CN111689934A - Single crystal of 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate and its preparation method - Google Patents
Single crystal of 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate and its preparation method Download PDFInfo
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Abstract
The invention discloses a single crystal of 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate, a preparation method and application thereof, belonging to the field of research on drug crystal forms. The invention adopts acid-base reaction-crystallization coupling method to obtain 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate single crystal with chemical formula C20H29KO7S, the crystal structure belongs to a monoclinic system, the space group is P1211, a =7.2362 Å, b =7.0368 Å, c =21.2746 Å =90 degrees, β =98.485 degrees, gamma =90 degrees, and V =1071.43 Å degrees3And Z = 2. Compared with the effective component 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate clinically used for Lianbizhi, the compound has the characteristics of low impurity content and almost no hygroscopicity under the premise of the same anti-inflammatory effect, and is more suitable for preparing high-purity pharmaceutical preparations. The preparation method has the characteristics of simple and convenient operation, short preparation time, low energy consumption, large-scale preparation and the like。
Description
Technical Field
The invention relates to a novel single crystal of 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate, a preparation method and application thereof, belonging to the field of pharmaceutical crystal form research.
Background
Andrographolide (Andrographolide) is a diterpene lactone monomer compound extracted from the whole herb or leaf of Andrographis paniculata (Burm. f.) Nees, and has a structure shown in formula 1. Andrographolide is clinically used for treating bacterial and viral upper respiratory tract infection and dysentery and is known as a natural antibiotic drug. Because andrographolide is insoluble in water and is usually only taken orally, in order to increase the water solubility, andrographolide is subjected to chemical structure modification to obtain sodium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate (formula 2), also called andrographolide sodium bisulfite, which is an effective component of Lianbizhi injection.
The Lianbizhi injection has the effects of resisting inflammation, resisting bacteria, regulating immune function and the like, and shows obvious pneumonia treatment effects when being used independently or being combined with other medicines (Shaoyuan, Yuanchunling, Yuanbizhi, observation of curative effect of Lianbizhi combined antibiotics for treating community-acquired pneumonia, northern pharmacy 2019,16(9): 114-. In addition, it is worth mentioning that the information disclosed in recent Chinese patents protects the hypolipidemic effect of andrographolide sodium bisulfite (Huyuejeng. andrographolide sodium bisulfite in preparing drugs for treating hyperlipidemia, CN201910735800.0.2019-11-29 and Huyuejeng. andrographolide sodium bisulfite in preparing promoters for promoting reverse cholesterol transport, CN201910736474.5.2019-12-13) and the anti-skin photoaging effect (Zhanyamakow. andrographolide sodium bisulfite in anti-skin photoaging and sunscreen cream, CN201811012551.4.2018-12-18).
Lianbizhi injection has exact treatment effect, but in the medication process, there are many reports related to adverse reactions, such as nephrotoxicity, anaphylactoid reaction and anaphylactic shock (east, Wanmeng butterfly, Wangwangqing, etc.. 4 kinds of andrographolide Chinese medicine injection adverse reaction analysis and reason exploration.Chinese medicine journal, 2016,41 (12)). The safety of the andrographis paniculata series of injections was found to be closely related to the related substances by analysis of the literature (Huzhou Hui, Wu Chun, Wang quan Jun, et al. two Nelumbo nucifera injection acute and long-term toxicity studies. journal of toxicology, 2010,24(06): 12-16; Hou J Q, Wang B L, Huang X J, et al. isolation and characterization of related injections in relation to related injections and clinical information in the same group of drugs and herbal medicine in the same group of drugs and herbal injection, Rsc Adv,2016,6(34): 28830-28837).
14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate has high water solubility and hygroscopicity, and can form hydrate (Liuli, antipyretic, anti-inflammatory and anti-infective medicine with immunological function, CN200910165110.2.2010-01-20) with non-stoichiometric ratio with water. In research work, the sodium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate is found to have various hydrate forms, and is difficult to crystallize and purify, so that the problem of product quality control is caused. Further research shows that when the sodium salt is changed into the potassium salt, the obtained novel salt type potassium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate has more excellent medicinal properties than 14-dehydroxy-13-dehydroandrographolide-12-sulfonate, has no hygroscopicity and good crystallinity, and can prepare products with higher purity and proper solubility.
