CN115010591B - 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 PDFInfo
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Abstract
The invention discloses a paeonol eutectic crystal and a preparation method thereof, relates to the technical field of pharmaceutical eutectic crystals, and particularly relates to the paeonol eutectic crystal formed by combining paeonol and an eutectic crystal former. 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, and the preferred paeonol eutectic disclosed by the invention has better stability and is beneficial to long-term storage of medicines. In addition, compared with easily sublimable paeonol, the paeonol eutectic disclosed by the invention has the advantage of being difficult to sublime. In addition, the preferred paeonol co-crystal improves the solubility of paeonol. A paeonol eutectic crystal can better realize the safety of production and storage of paeonol and the effectiveness of clinical application.
Description
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 (Pae) is an effective component extracted from dried root bark of Paeonia suffruticosa Andr of Ranunculaceae, and is a natural phenolic compound with chemical formula of C 9 H 10 O 3 The molecular weight is: 166.174, the chemical formula is as follows:
many experimental studies show that the structural skeleton of paeonol ketone has wide biological activity. The paeonol has the main pharmacological activity of resisting inflammation, has good clinical significance, and has the effects of dilating cardiovascular vessels, 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 is available in the dosage forms of ointment, cream, tablet, injection and dripping pill. Chinese patent of a preparation method of a refined and purified paeonol preparation, authorization number: CN102499913B, which shows that paeonol is unstable to heat and easily decomposed and oxidized during purification, so that 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 paeonol eutectic crystal with the advantages of thermal stability and solubility is provided by the invention, and comprises the eutectic crystal formed by combining paeonol and a eutectic crystal forming substance; 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 °,40.844 °,41.583 °,42.194 °,42.608 °, 43.43.845 °, 43.27.27.44 °, 0 ± 2 ° of tolerance.
Preferably, the paeonol and 2-aminobenzothiazole eutectic crystal has the following characteristic peaks expressed by an angle 2 theta in an X-ray powder diffraction pattern: 6.077 °,8.584 °,12.163 °,12.873 °,13.725 °,15.387 °,17.016 °,17.324 °,18.272 °,18.99 °,20.88 °,21.25 °,22.041 °,22.687 °,22.986 °,23.727 °,24.441 °,27.461 °,28.619 °,28.896 °,29.797 °,30.268 °,30.594 °,32.254 °,33.209 °,33.694 °,34.251 °,34.737 °,35.029 °,36.064 °,36.395 °,37.021 °,37.871 °,39.114 °,41.035 °,41.291 °,43.494 °, and an error tolerance of ± 0.2 ° 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 °,10.422 °,11.313 °,13.056 °,13.763 °,14.007 °,15.602 °,15.954 °,16.621 °,19.277 °,19.91 °,20.979 °,21.962 °,22.926 °,23.367 °,24.004 °,25.817 °,26.648 °,27.153 °,27.677 °,28.164 °,29.185 °,31.667 °,32.302 °,33.315 °,33.628 °,34.24 °,36.653 °,37.006 °,38.168 °,38.62 °,38.963 °,39.806 °,40.431 °, 42.269 °,42.756 °,43.259 °,43.548 °, 44.03144 °, with an error tolerance of ± 0.2 °.
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 43.897 ° with a tolerance of ± 0.2 °.
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 °,10.86 °,12.45 °,12.935 °,14.335 °,14.558 °,16.616 °,18.11 °,18.836 °,19.104 °,21.416 °,21.844 °,22.479 °,23.018 °,23.651 °,25.189 °,26.259 °,26.649 °,27.41 °,27.675 °,28.363 °,28.874 °,29.154 °,30.103 °,31.9 °,32.276 °,33.365 °,35.647 °,35.908 °,37.245 °,37.512 °,37.95 °,38.255 °,39.201 °,39.675 °,40.008 °,42.738 °,44.12 °, with a tolerance of ± 0.2 °.
