection varies slightly from instrument to instrument and from sample to sample. There is a tolerance of + -0.3 deg.C for mass change depending on the condition of the instrument used in this test.
In the context of the present invention, the 2 θ values in the X-ray powder diffraction pattern are all in degrees (°).
The term "peak" when referring to a spectrum or/and data appearing in a graph refers to a feature that one skilled in the art can identify that is not attributable to background noise.
The invention relates to co-crystals of said paeonol, which are present in substantially pure crystalline form.
By "substantially pure" is meant that a crystalline form is substantially free of one or more additional crystalline forms, i.e., the crystalline form is at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9% pure, or the crystalline form contains additional crystalline forms, the percentage of which in the total volume or weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
By "substantially free" is meant that the percentage of one or more other crystalline forms in the total volume or total weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
The "relative intensity" (or "relative peak height") in the XRPD pattern refers to the ratio of the intensity of the first strong peak to the intensity of the other peaks when the intensity of the first strong peak is 100% of all the diffraction peaks in the X-ray powder diffraction pattern (XRPD).
"room temperature" in the present invention means a temperature of from about 10 ℃ to about 40 ℃. In some embodiments, "room temperature" refers to a temperature of from about 20 ℃ to about 30 ℃; in other embodiments, "room temperature" refers to 20 ℃, 22.5 ℃, 25 ℃, 27.5 ℃, and the like.
All analyses below were performed at room temperature unless otherwise specified in the parameters.
X-ray powder diffraction (XRPD) the cocrystals or salts of the examples were subjected to RigakuUltimaIV powder diffractometer using Cu target irradiation (40 kV, 40 mA) at room temperature using a D/tex ultra detector. The scan range is from 3 ° to 45 ° in the 2 θ interval, and the scan speed is 20 °/min.
Differential Scanning Calorimetry (DSC) analysis was performed on the co-crystals or salts in the examples, with the following operating and analytical steps: a TAQ2000 differential scanning calorimeter is adopted, an N2 atmosphere is adopted, and the temperature rising speed is 10 ℃ per min. In the DSC chart, the abscissa represents Temperature (DEG C) and the ordinate represents the heat flow rate (HeatFlow, W/g) released per unit mass of the substance.
Thermogravimetric (TGA) analysis of the co-crystals in the examples was performed as follows: a TAQ500 thermogravimetric analyzer is adopted, an N2 atmosphere is adopted, and the temperature rising speed is 10 ℃ per min. In the TGA chart, the abscissa represents Temperature (deg.C) and the ordinate represents mass percent (Weight%).
The dissolution analysis of the co-crystals in the examples was carried out by the following operating and analytical procedures: the dissolution rates of paeonol eutectic at 10 time points of 5min, 10min, 15min, 30min, 45min, 60min, 90min, 120min, 180min and 24h are measured by adopting an Agilent1260 series high performance liquid chromatograph and adopting a buffer salt solution with pH =2.0 as a dissolution medium.
Carrying out sublimation rate analysis on the eutectic in the embodiment, wherein the operation and analysis steps are as follows: the method comprises the steps of testing the sample amount to be 4-10mg by utilizing an Intrasic DVS system, paving ground and sieved paeonol and paeonol eutectic powder at the bottom of an evaporation pan to ensure that sublimation surface areas are approximately equal, wherein the diameter of the evaporation pan of the sample is 10mm, the temperature is 40 ℃, the humidity is 10% RH, the testing time is 24h, and the sublimation rate is the sample amount of sublimation weight loss in unit time under the condition of unit area, and the unit is mg/(min mm 2).
For single crystal X-ray diffraction (SCXRD) analysis in the examples, the operating and analysis steps were as follows: diffraction data were collected using a CCD under Cu-ka radiation (λ =0.83 a) on a Bruker D8 vensource diffractometer, and data integration and reduction were performed using APEX3 software. The structure was resolved by direct method using OLEX2 software and refined on F2 by full matrix least squares using SHELXL program.
The polarized light microscope was model DM750P and the heating device was model XRN-350.
The above description is only a preferred embodiment of the present invention, and the scope of the present invention is not limited to the above embodiment, but equivalent modifications or changes made by those skilled in the art according to the present disclosure should be included in the scope of the present invention as set forth in the appended claims.