Disclosure of Invention
The invention aims to provide a single crystal of 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate with no hygroscopicity and good crystallinity.
The invention also aims to provide a preparation method of the single crystal of 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate.
In order to realize the purpose of the invention, the technical scheme is as follows:
the raw material selected by the invention is 14-dehydroxy-13-dehydroandrographolide-12-sulfonic acid with the name of Andrographide Hydrogen Sulfite in English and the chemical formula is C20H30O7S, formula weight is 414.51, in the molecule, C3, C4 and C9 are R configuration, C5 and C10 are S configuration, 12C is R/S configuration, the structural formula is shown in formula 3, namely the raw material 14-dehydroxy-13-dehydroandrographolide-12-sulfonic acid is a mixture of products with 12R and 12S configurations, and the content (HPLC)>98.5 percent; the invention selects Potassium hydroxide with English name of Potasssium hydroxide, chemical formula of KOH, formula weight of 56.11 and analytically pure content.
The single crystal (figure 1) of 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate (formula 4) prepared by the invention has the following characteristics:
the 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate monocrystal prepared by the invention is a uniform and stable solid state, and is a colorless transparent flaky solid in appearance. The crystal structure is characterized in that: an asymmetric unit in the crystal structure of the monocrystal comprises a 14-dehydroxy-13-dehydroandrographolide-12R-sulfonate anion, a 14-dehydroxy-13-dehydroandrographolide-12S-sulfonate anion and two potassium ions; having a chemical formula of C20H29KO7S, the formula weight is 452.60; the crystal is monoclinic system, space group is P1211,
α＝90°，β＝98.485°，γ＝90°，
Z＝2。
in order to analyze the difference between potassium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate and sodium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate from crystal structure, the invention adopts a water-dissolving and natural volatilization method to obtain single crystals of sodium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate, and carries out X-ray single crystal diffraction measurement (figure 2), wherein the comparison of X-ray single crystal diffraction results of potassium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate and sodium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate is shown in Table 1. As can be seen from Table 1, the single crystal of sodium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate contained 5 molecules of water, 4 of which were coordinated water and 1 of which was hydrogen bonded, while the single crystal of potassium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate contained no water molecules.
The 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate monocrystal prepared by the invention is a uniform and stable solid form. The 14-dehydroxy-13-dehydroandrographolide-12-sulfonic acid potassium single crystal was subjected to auxiliary verification by X-ray powder diffraction (P-XRD) technique, and the X-ray powder diffraction at 2 θ ° angle showed characteristic peaks at 2 θ ═ 8.5 ± 0.1, 12.7 ± 0.1, 13.7 ± 0.1, 16.0 ± 0.1, 16.9 ± 0.1, 17.8 ± 0.1 (fig. 3). For comparison with the single crystal of 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate, FIG. 4 shows the X-ray powder diffraction pattern of the single crystal of 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate.
TABLE 114-dehydroxy-13-dehydroandrographolide-12-sulfonate potassium/sodium X-ray single crystal diffraction data
The 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate monocrystal prepared by the invention is a uniform and stable solid form. The auxiliary verification is carried out on the 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate single crystal by adopting a thermal-gravimetric analysis (TG-DSC) technology, a TG-DSC spectrum has no weight loss at 50-200 ℃, and a melting endothermic peak appears at 287 +/-2 ℃ (figure 5). For comparison with the single crystal of 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate, fig. 6 shows the TG-DSC profile of the single crystal of 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate, which shows that the single crystal of 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate melts with weight loss at 83.56 ℃.
