CN111635383A - Single crystal of 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate and preparation method thereof - Google Patents
Single crystal of 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate and preparation method thereof Download PDFInfo
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- C30B7/00—Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions
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Abstract
The invention discloses a single crystal of 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate, a preparation method and application, belonging to the field of medicine crystal form research. The invention adopts acid-base reaction-crystallization coupling method to obtain 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate single crystal with chemical formula C40H64CaO17S2.C3H6O.4(H2O), the crystal structure belongs to the monoclinic system, the space group is P1211, a =18.2539 Å, b =15.3118 Å, c =18.3718 Å =90 °, β =91.2637 °, γ =90 °, V =5133.65 Å ″3And Z = 4. The 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate has good crystallization property, and can be used for clinical application of lotusPreparing 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate as effective component of BIZHI.
Description
Technical Field
The invention relates to a novel single crystal of 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate salt, a preparation method and application, belonging to the field of medicine crystal form research.
Background
Andrographolide (Andrographolide) is diterpene lactone compound extracted from whole herb or leaf of herba Andrographitis, and has structure shown in formula 1. Andrographolide has antibacterial and antiviral biological activity, and is known as natural antibiotic medicine. Because andrographolide is poor in water solubility, it is usually administered only orally, and in order to increase its water solubility, andrographolide is subjected to chemical structure modification to obtain a water-soluble compound, Sodium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate (formula 2), also known as 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 exact pneumonia treatment effects when being used independently or being combined with other medicines (Shaoyuan, Yuanchunling, Yuanbizhi, observation of curative effect of Lianbizhi combined antibiotics on 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 and anti-photoaging effects of andrographolide sodium bisulfite (Huyuan, application of andrographolide sodium bisulfite in preparing drugs for treating hyperlipidemia, CN201910735800.0.2019-11-29 and Huyuan, application of andrographolide sodium bisulfite in preparing promoters for promoting reverse cholesterol transport, CN201910736474.5.2019-12-13; Zhanyasu, application of andrographolide sodium bisulfite for resisting photoaging of skin and sunscreen cream, CN201811012551.4.2018-12-18).
14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate is prone to generate various impurities during preparation and storage (Hou J Q, Wang B L, Huang X J, et al, isolation and catalysis of related microorganisms in anhydro phosphate sodium injection, Rsc Adv,2016,6(34):28830-28837), and 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate is highly water-soluble, has hygroscopicity, and can form non-stoichiometric hydrate with water (Liu power, antipyretic, anti-inflammatory, anti-infective drug with immune effect and preparation and use thereof, CN200910165110.2.2010-01-20). In the research work, the research finds that the related substances of the 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate are complex and are easy to form hydrates, so that the related substances are difficult to crystallize and purify, the difficulty in controlling the quality of the product is high, and a method for improving the purity of the product is urgently needed to be found.
Disclosure of Invention
The invention aims to provide a single crystal of 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate with good crystallinity.
Another objective of the invention is to provide a method for preparing a single crystal of 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate.
The third purpose of the invention is to provide the application of the 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate monocrystal in the preparation process of high-purity 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate.
In order to realize the purpose of the invention, the technical scheme is as follows:
the inventor of the invention researches and discovers that when the sodium salt is changed into the calcium salt, the obtained novel salt type 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate has more excellent crystallization property than 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate, can obtain uniform and stable 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate single crystal, the single crystal is acidified to obtain 14-dehydroxy-13-dehydroandrographolide-12-sulfonic acid solid, which is reacted with NaOH in equal amount and crystallized, 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate with content (HPLC) > 99.9% can be obtained.
The raw material selected by the invention is 14-dehydroxy-13-dehydroandrographolide-12-sulfonic acid (formula 3), the name of English is Andrographide Hydrogen Sulfite, and the chemical formula is C20H30O7S, formula weight is 414.5, in the molecule, C3, C4, C9 and C12 are R configuration, C5 and C10 are S configuration, the structural formula is shown as formula 3, and the content (HPLC)>97 percent; the calcium hydroxide with the English name of calcium hydroxide and the chemical formula of Ca (OH) is selected2The formula weight is 74.1, and the content is analytically pure.