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 °,12.27 °,13.038 °,14.128 °,14.399 °,15.697 °,17.693 °,18.483 °,19.635 °,20.012 °,22.488 °,23.336 °,23.705 °,24.015 °,24.619 °,25.136 °,25.694 °,26.336 °,26.686 °,27.248 °,27.544 °,27.948 °,28.473 °,29.245 °,29.971 °,30.789 °,32.134 °,32.623 °,33.733 °,34.51 °,35.099 °,35.567 °,35.893 °,36.796 °,37.776 °,38.268 °,39.33 °,39.917 °,40.754 °,41.975 °,43.004 °,44.111 °, and ± 0.2 ° are tolerance errors.
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 °,9.24 °,10.94 °,13.338 °,14.501 °,15.001 °,15.82 °,16.363 °,17.521 °,17.78 °,18.939 °,19.483 °,20.379 °,21.161 °,22.056 °,22.901 °,23.22 °,24.332 °,24.74 °,25.36 °,25.963 °,26.999 °,27.44 °,28.576 °,29.299 °,30.478 °,32.857 °,33.241 °,34.262 °,35.481 °,36.139 °,37.458 °,38.6 °,39.781 °,40.94 °,41.461 °,43.761 °, with a tolerance of ± 0.2 °.
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 °,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 a tolerance of ± 0.2 °.
Preferably, the difference scanning calorimetry spectrogram of the paeonol eutectic and the 2-amino-6-methylbenzothiazole eutectic 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 eutectic with the 3, 4-dihydroxy benzoic acid 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 crystal and 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 ℃;
the differential scanning calorimetry of the paeonol and propyl gallate eutectic 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 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 3, 4-dihydroxy benzoic acid eutectic has 51.26 percent weight loss within the temperature range of 100-165 ℃; the paeonol and 3, 4-dihydroxy benzoic acid eutectic has 36.84 percent weight loss within the temperature range of 190-300 ℃;
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 gallic acid eutectic have 32.73% weight loss within the temperature range of 217-298 ℃;
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 lost by 57.23% in weight within 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 2, 5-dihydroxy benzoic acid eutectic is subjected to weight loss of 54.46 percent within the temperature range of 25-150 ℃; the paeonol and 2, 5-dihydroxy benzoic acid eutectic has 46.51 percent of weight loss within the temperature range of 150-220 ℃;
the paeonol and propyl gallate eutectic crystal is subjected to weight loss of 46.58 percent within the temperature range of 25-165 ℃; the paeonol and propyl gallate eutectic crystal has 57.13 percent weight loss within 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 molar ratio of 3;
in the cocrystal of paeonol and 2-aminobenzothiazole, paeonol and 2-aminobenzothiazole are present in a molar ratio of 2;
in the eutectic of paeonol and 3, 4-dihydroxybenzoic acid, the paeonol and the 3, 4-dihydroxybenzoic acid exist in a molar ratio of 1;
in the eutectic of paeonol and gallic acid, the paeonol and the gallic acid exist in a molar ratio of 1;
in the eutectic of paeonol and 3, 5-difluorobenzoic acid, paeonol and 3, 5-difluorobenzoic acid are present in a molar ratio of 1;
in the eutectic of paeonol and urea, the paeonol and the urea exist in a molar ratio of 1;
in the eutectic of paeonol and 2, 5-dihydroxybenzoic acid, the paeonol and the 2, 5-dihydroxybenzoic acid exist in a molar ratio of 1;
in the co-crystal of paeonol and propyl gallate, paeonol and propyl gallate are present in a 1.
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 to 2, adding a solvent, heating, and stirring until the paeonol and the eutectic formation are completely dissolved; standing and volatilizing at room temperature for 1-5 days, precipitating crystals, and vacuum drying at 40 ℃ to obtain the paeonol pharmaceutical eutectic.
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 to 2; then standing and cooling for 1 to 2 days at the temperature of minus 20 ℃, precipitating crystals, and drying in vacuum at the temperature of 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 to 2, adding an organic solvent into the mixture, stirring and separating the mixture, and drying the mixture 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 preparation, solid preparation, and semisolid preparation.
An application of paeonol eutectic and its composition in preparing the medicines for better playing its anti-inflammatory action and reducing the sublimation loss of paeonol in production and storage is disclosed.