The preparation method of the 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate single crystal adopts an acid-base reaction-crystallization coupling method. Mixing 14-dehydroxy-13-dehydroandrographolide-12-sulfonic acid and potassium hydroxide according to the weight ratio of 1: 1 (mol: mol), adding the mixture into water (the amount of water is 1.5-2.0 times of the mass of 14-dehydroxy-13-dehydroandrographolide-12-sulfonic acid), heating to 60 ℃ to dissolve the mixture to obtain a clear solution, and then carrying out gradient cooling and filtration to obtain a uniform and stable 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate single crystal.
In the preparation process of the single crystal, the cooling gradient is a key factor influencing the preparation of the single crystal, a clarified solution is obtained by heating at 60 ℃, heating is stopped, the temperature is naturally reduced to 45 ℃, after the temperature is kept at 45 ℃ for 2 hours, the temperature is naturally reduced to 20 ℃, crystallization is carried out for 24-48 hours, filtering is carried out, and a filter cake is subjected to vacuum drying overnight at room temperature to obtain a uniform and stable 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate single crystal. The yield is more than 50%.
The concentration of the 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate directly influences the precipitation speed of the single crystal. Therefore, the growth rate of the crystal is controlled by controlling the concentration. Wherein the mass ratio of the 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate to the water is controlled to be 1: 1.5 to 2.0 (g: g).
The method of the invention has the following beneficial effects:
1. the invention adopts acid-base reaction-crystallization coupling method to prepare 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate for the first time, and the obtained new salt type has better crystallinity, almost no hygroscopicity and no hydrate formation compared with 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate by controlling the concentration of reactants and gradient cooling of reaction liquid, and the solubility of the obtained new salt type is far higher than the limit of the solubility of an injection more than 10g/L and is far higher than the limit of the solubility of an oral preparation more than 0.1g/L (Shenfang, Su 39040, Zhonwei clarification, research and development of salt-forming drugs, 2012(04): 11-17.
2. The content of the potassium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate prepared by the preparation method is more than 99.99 percent (figure 7) through HPLC analysis, and the sodium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate which is difficult to purify is obviously improved. From the perspective of drug development, the new drug development should comply with the basic principle of "safety, effectiveness, and controllable quality", impurities of the raw material drugs are important factors affecting the safety of the drugs, 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate has great purification difficulty due to poor crystallinity, and has a correlation relationship between impurities and side effects, while the content of the 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate single crystal obtained by the invention can reach 99.99%, which is far higher than the limit of the related guiding principle of impurity research, and requires "piceid, hufu, lisu, and the like". The research on the control limit of impurities and harmful substances in the drugs progresses. Yueyue, luoyuan, Stangying, and the like, chemical medicine impurity research progress, pharmaceutical progress 2015,039(007) 533 and 539', and can effectively reduce the difficulty of the subsequent preparation process.
3. The preparation method adopted by the invention is simple and convenient to operate, short in preparation time, low in energy consumption and applicable to large-scale application.
4. The potassium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate prepared by the invention is evaluated by a xylene-induced mouse ear swelling model, and the anti-inflammatory effect of the potassium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate is the same as that of sodium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate.
Drawings
FIG. 1 is an X-ray single crystal diffraction pattern of 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate;
FIG. 2 is a 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate X-ray single crystal diffraction pattern;
FIG. 3 is an X-ray powder diffraction pattern of 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate;
FIG. 4 is an X-ray powder diffraction pattern of 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate;
FIG. 5 is a TG-DSC spectrum of 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate;
FIG. 6 is a TG-DSC spectrum of 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate;
FIG. 7 is an HPLC chromatogram of 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate.
Detailed Description
The present invention will be further described with reference to the following examples.
The structure and performance of the instrument used for preparing and detecting the crystal form are as follows:
the X-ray single crystal diffraction analysis adopts a Japan science Gemini E single crystal diffractometer and a Cu-K alpha target, and data are collected under 293K.
X-ray powder diffraction analysis adopts a Bruker D8 advanced X-ray diffractometer, a Cu-Ka target, a nickel monochromator, a working voltage of 40kV, a working current of 40mA and a step size of 0.020.