The single crystal (figure 1) of 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate (formula 4) prepared by the invention has the following characteristics:
the 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate single crystal prepared by the invention is a uniform and stable solid form, and is a colorless transparent granular solid in appearance. The crystal structure is characterized in that: has a chemical formula of C40H64CaO17S2.C3H6O.4(H2O), formula weight is 1051.3; the crystal is monoclinic system, space group is P1211,
α＝90°，β＝91.2637°，γ＝90°，
Z＝4。
in order to analyze the difference between the 14-dehydroxy-13-dehydroandrographolide-12-sulfonic acid calcium acetone solvate and the 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate from the crystal structure, the invention adopts a water-soluble natural volatilization method to obtain a single crystal of 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate, and carries out X-ray single crystal diffraction measurement (figure 2), and the comparison of the X-ray single crystal diffraction results of the 14-dehydroxy-13-dehydroandrographolide-12-sulfonic acid calcium acetone solvate and the 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate is shown in Table 1. As can be seen from table 1, the structural unit of the single crystal of 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate contains 1 14-dehydroxy-13-dehydroandrographolide-12-sulfonate ion, 1 sodium ion, and 5 water molecules, wherein 4 of the 5 water molecules are coordinating water molecules, and 1 is hydrogen bonding water molecule; and the structural unit of the 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate monocrystal contains 2 14-dehydroxy-13-dehydroandrographolide-12-sulfonate ions, 1 calcium ion, 1 acetone molecule and 7 water molecules, wherein 3 of the 7 water molecules are coordinated water and 4 are hydrogen bonding water molecules.
The 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate single crystal prepared by the invention is a uniform and stable solid form. The single crystal of 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate was subjected to auxiliary verification by using an X-ray powder diffraction (P-XRD) technique, and the X-ray powder diffraction represented by an angle of 2 theta ° has characteristic peaks at 7.6 ± 0.1, 13.5 ± 0.1, 14.7 ± 0.1, 19.4 ± 0.1, 19.9 ± 0.1, and 23.7 ± 0.1, wherein the relative intensity of the characteristic peak at 13.5 ± 0.1 is 100%. (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 calcium acetone solvate/sodium X-ray single crystal diffraction data
The 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate single crystal prepared by the invention is a uniform and stable solid form. The thermal-gravimetric analysis (TG-DSC) technology is adopted to perform auxiliary verification on the 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate single crystal, and the characteristic endothermic peaks of the TG-DSC spectrum appear at 67 +/-5 ℃ and 263 +/-5 ℃ (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-calcium sulfonate acetone solvate monocrystal adopts an acid-base reaction-crystallization coupling method. Mixing 14-dehydroxy-13-dehydroandrographolide-12-sulfonic acid and calcium hydroxide according to the weight ratio of 1: 0.5 (mol: mol), adding the mixture into water (the amount of water is 10.5-12.5 times of the mass of 14-dehydroxy-13-dehydroandrographolide-12-sulfonic acid), heating to 60 ℃ to dissolve the mixture to obtain a clear solution, then adding acetone with the same volume as the water, and obtaining a uniform and stable 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate monocrystal through gradient cooling and filtration.
In the preparation process of the single crystal, the temperature reduction gradient is a key factor influencing the preparation of the single crystal, a clarified solution is obtained by heating at 60 ℃, after acetone with the same volume as water is added, the heating is stopped, the temperature is naturally reduced to 50 ℃, after the temperature is kept at 50 ℃ for 2 hours, the temperature is naturally reduced to 20 ℃, crystallization is carried out for 24 to 48 hours, filtration and vacuum drying at room temperature overnight are carried out, and a uniform and stable 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate single crystal is obtained, wherein the yield is more than 70 percent. The X-ray single crystal diffraction data of the 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate single crystal are shown in figure 1.
The concentration of the 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate 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-calcium sulfonate acetone solvate to water is controlled to be 1: 10.5 to 12.5 (g: g).
The method of the invention has the following beneficial effects:
1. the invention adopts acid-base reaction-crystallization coupling method for preparing 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate single crystal for the first time, and by controlling the reactant concentration and the gradient cooling of reaction liquid, the obtained solvate has stable property and good crystallinity, and the HPLC content can reach more than 99.9 percent (figure 7).