Claims (17)

1. A paeonol co-crystal with thermal stability and solubility advantages is characterized by comprising a co-crystal formed by combining paeonol and a co-crystal former; the eutectic formation product is any one of 2-amino-6-methylbenzothiazole, 2-aminobenzothiazole, 3, 4-dihydroxybenzoic acid, gallic acid, 3, 5-difluorobenzoic acid, urea, 2, 5-dihydroxybenzoic acid and propyl gallate.
2. A paeonol co-crystal with thermal stability and solubility advantages according to claim 1, wherein the paeonol co-crystal with 2-amino-6-methylbenzothiazole has the following characteristic peaks expressed in terms of angle 2 theta in an X-ray powder diffraction pattern: 6.67 °, 8.188 °, 10.295 °, 10.884 °, 13.01 °, 15.37 °, 16.177 °, 16.376 °, 17.608 °, 19.575 °, 19.712 °, 20.244 °, 20.821 °, 21.445 °, 21.933 °, 22.292 °, 23.598 °, 23.965 °, 24.9 °, 25.421 °, 26.515 °, 27.086 °, 27.736 °, 27.917 °, 28.861 °, 29.205 °, 30.115 °, 30.352 °, 31.424 °, 31.728 °, 32.174 °, 32.907 °, 33.251 °, 33.741 °, 34.489 °, 34.771 °, 35.582 °, 35.898 °, 36.423 °, 36.85 °, 37.271 °, 38.124 °, 38.628 °, 39.717 °, 40.185 °, 40.844 °, 41.583 °, 42.194 °, 42.608 °, 43.512 °, 43.845 °, 44.27 °, with an error tolerance of ± 0.2 °.
3. A paeonol co-crystal with thermal stability and solubility advantages according to claim 1, wherein the paeonol co-crystal with 2-aminobenzothiazole has the following characteristic peaks expressed in terms of angle 2 theta in an X-ray powder diffraction pattern: 6.077 degrees, 8.584 degrees, 12.163 degrees, 12.873 degrees, 13.725 degrees, 15.387 degrees, 17.016 degrees, 17.324 degrees, 18.272 degrees, 18.99 degrees, 20.88 degrees, 21.25 degrees, 22.041 degrees, 22.687 degrees, 22.986 degrees, 23.727 degrees, 24.441 degrees, 27.461 degrees, 28.619 degrees, 28.896 degrees, 29.797 degrees, 30.268 degrees, 30.594 degrees, 32.254 degrees, 33.209 degrees, 33.694 degrees, 34.251 degrees, 34.737 degrees, 35.029 degrees, 36.064 degrees, 36.395 degrees, 37.021 degrees, 37.871 degrees, 39.114 degrees, 41.035 degrees, 41.291 degrees, 43.494 degrees, and an error tolerance of +/-0.2 degrees exists.
4. A paeonol co-crystal having thermal stability and solubility advantages according to claim 1, wherein the paeonol co-crystal with 3, 4-dihydroxybenzoic acid has the following characteristic peaks expressed in terms of angle 2 θ in an X-ray powder diffraction pattern: 9.683 degrees, 10.422 degrees, 11.313 degrees, 13.056 degrees, 13.763 degrees, 14.007 degrees, 15.602 degrees, 15.954 degrees, 16.621 degrees, 19.277 degrees, 19.91 degrees, 20.979 degrees, 21.962 degrees, 22.926 degrees, 23.367 degrees, 24.004 degrees, 25.817 degrees, 26.648 degrees, 27.153 degrees, 27.677 degrees, 28.164 degrees, 29.185 degrees, 31.667 degrees, 32.302 degrees, 33.315 degrees, 33.628 degrees, 34.24 degrees, 36.653 degrees, 37.006 degrees, 38.168 degrees, 38.62 degrees, 38.963 degrees, 39.806 degrees, 40.431 degrees, 42.031 degrees, 42.756 degrees, 43.259 degrees, 43.548 degrees and 44.269 degrees, and error tolerance of +/-0.2 degrees exists.