Compared with the prior art, the invention has the following beneficial effects:
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 drugs, 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 pharmaceutical 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 eutectic obtained 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) spectrum of the eutectic of paeonol and 3, 4-dihydroxybenzoic acid prepared in example 3.
FIG. 9 is a thermogravimetric analysis (TGA) spectrum of a cocrystal of paeonol and 3, 4-dihydroxybenzoic acid obtained in example 3.
FIG. 10 is an X-ray powder diffraction (XRPD) pattern of paeonol and gallic acid obtained 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) spectrum 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 obtained 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) chart of the co-crystal 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 co-crystal of paeonol and paeonol.
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 techniques 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 a person 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 into a 10mL glass bottle, 0.5mL of methanol is added, magnetic stirring is carried out, suspension is carried out for 24 hours, supernatant 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 °,40.844 °,41.583 °,42.194 °,42.608 °, 43.512.27.43.27 °, 43.44.27 °, 0 ° tolerance ± 2 ° exists.
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 shows that Tonset is 88.67 ℃ and Tpeak is 88.85 ℃. In a TGA spectrogram of the paeonol and 2-amino-6-methylbenzothiazole eutectic crystal, the paeonol and 2-amino-6-methylbenzothiazole eutectic crystal is gradually decomposed and weightless 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 in 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 an eutectic sample of paeonol and 2-aminobenzothiazole, which was designated as 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 °,8.584 °,12.163 °,12.873 °,13.725 °,15.387 °,17.016 °,17.324 °,18.272 °,18.99 °,20.88 °,21.25 °,22.041 °,22.687 °,22.986 °,23.727 °,24.441 °,27.461 °,28.619 °,28.896 °,29.797 °,30.268 °,30.594 °,32.254 °,33.209 °,33.694 °,34.251 °,34.737 °,35.029 °,36.064 °,36.395 °,37.021 °,37.871 °,39.114 °,41.035 °,41.291 °,43.494 °, and an error tolerance of ± 0.2 ° exists.
In the embodiment, in a DSC spectrogram of the paeonol and 2-aminobenzothiazole eutectic, a 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 FIGS. 7 to 9, the preparation of 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 theta in an X-ray powder diffraction pattern of Cu-Ka ray: 9.683 °,10.422 °,11.313 °,13.056 °,13.763 °,14.007 °,15.602 °,15.954 °,16.621 °,19.277 °,19.91 °,20.979 °,21.962 °,22.926 °,23.367 °,24.004 °,25.817 °,26.648 °,27.153 °,27.677 °,28.164 °,29.185 °,31.667 °,32.302 °,33.315 °,33.628 °,34.24 °,36.653 °,37.006 °,38.168 °,38.62 °,38.963 °,39.806 °, 03140.431 °,42.756 °,43.259 °,43.548 °, 44.44 °, with a tolerance of ± 0.2 °.
In this example, in the DSC spectrum of the eutectic of paeonol and 3, 4-dihydroxybenzoic acid, the differential scanning calorimetry spectrum of the eutectic of paeonol and 3, 4-dihydroxybenzoic acid showed that the Tonset was 126.55 ℃ and 203.10 ℃ and the Tpeak was 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 3, 4-dihydroxy benzoic acid eutectic has 51.26 percent weight loss within the temperature range of 100-165 ℃; the paeonol and 3, 4-dihydroxybenzoic acid eutectic has 36.84 percent weight loss within the temperature range of 190-300 ℃; the first endothermic peak is the endothermic melting of 3, 4-dihydroxybenzoic acid, and paeonol sublimed from the eutectic powder alone.
Example 4:
as shown in the comprehensive graphs of 10-12, the preparation of paeonol and gallic acid
200.0mg of paeonol and 204.7mg of gallic acid 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 is removed by centrifugation, and the obtained precipitate is paeonol and gallic acid eutectic powder which is named as S4.
In this example, paeonol and gallic acid have the following characteristic peaks expressed by an angle 2 θ in an X-ray powder diffraction pattern of Cu — K α radiation: 7.21 °,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 a tolerance of ± 0.892 °.