TG-DSC analysis, adopting Q600 thermogravimetric analyzer of TA company in America, and the heating rate is 10K/min. N is a radical of2The protection was passed through the DSC cell at a rate of 20 mL/min.
High Pressure Liquid Chromatography (HPLC) assay conditions using C18Chromatographic column (250mm × 4.6.6 mm, 5 μ M) with mobile phase of methanol-acetonitrile-0.02M potassium dihydrogen phosphate solution (5: 24: 75), UV full wavelength detection, column temperature of 30 deg.C, flow rate of 1.0mL/min, and sample injection volume of 10 μ L.
The solubility determination method is carried out according to the solubility determination test method of the Chinese pharmacopoeia 2015 edition.
The hygroscopicity test is carried out according to the guiding principle of the hygroscopicity test of the medicines in the Chinese pharmacopoeia 2015 edition.
Experimental example 1:
adding 41.5g (0.1mol) of 14-dehydroxy-13-dehydroandrographolide-12-sulfonic acid (with the content of 98.6 percent) and 5.6g (0.1mol) of potassium hydroxide (analytically pure) into 80ml of water, heating at 60 ℃ for 10min to obtain a clear solution, stopping heating, naturally cooling to 45 ℃, keeping at 45 ℃ for 2 hours, naturally cooling to 20 ℃, crystallizing for 30 hours, filtering, and vacuum drying a filter cake at room temperature overnight to obtain 23.1g of uniform and stable 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate single crystals. The yield is 51.0 percent and the content is 99.99 percent.
The crystal structure and characteristics of the single crystals of potassium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate prepared according to the method of experimental example 1 are shown in fig. 1, 3 and 5, and the content is shown in fig. 7.
As shown in fig. 1, in the crystal structure of the 14-dehydroxy-13-dehydroandrographolide-12-sulfonic acid potassium single crystal, the asymmetric unit comprises one 14-dehydroxy-13-dehydroandrographolide-12R-sulfonate anion, one 14-dehydroxy-13-dehydroandrographolide-12S-sulfonate anion and two potassium ions; having a chemical formula of C20H29KO7S, the formula weight is 452.60; the crystal is monoclinic system, space group is P1211,
α＝90°，β＝98.485°，γ＝90°，
Z＝2。
as shown in FIG. 1, in the crystal structure of the potassium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate single crystal, each potassium ion forms a coordinate bond with the oxygen atom of three sulfonic acid groups and the hydroxyl group of 1 lactone ring. 14-dehydroxy-13-dehydroandrographolide-12R-sulfonate anion and 14-dehydroxy-13-dehydroandrographolide-12S-sulfonate anion are distributed on two sides of a bridge chain formed by potassium ions in a mirror image mode.
As shown in fig. 3, in the case of the potassium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate, which was confirmed by X-ray powder diffraction (P-XRD) technique, characteristic peaks were observed at 2 θ ° angles of 8.5 ± 0.1, 12.7 ± 0.1, 13.7 ± 0.1, 16.0 ± 0.1, 16.9 ± 0.1, and 17.8 ± 0.1.
As shown in figure 5, the thermal-gravimetric analysis (TG-DSC) technology is adopted to perform auxiliary verification on the 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate, and the TG-DSC spectrum has no weight loss at 50-200 ℃, and a melting endothermic peak appears at 287 +/-2 ℃.
The solubility of the obtained single crystal of potassium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate and the obtained single crystal of sodium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate were measured according to the method specified in chinese pharmacopoeia 2015 edition, and the obtained research results are shown in table 2.
TABLE 214 Dehydro-13-dehydroandrographolide-12-sulfonic acid Potassium/sodium salt solubility
| Compound (I) | Water (g/L) | Methanol (g/L) | Ethanol (g/L) | Chloroform (g/L) |
| 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate | 241.8 | 86.8 | 25.8 | 1.7 |
| 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate | 544.9 | 99.7 | 32.9 | 9.6 |
As can be seen from Table 2, the solubility of potassium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate in water at room temperature is 241.8g/L, which is much higher than the limit of solubility >10g/L for injection, and much higher than the limit of solubility >0.1g/L for oral preparation.