5. A paeonol co-crystal with thermal stability and solubility advantages according to claim 1, wherein the X-ray powder diffraction pattern of the paeonol co-crystal with gallic acid has the following characteristic peaks expressed in terms of angle 2 theta: 7.21 °, 7.982 °, 8.425 °, 9.866 °, 10.613 °, 11.143 °, 11.425 °, 12.259 °, 13.433 °, 13.772 °, 14.59 °, 15.397 °, 16.137 °, 16.938 °, 17.338 °, 18.405 °, 18.923 °, 19.566 °, 20.763 °, 21.14 °, 21.958 °, 22.458 °, 23.165 °, 23.407 °, 24.034 °, 24.802 °, 25.796 °, 26.844 °, 27.934 °, 29.082 °, 29.458 °, 30.344 °, 31.281 °, 31.675 °, 31.947 °, 33.1 °, 33.951 °, 34.448 °, 35.119 °, 37.152 °, 37.94 °, 39.137 °, 40.596 °, 41.604 °, 42.557 °, 43.316 °, 43.897 °, and an error tolerance of ± 0.2 ° exists.
6. The paeonol eutectic crystal with thermal stability and solubility advantages as claimed in claim 1, wherein the paeonol eutectic crystal with 3, 5-difluorobenzoic acid has the following characteristic peaks expressed in terms of angle 2 theta in an X-ray powder diffraction pattern: 10.537 degrees, 10.86 degrees, 12.45 degrees, 12.935 degrees, 14.335 degrees, 14.558 degrees, 16.616 degrees, 18.11 degrees, 18.836 degrees, 19.104 degrees, 21.416 degrees, 21.844 degrees, 22.479 degrees, 23.018 degrees, 23.651 degrees, 25.189 degrees, 26.259 degrees, 26.649 degrees, 27.41 degrees, 27.675 degrees, 28.363 degrees, 28.874 degrees, 29.154 degrees, 30.103 degrees, 31.9 degrees, 32.276 degrees, 33.365 degrees, 35.647 degrees, 35.908 degrees, 37.245 degrees, 37.512 degrees, 37.95 degrees, 38.255 degrees, 39.201 degrees, 39.675 degrees, 40.008 degrees, 42.738 degrees, 44.12 degrees, and an error tolerance of +/-0.2 degrees exists.
7. A paeonol co-crystal having thermal stability and solubility advantages according to claim 1, wherein the X-ray powder diffraction pattern of the paeonol co-crystal with urea has the following characteristic peaks expressed in terms of angle 2 θ: 6.106 degrees, 12.27 degrees, 13.038 degrees, 14.128 degrees, 14.399 degrees, 15.697 degrees, 17.693 degrees, 18.483 degrees, 19.635 degrees, 20.012 degrees, 22.488 degrees, 23.336 degrees, 23.705 degrees, 24.015 degrees, 24.619 degrees, 25.136 degrees, 25.694 degrees, 26.336 degrees, 26.686 degrees, 27.248 degrees, 27.544 degrees, 27.948 degrees, 28.473 degrees, 29.245 degrees, 29.971 degrees, 30.789 degrees, 32.134 degrees, 32.623 degrees, 33.733 degrees, 34.51 degrees, 35.099 degrees, 35.567 degrees, 35.893 degrees, 36.796 degrees, 37.776 degrees, 38.268 degrees, 39.33 degrees, 39.917 degrees, 40.754 degrees, 41.975 degrees, 43.004 degrees and 44.111 degrees, and an error tolerance of +/-0.2 degrees exists.
8. A paeonol co-crystal having thermal stability and solubility advantages according to claim 1, wherein the paeonol co-crystal with 2, 5-dihydroxybenzoic acid has the following characteristic peaks expressed in terms of angle 2 θ in an X-ray powder diffraction pattern: 7.514 degrees, 9.24 degrees, 10.94 degrees, 13.338 degrees, 14.501 degrees, 15.001 degrees, 15.82 degrees, 16.363 degrees, 17.521 degrees, 17.78 degrees, 18.939 degrees, 19.483 degrees, 20.379 degrees, 21.161 degrees, 22.056 degrees, 22.901 degrees, 23.22 degrees, 24.332 degrees, 24.74 degrees, 25.36 degrees, 25.963 degrees, 26.999 degrees, 27.44 degrees, 28.576 degrees, 29.299 degrees, 30.478 degrees, 32.857 degrees, 33.241 degrees, 34.262 degrees, 35.481 degrees, 36.139 degrees, 37.458 degrees, 38.6 degrees, 39.781 degrees, 40.94 degrees, 41.461 degrees and 43.761 degrees, and an error tolerance of +/-0.2 degrees exists.