In the present example, in the DSC spectra of the paeonol and gallic acid eutectic, the differential scanning calorimetry spectra of the paeonol and gallic acid eutectic show that Tonset is 139.26 ℃ and 238.18 ℃, and 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 corresponds to the endothermic melting of gallic acid.
Example 5:
as shown in FIGS. 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-Ka rays: 10.537 °,10.86 °,12.45 °,12.935 °,14.335 °,14.558 °,16.616 °,18.11 °,18.836 °,19.104 °,21.416 °,21.844 °,22.479 °,23.018 °,23.651 °,25.189 °,26.259 °,26.649 °,27.41 °,27.675 °,28.363 °,28.874 °,29.154 °,30.103 °,31.9 °,32.276 °,33.365 °,35.647 °,35.908 °,37.245 °,37.512 °,37.95 °,38.255 °,39.201 °,39.675 °,40.008 °,42.738 °,44.12 °, with an error tolerance of ± 0.2 °.
In the example, in a DSC spectrum of the eutectic crystal of paeonol and 3, 5-difluorobenzoic acid, a differential scanning calorimetry spectrum of the eutectic crystal 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 3, 5-difluorobenzoic acid eutectic are gradually decomposed and weightless 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 °,12.27 °,13.038 °,14.128 °,14.399 °,15.697 °,17.693 °,18.483 °,19.635 °,20.012 °,22.488 °,23.336 °,23.705 °,24.015 °,24.619 °,25.136 °,25.694 °,26.336 °,26.686 °,27.248 °,27.544 °,27.948 °,28.473 °,29.245 °,29.971 °,30.789 °,32.134 °,32.623 °,33.733 °,34.51 °,35.099 °,35.567 °,35.893 °,36.796 °,37.776 °,38.268 °,39.33 °,39.917 °,40.754 °,41.975 °,43.004 °,44.111 °, and ± 0.2 ° are tolerance errors.
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 the temperature range of 25-138 ℃, and the paeonol is independently sublimated from the eutectic powder corresponding to a first endothermic peak of DSC; the paeonol and urea eutectic has 35.56% weight loss in the temperature range of 138-198 ℃, corresponds to a second endothermic peak, and is endothermic melting of urea.
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 in terms of angle 2 θ in the X-ray powder diffraction pattern of Cu — K α radiation: 7.514 °,9.24 °,10.94 °,13.338 °,14.501 °,15.001 °,15.82 °,16.363 °,17.521 °,17.78 °,18.939 °,19.483 °,20.379 °,21.161 °,22.056 °,22.901 °,23.22 °,24.332 °,24.74 °,25.36 °,25.963 °,26.999 °,27.44 °,28.576 °,29.299 °,30.478 °,32.857 °,33.241 °,34.262 °,35.481 °,36.139 °,37.458 °,38.6 °,39.781 °,40.94 °,41.461 °,43.761 °, with a tolerance of ± 0.2 °.
In the example, the differential scanning calorimetry spectrogram of the paeonol eutectic and the 2, 5-dihydroxy benzoic acid eutectic shows that the Tonset is 92 ℃ and 200.22 ℃, and the Tpeak is 95.89 ℃ and 202.45 ℃; the paeonol and 2, 5-dihydroxy benzoic acid eutectic is subjected to 54.46% weight loss in a temperature range of 25-150 ℃, and the paeonol is singly molten corresponding to the first endothermic peak of DSC; the paeonol and 2, 5-dihydroxy benzoic acid eutectic has 46.51% weight loss in the temperature range of 150-220 ℃, corresponds to a second endothermic peak, and is endothermic melting of 2, 5-dihydroxy benzoic acid.
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 dissolving, and the solution is quickly volatilized through opening to obtain the 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 a tolerance of ± 0.2 °.
In the embodiment, the 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 ℃; 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 ℃, and is endothermic melting of propyl gallate corresponding to the second endothermic peak.
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, the parameters of which are shown in the following table:
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:
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:
the paeonol and 3, 4-dihydroxy benzoic acid crystal belong to a monoclinic system, a P21/c space group, and the minimum asymmetric unit of the paeonol and 3, 4-dihydroxy benzoic acid 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:
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.