The obtained potassium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate single crystal and sodium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate were subjected to hygroscopicity measurement according to the method specified in chinese pharmacopoeia 2015 edition, and the obtained study results are shown in table 3.
TABLE 314 dehydroxy-13-dehydroandrographolide-12-sulfonic acid potassium/sodium salt hygroscopic
| Compound (I) | Moisture-wicking property |
| 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate | 0.02％ |
| 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate | 1.89％ |
As can be seen from Table 3, potassium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate has almost no hygroscopicity and no special requirement for storage conditions, while sodium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate has an increased weight of 1.89% under the experimental conditions and provides sealing requirements for storage conditions.
The anti-inflammatory effect evaluation of 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate single crystals and 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate single crystals is carried out by adopting a xylene-induced mouse ear swelling model, 50 Kunming mice with half weight and 18-22 g weight are taken and randomly divided into 5 groups, and each group comprises 10 mice, namely a blank control group, two dosage groups (160mg/kg and 80mg/kg) of 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate and two dosage groups (160mg/kg and 80mg/kg) of 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate. The preparation is administered by intramuscular injection 1 time per day for 3 days. 1 hour after the last administration, 0.03mL of analytically pure xylene was applied to each of the right and left ears of the mice, respectively. After 3 hours, the mice were sacrificed by cervical dislocation, the ear pieces were taken with a punch of 9mm diameter, weighed, and the experimental data averaged, with the results shown in table 4.
TABLE 414 anti-inflammatory action of dehydroxy-13-dehydroandrographolide-12-sulfonic acid potassium/sodium salt
As can be seen from table 4, potassium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate has the same anti-inflammatory effect as sodium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate, and both of them have significant anti-inflammatory effects compared to the blank control group.
Experimental example 2:
adding 83.0g (0.2mol) of 14-dehydroxy-13-dehydroandrographolide-12-sulfonic acid (with the content of 98.5 percent) and 11.2g (0.2mol) of potassium hydroxide (analytically pure) into 160ml of water, heating at 60 ℃ for 12min to obtain a clear solution, stopping heating, naturally cooling to 45 ℃, keeping at 45 ℃ for 2 hours, naturally cooling to 20 ℃, crystallizing for 36 hours, filtering, and vacuum drying a filter cake at room temperature overnight to obtain 47.9g of uniform and stable 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate single crystals. The yield is 52.9 percent, and the content is 99.99 percent.
The crystal structure and characteristics of the single crystals of potassium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate prepared according to the method of experimental example 2 are shown in fig. 1, 3 and 5, and the content is shown in fig. 7. The peak results of fig. 7 are as follows:
Peak Results
| Name | RT | Area | Height | USP Resolution | USP Plate | ％Area | ||
| 1 | 7.663 | 722 | 102 | 2.606124e+004 | 0.01 | |||
| 2 | 16.574 | 8513448 | 267758 | 1.572405e+001 | 4.937177e+003 | 99.99 |
experimental example 3:
207.5g (0.5mol) of 14-dehydroxy-13-dehydroandrographolide-12-sulfonic acid (with the content of 98.5 percent) and 28.0g (0.5mol) of potassium hydroxide (analytically pure) are added into 350ml of water, the mixture is heated for 15min at 60 ℃ to obtain a clear solution, then the heating is stopped, the temperature is naturally reduced to 45 ℃, the mixture is kept at 45 ℃ for 2 hours, then the temperature is naturally reduced to 20 ℃, crystallization is carried out for 48 hours, filtering is carried out, and a filter cake is dried in vacuum at room temperature overnight to obtain 131.2g of uniform and stable 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate single crystals. The yield is 58.0 percent and the content is 99.99 percent.
The crystal structure and characteristics of the single crystals of potassium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate prepared according to the method of experimental example 3 are shown in fig. 1, 3 and 5, and the content is shown in fig. 7.