9. A paeonol co-crystal having thermal stability and solubility advantages according to claim 1, wherein the paeonol co-crystal with propyl gallate has the following characteristic peaks expressed in terms of angle 2 θ in an X-ray powder diffraction pattern: 4.441 degrees, 8.938 degrees, 12.623 degrees, 13.223 degrees, 13.46 degrees, 13.738 degrees, 15.101 degrees, 16.263 degrees, 17.617 degrees, 17.943 degrees, 18.34 degrees, 19.141 degrees, 20.801 degrees, 21.14 degrees, 21.958 degrees, 22.616 degrees, 24.193 degrees, 24.444 degrees, 25.4 degrees, 26.022 degrees, 27.056 degrees, 27.876 degrees, 29.643 degrees, 31.8 degrees, 32.418 degrees, 33.152 degrees, 34.597 degrees, 35.814 degrees, 36.45 degrees, 37.305 degrees, 37.901 degrees, 38.702 degrees, 39.154 degrees, 40.061 degrees, 40.639 degrees, 41.244 degrees, 42.343 degrees, 43.218 degrees, 44.454 degrees, and an error tolerance of +/-0.2 degrees exists.
10. The paeonol co-crystal with thermal stability and solubility advantages as claimed in claim 1, wherein the difference scanning calorimetry spectrum of the paeonol co-crystal with 2-amino-6-methylbenzothiazole shows Tonset of 88.67 ℃ and Tpeak of 88.85 ℃;
the differential scanning calorimetry spectrogram of the paeonol and 2-aminobenzothiazole eutectic shows that the Tonset is 59.17 ℃ and the Tpeak is 60.68 ℃;
the differential scanning calorimetry spectrogram of the paeonol and 3, 4-dihydroxy benzoic acid eutectic shows that the Tonset is 126.55 ℃ and 203.10 ℃, and the Tpeak is 128.15 ℃ and 204.13 ℃;
the differential scanning calorimetry spectrogram of the paeonol eutectic crystal with the gallic acid shows that the Tonset is 139.26 ℃ and 238.18 ℃, and the Tpeak is 141.85 ℃ and 248.20 ℃;
the differential scanning calorimetry spectrogram of the paeonol eutectic with the 3, 5-difluorobenzoic acid shows that the Tonset is 91.44 ℃, and the Tpeak is 92.24 ℃;
the differential scanning calorimetry spectrogram of the paeonol and urea eutectic shows that the Tonset is 111.25 ℃ and 131.61 ℃, and the Tpeak is 115.07 ℃ and 132.87 ℃;
the differential scanning calorimetry spectrogram of the paeonol and 2, 5-dihydroxy benzoic acid eutectic shows that the Tonset is 92 ℃ and 200.22 ℃, and the Tpeak is 95.89 ℃ and 202.45 ℃;
a differential scanning calorimetry spectrogram of the paeonol and propyl gallate eutectic crystal shows that the Tonset is 78.36 ℃ and 138.20 ℃, and the Tpeak is 80.55 ℃ and 177.48 ℃.