Single crystal X-ray diffraction (SCXRD) structure of paeonol and 3, 5-difluorobenzoic acid, the parameters are as follows:
the paeonol and 3, 5-difluorobenzoic acid crystal belong to a triclinic system, P-1 space group, and the minimum asymmetric unit of the crystal consists 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:
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:
the paeonol and 2, 5-dihydroxy benzoic acid crystal belong to a triclinic crystal system, a 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:
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 sample, and the stability of the eutectic sample 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: accelerated test, which 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 test condition of the test is 40 ℃,75% RH, samples are placed in the accelerated test condition, and sampling detection is carried out on the 5 th day and the 10 th day; h: high humidity test, which examines the stability of the drug under 92.5% RH conditions, samples were placed therein and sampled for testing on day 5 and day 10; 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:
according to the stability test result of 10 days, the S3, the S4, the S5 and the S7 have good stability under the conditions of acceleration, high humidity, illumination and high temperature; s1 and S2 are unstable under high temperature conditions, S6 is unstable under acceleration conditions, and S8 is unstable under both high temperature and acceleration conditions; whereas for Pae it melts directly at high temperature, sublimation also 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 Agilent1260 series high performance liquid chromatograph.
From the above results, it can be seen that: in a buffer solution 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 pan 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 pan, 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
The sublimation weight loss rate sequence of paeonol and eutectic samples under the condition of 10 ℃ and RH is Pae > S5> S2> S7= S8= S1> S6> S3> S4, and compared with paeonol, the sublimation rate of all eutectic samples is reduced by at least one order of magnitude, wherein the sublimation rate of the S3 and S4 eutectic samples with solubility advantage is reduced by 333 times and 167 times, so that the safety of production and storage of the paeonol can be obviously improved, the environmental pollution caused by the sublimation loss of the paeonol or the effective content loss in the preparation in the production or storage process is avoided, and the effectiveness, the safety and the 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.
Information such as change, crystallinity, crystal structure state and the like of the crystal form can be detected by X-ray powder diffraction (XRPD), and the method 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. Also, the 2 θ measurement of the XRPD pattern may have experimental error, and the 2 θ measurement of the XRPD pattern may differ slightly from instrument to instrument and from sample to sample, so the 2 θ values cannot be considered 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 for measuring the change in energy difference between a sample and an inert reference (commonly α -Al2O 3) 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 peaks have a tolerance of ± 3 ℃ 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 ℃ for mass variation, depending on the instrument used in the 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 crystal form is substantially free of one or more additional crystal forms, i.e., the crystal 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 crystal form contains additional crystal forms, the percentage of which in the total volume or weight of the crystal 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 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%.
"relative intensity" (or "relative peak height") in an 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 (40kV, 40mA) 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 percentage (Weight%).
The dissolution analysis was performed on the co-crystals in the examples, with the following operating and analytical steps: 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.
The sublimation rate of the eutectic in the examples was analyzed by the following steps: utilizing an Intrasic DVS system to test the sample amount to be 4-10mg, paving the ground and sieved paeonol and paeonol eutectic powder at the bottom of an evaporation pan to ensure that the 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 test 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 & lt 2 & gt).
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 v method diffractometer, and data integration and reduction were performed using APEX3 software. The structure was resolved by direct method using the OLEX2 software and refined on F2 by full matrix least squares using the SHELXL program.
The polarized light microscope is model DM750P and the heating device is 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 disclosure of the present invention should be included in the scope of the present invention as set forth in the appended claims.