Experimental example 4:
207.5g (0.5mol) of 14-dehydroxy-13-dehydroandrographolide-12-sulfonic acid (with the content of 98.5 percent) and 28.0g (0.5mol) of potassium hydroxide (analytically pure) are added into 380ml of water, the mixture is heated for 15min at 60 ℃ to obtain a clear solution, then the heating is stopped, the temperature is naturally reduced to 45 ℃, the mixture is kept at 45 ℃ for 2 hours, then the temperature is naturally reduced to 20 ℃, crystallization is carried out for 45 hours, filtering is carried out, and a filter cake is dried in vacuum at room temperature overnight to obtain 125.1g of uniform and stable 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate single crystals. The yield was 55.3%, and the content was 99.99%.
The crystal structure and characteristics of the single crystals of potassium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate prepared according to the method of experimental example 4 are shown in fig. 1, 3 and 5, and the content is shown in fig. 7.
The single crystal of 14-dehydroxy-13-dehydroandrographolide-12-sulfonate, the preparation method and the application thereof disclosed and claimed in the present invention can be implemented by those skilled in the art by referring to the contents of the present invention, and by appropriately changing the conditions and routes, etc., although the method and the preparation technique of the present invention have been described by the preferred embodiments, it is obvious to those skilled in the art that the final preparation technique can be implemented by modifying or recombining the method and the technical routes described herein without departing from the contents, spirit and scope of the present invention. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and content of the invention.
Claims (7)
1. A single crystal of 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate is characterized in that: having a chemical formula of C20H29KO7S, formula is452.60, respectively; the crystal structure is monoclinic system, space group is P1211,
α＝90°，β＝98.485°，γ＝90°，
and Z is 2, and the chemical structure is as follows:
2. the single crystal of 14-dehydroxy-13-dehydroandrographolide-12-sulfonic acid potassium salt according to claim 1, wherein the X-ray powder diffraction pattern at 2 Θ ° has characteristic peaks at 8.5 ± 0.1, 12.7 ± 0.1, 13.7 ± 0.1, 16.0 ± 0.1, 16.9 ± 0.1, 17.8 ± 0.1.
3. The single crystal of 14-dehydroxy-13-dehydroandrographolide-12-sulfonic acid potassium salt according to claim 1, wherein the TG-DSC profile of the single crystal exhibits a characteristic melting endotherm at 287 ± 2 ℃.
4. The single crystal of claim 1, wherein the crystal structure of the single crystal comprises an asymmetric unit comprising a 14-dehydroxy-13-dehydroandrographolide-12R-sulfonate anion, a 14-dehydroxy-13-dehydroandrographolide-12S-sulfonate anion, and two potassium ions.
5. The single crystal of 14-dehydroxy-13-dehydroandrographolide-12-sulfonic acid potassium salt according to any one of claims 1 to 4, wherein the content of the single crystal prepared by high pressure liquid phase analysis (HPLC) is > 99.99%.
6. A method for preparing a single crystal of 14-dehydroxy-13-dehydroandrographolide-12-sulfonic acid potassium salt according to claims 1 to 4, which is carried out by: mixing 14-dehydroxy-13-dehydroandrographolide-12-sulfonic acid and potassium hydroxide according to a molar ratio of 1: 1, adding the mixture into water, wherein the amount of the water is 1.5-2.0 times of the mass of 14-dehydroxy-13-dehydroandrographolide-12-sulfonic acid, heating to 60 ℃ for dissolution to obtain a clear solution, and then carrying out gradient cooling, crystallization, filtration and room-temperature vacuum drying overnight to obtain the 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate single crystal.
7. The method for preparing a single crystal of 14-dehydroxy-13-dehydroandrographolide-12-sulfonic acid potassium according to claim 6, wherein the gradient cooling selection comprises: heating at 60 ℃ to react to obtain a clear solution, naturally cooling to 45 ℃, keeping at 45 ℃ for 2 hours, naturally cooling to 20 ℃, crystallizing for 24-48 hours, filtering, and vacuum drying a filter cake at room temperature overnight to obtain the 14-dehydroxy-13-dehydroandrographolide-12-potassium sulfonate monocrystal.
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