11. A paeonol eutectic crystal with thermal stability and solubility advantages as claimed in claim 1, wherein the paeonol eutectic crystal with 2-amino-6-methylbenzothiazole is gradually decomposed and weightless after being melted in a temperature range of 25-200 ℃;
the paeonol and 2-aminobenzothiazole eutectic is gradually decomposed and weightless after being melted in the temperature range of 25-200 ℃;
the paeonol and 3, 4-dihydroxy benzoic acid eutectic has no obvious weight loss in the temperature range of 25-100 ℃; the paeonol and the 3, 4-dihydroxybenzoic acid eutectic have 51.26 percent weight loss within the temperature range of 100-165 ℃; the paeonol and the 3, 4-dihydroxybenzoic acid eutectic have 36.84 percent weight loss within the temperature range of 190-;
the paeonol and gallic acid eutectic has no obvious weight loss within the temperature range of 25-88 ℃; the paeonol and the gallic acid eutectic are subjected to weight loss of 41.21 percent within the temperature range of 88-144 ℃; the paeonol and the gallic acid eutectic have 32.73 percent weight loss within the temperature range of 217 ℃ and 298 ℃;
melting the paeonol and the 3, 5-difluorobenzoic acid eutectic at the temperature of between 25 and 150 ℃ and then gradually decomposing and losing weight;
the paeonol and urea eutectic is 57.23 percent of weight loss in the temperature range of 25-138 ℃; the paeonol and urea eutectic has 35.56 percent weight loss within the temperature range of 138-198 ℃;
the paeonol and the 2, 5-dihydroxybenzoic acid eutectic are subjected to 54.46% weight loss in a temperature range of 25-150 ℃; the paeonol and 2, 5-dihydroxybenzoic acid eutectic has 46.51 percent weight loss within the temperature range of 150-220 ℃;
the paeonol and propyl gallate eutectic crystal is subjected to weight loss of 46.58% within the temperature range of 25-165 ℃; the paeonol and propyl gallate eutectic crystal has 57.13 percent weight loss in the temperature range of 175-257 ℃.
12. A paeonol co-crystal having thermal stability and solubility advantages according to claim 1, wherein in the co-crystal of paeonol and 2-amino-6-methylbenzothiazole, paeonol and 2-amino-6-methylbenzothiazole are present in a molar ratio of 3: 2;
or in the eutectic of paeonol and 2-aminobenzothiazole, the paeonol and the 2-aminobenzothiazole exist in a molar ratio of 2: 1;
or in the eutectic of the paeonol and the 3, 4-dihydroxybenzoic acid, the paeonol and the 3, 4-dihydroxybenzoic acid exist in a molar ratio of 1: 1;
or in the eutectic of paeonol and gallic acid, the paeonol and the gallic acid exist in a molar ratio of 1: 1;
or in the eutectic of paeonol and 3, 5-difluorobenzoic acid, the paeonol and the 3, 5-difluorobenzoic acid exist in a molar ratio of 1: 1;
or in the eutectic of paeonol and urea, the paeonol and the urea exist in a molar ratio of 1: 2;
or in the eutectic of the paeonol and the 2, 5-dihydroxybenzoic acid, the paeonol and the 2, 5-dihydroxybenzoic acid exist in a molar ratio of 1: 1;
or in the eutectic of paeonol and propyl gallate, the paeonol and the propyl gallate are present in a molar ratio of 1: 1.
13. The preparation method of the paeonol eutectic is characterized by comprising the following specific steps of: mixing paeonol and an eutectic formation according to a molar ratio of 0.5-2: 1, adding a solvent, heating, and stirring until the paeonol and the eutectic formation are completely dissolved; and standing and volatilizing at room temperature for 1-5 days, separating out crystals, and drying in vacuum at 40 ℃ to obtain the paeonol eutectic crystal.
14. The preparation method of the paeonol eutectic is characterized by comprising the following specific steps of: mixing paeonol and an eutectic formation according to the molar ratio of 0.5-2: 1, adding an organic solvent, heating to 40 ℃, and stirring until the paeonol and the eutectic formation are completely dissolved; and standing at-20 ℃ for cooling for 1-2 days to precipitate crystals, and drying in vacuum at 40 ℃ to obtain the paeonol eutectic.
15. The preparation method of the paeonol eutectic is characterized by comprising the following specific steps of: mixing paeonol and the eutectic formation according to the molar ratio of 0.5-2: 1, adding an organic solvent, stirring and separating, and drying in vacuum at 40 ℃ to obtain the paeonol eutectic.
16. A pharmaceutical composition, comprising a paeonol co-crystal as an active ingredient and an acceptable carrier; the dosage form of the pharmaceutical composition is selected from the group consisting of: liquid, solid, semi-solid formulations.
17. An application of paeonol eutectic and its composition in preparing the medicines for treating the inflammation and inflammation of human body and reducing the sublimation loss of paeonol in production and storage is disclosed.
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