Claims (5)
1. A paeonol eutectic crystal is characterized in that the paeonol eutectic crystal is formed by combining paeonol and an eutectic crystal formation substance selected from 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 the cocrystal of paeonol and 2-amino-6-methylbenzothiazole, paeonol and 2-amino-6-methylbenzothiazole are present in a molar ratio of 3;
in an X-ray powder diffraction pattern of the paeonol and 2-amino-6-methylbenzothiazole eutectic, the paeonol eutectic crystal has the following characteristic peaks expressed by an angle 2 theta: 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 °,40.844 °,41.583 °,42.194 °,42.608 °, 43.43.845.27 °, 43.44.27 °, 0 ± 2 ° of tolerance;
the differential scanning calorimetry spectrogram of the paeonol and 2-amino-6-methylbenzothiazole eutectic shows that the Tonset is 88.67 ℃, and the Tpeak is 88.85 ℃;
the paeonol and 2-amino-6-methylbenzothiazole eutectic is gradually decomposed and weightless after being melted in a temperature range of 25-200 ℃;
in the eutectic of paeonol and 2-aminobenzothiazole, the paeonol and the 2-aminobenzothiazole exist in a molar ratio of 2;
in an X-ray powder diffraction spectrum of the paeonol and 2-aminobenzothiazole eutectic, the characteristic peaks expressed by the angle 2 theta are as follows: 6.077 °,8.584 °,12.163 °,12.873 °,13.725 °,15.387 °,17.016 °,17.324 °,18.272 °,18.99 °,20.88 °,21.25 °,22.041 °,22.687 °,22.986 °,23.727 °,24.441 °,27.461 °,28.619 °,28.896 °,29.797 °,30.268 °,30.594 °,32.254 °,33.209 °,33.694 °,34.251 °,34.737 °,35.029 °,36.064 °,36.395 °,37.021 °,37.871 °,39.114 °,41.035 °,41.291 °,43.494 °, with an error tolerance of ± 0.2 °;
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 paeonol and 2-aminobenzothiazole eutectic is gradually decomposed and weightless after being melted in a temperature range of 25-200 ℃;
in the eutectic of paeonol and 3, 4-dihydroxybenzoic acid, the paeonol and the 3, 4-dihydroxybenzoic acid exist in a molar ratio of 1;
in an X-ray powder diffraction pattern of the paeonol and 3, 4-dihydroxy benzoic acid eutectic, the characteristic peaks expressed by the angle 2 theta are as follows: 9.683 °,10.422 °,11.313 °,13.056 °,13.763 °,14.007 °,15.602 °,15.954 °,16.621 °,19.277 °,19.91 °,20.979 °,21.962 °,22.926 °,23.367 °,24.004 °,25.817 °,26.648 °,27.153 °,27.677 °,28.164 °,29.185 °,31.667 °,32.302 °,33.315 °,33.628 °,34.24 °,36.653 °,37.006 °,38.168 °,38.62 °,38.963 °,39.806 °,40.431 °, 42.269 °,42.756 °,43.259 °,43.548 °, 44.03144 °, with an error tolerance of ± 0.2 °;
the differential scanning calorimetry spectrogram of the paeonol eutectic with the 3, 4-dihydroxy benzoic acid shows that the Tonset is 126.55 ℃ and 203.10 ℃, and the Tpeak is 128.15 ℃ and 204.13 ℃;
the paeonol and 3, 4-dihydroxy benzoic acid eutectic has no obvious weight loss in the temperature range of 25-100 ℃; the paeonol and 3, 4-dihydroxy benzoic acid eutectic has 51.26 percent weight loss within the temperature range of 100-165 ℃; the paeonol and 3, 4-dihydroxy benzoic acid eutectic has 36.84 percent weight loss within the temperature range of 190-300 ℃;
in the eutectic of paeonol and gallic acid, the paeonol and the gallic acid exist in a molar ratio of 1;
the X-ray powder diffraction pattern of the paeonol and gallic acid eutectic has the following characteristic peaks expressed by an 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 ° with a tolerance of ± 0.892 °;
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 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 gallic acid eutectic have 32.73% weight loss within the temperature range of 217-298 ℃;
in the eutectic of paeonol and 3, 5-difluorobenzoic acid, paeonol and 3, 5-difluorobenzoic acid are present in a molar ratio of 1;
in an X-ray powder diffraction pattern of the paeonol and 3, 5-difluorobenzoic acid eutectic, the paeonol eutectic crystal has the following characteristic peaks expressed by an angle 2 theta: 10.537 °,10.86 °,12.45 °,12.935 °,14.335 °,14.558 °,16.616 °,18.11 °,18.836 °,19.104 °,21.416 °,21.844 °,22.479 °,23.018 °,23.651 °,25.189 °,26.259 °,26.649 °,27.41 °,27.675 °,28.363 °,28.874 °,29.154 °,30.103 °,31.9 °,32.276 °,33.365 °,35.647 °,35.908 °,37.245 °,37.512 °,37.95 °,38.255 °,39.201 °,39.675 °,40.008 °,42.738 °,44.12 °, with a tolerance of ± 0.2 °;
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 ℃;
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;
in the eutectic of paeonol and urea, the paeonol and the urea exist in a molar ratio of 1;
the X-ray powder diffraction spectrum of the paeonol and urea eutectic has the following characteristic peaks expressed by an angle 2 theta: 6.106 °,12.27 °,13.038 °,14.128 °,14.399 °,15.697 °,17.693 °,18.483 °,19.635 °,20.012 °,22.488 °,23.336 °,23.705 °,24.015 °,24.619 °,25.136 °,25.694 °,26.336 °,26.686 °, 27.686 °,27.544 °,27.948 °,28.473 °,29.245 °,29.971 °,30.789 °,32.134 °,32.623 °,33.733 °,34.51 °,35.099 °,35.567 °,35.893 °,36.796 °,37.776 °,38.268 °,39.33 °,39.917 °,40.754 °,41.975 °,43.004 °,44.111 °, and ± 0.2 ° error tolerance;
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 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 ℃;
in the eutectic of paeonol and 2, 5-dihydroxybenzoic acid, the paeonol and the 2, 5-dihydroxybenzoic acid exist in a molar ratio of 1;
in an X-ray powder diffraction pattern of the paeonol and 2, 5-dihydroxy benzoic acid eutectic, the characteristic peaks expressed by the angle 2 theta are as follows: 7.514 °,9.24 °,10.94 °,13.338 °,14.501 °,15.001 °,15.82 °,16.363 °,17.521 °,17.78 °,18.939 °,19.483 °,20.379 °,21.161 °,22.056 °,22.901 °,23.22 °,24.332 °,24.74 °,25.36 °,25.963 °,26.999 °,27.44 °,28.576 °,29.299 °,30.478 °,32.857 °,33.241 °,34.262 °,35.481 °,36.139 °,37.458 °,38.6 °,39.781 °,40.94 °,41.461 °,43.761 °, with a tolerance of ± 0.2 ° being present;
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 ℃;
the paeonol and 2, 5-dihydroxy benzoic acid eutectic is subjected to weight loss of 54.46 percent within the temperature range of 25-150 ℃; the paeonol and 2, 5-dihydroxy benzoic acid eutectic has 46.51 percent weight loss within the temperature range of 150-220 ℃;
in the co-crystal of paeonol and propyl gallate, the paeonol and propyl gallate are present in a 1;
in an X-ray powder diffraction pattern of the paeonol and propyl gallate eutectic, the characteristic peaks expressed by the angle 2 theta are as follows: 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 a tolerance of ± 0.2 °;
the 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 ℃;
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 within the temperature range of 175-257 ℃.
2. The preparation method of the paeonol co-crystal according to claim 1, which is characterized by comprising the following specific steps of: mixing paeonol and an eutectic formation according to a molar ratio of 0.5 to 2, adding a solvent, heating, and stirring until the paeonol and the eutectic formation are completely dissolved; standing at room temperature, volatilizing for 1-5 days, precipitating crystals, and drying in vacuum at 40 ℃ to obtain the paeonol eutectic crystal.
3. The preparation method of the paeonol co-crystal according to claim 1, which is characterized by comprising the following specific steps of: mixing paeonol and an eutectic formation according to a molar ratio of 0.5 to 2; then standing and cooling for 1 to 2 days at the temperature of minus 20 ℃, precipitating crystals, and drying in vacuum at the temperature of 40 ℃ to obtain the paeonol eutectic crystal.
4. The preparation method of the paeonol co-crystal according to claim 1, which is characterized by comprising the following specific steps of: mixing paeonol and an eutectic formation according to the molar ratio of 0.5-2.
5. A pharmaceutical composition of paeonol co-crystal according to claim 1, wherein the pharmaceutical composition comprises 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.
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