2. After the 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate prepared by the preparation method is acidified and becomes sodium salt, the HPLC content of the obtained 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate can reach more than 99.9 percent (figure 8), and the method provides a new way for preparing high-purity 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate. From the perspective of drug development, the new drug development should comply with the basic principle of "safety, effectiveness, controllable quality", the impurities of the raw material drugs are important factors affecting the drug safety, the 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate has great purification difficulty due to poor crystallinity, and the impurities and side effects have a correlation relationship, while the 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate obtained by the invention has HPLC content of over 99.9%, which is far higher than the limit requirements of the related guiding principle of impurity research, such as "all-grass, Haofu, Lishirigo, and the like; 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.
Drawings
FIG. 1 is an X-ray single crystal diffraction pattern of 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate of the present invention;
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 the 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate of the present invention;
FIG. 4 is an X-ray powder diffraction pattern of 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate;
FIG. 5 is a TG-DSC of 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate of the present invention;
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-calcium sulfonate acetone solvate of the present invention;
FIG. 8 is an HPLC chromatogram of 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate prepared by the invention;
FIG. 9 is a unit cell stacking pattern of 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate of the present invention.
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 C18Chromatography column (250mm × 4.6.6 mm, 5 μm) with mobile phase ofmethanol-acetonitrile-0.02M potassium dihydrogen phosphate solution (5: 24:75), UV full wavelength detection, column temperature 30 deg.C, flow rate 1.0mL/min, sample volume 10 μ L.
The solubility determination method is carried out according to the solubility determination test method of 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 97.1 percent) and 3.7g (0.05mol) of calcium hydroxide (analytically pure) into 500mL of water, heating at 60 ℃ for 10min to obtain a clear solution, then keeping the temperature at 60 ℃, adding 500mL of acetone, stopping heating, naturally cooling to 50 ℃, keeping the temperature at 50 ℃ for 2 hours, naturally cooling to 20 ℃, crystallizing for 30 hours, filtering, and carrying out vacuum drying on a filter cake at room temperature overnight to obtain 36.9g of a uniform and stable 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate single crystal. Yield 70.2% and content 99.95% (HPLC, fig. 7, table 2).
TABLE 214-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate Single Crystal HPLC test results
Peak Results
| Name | RT | Area | Height | USP Resolution | USP Plate Count | ％Area | |
| 1 | 7.674 | 2491 | 342 | 2.532020e+004 | 0.03 | ||
| 2 | 8.504 | 734 | 96 | 4.298152e+000 | 3.089206e+004 | 0.01 | |
| 3 | 11.191 | 517 | 71 | 1.385272e+001 | 5.303544e+004 | 0.01 | |
| 4 | 14.956 | 919 | 103 | 1.752783e+001 | 6.468467e+004 | 0.01 | |
| 5 | 16.596 | 8754973 | 274679 | 2.768199e+000 | 4.884993e+003 | 99.95 | |
| 6 | 29.417 | 15 | 18 | 2.663958e+001 | 8.513429e+007 | 0.00 |
The single crystals of 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate prepared according to the method of experimental example 1 above have the crystal structures and characteristics shown in fig. 1, 3 and 5, and the content is shown in fig. 7.
As shown in fig. 1, the structural unit of the 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate single crystal contains 2 14-dehydroxy-13-dehydroandrographolide-12-sulfonate ions, 1 calcium ion, 1 acetone molecule and 7 water molecules, wherein 3 of the 7 water molecules are coordinated water and 4 are hydrogen bonding water molecules; having a chemical formula of C40H64CaO17S2.C3H6O.4(H2O), formula weight is 1051.3; the crystal is monoclinic system, space group is P1211,
α＝90°，β＝91.2637°，γ＝90°，
Z＝4。
as shown in FIG. 1, in the crystal structure of the single crystal of 14-dehydroxy-13-dehydroandrographolide-12-sulfonate calcium acetone solvate, each calcium ion is in 7-coordination, wherein each calcium ion forms a coordination bond with 3 oxygen atoms of water molecules, 2 oxygen atoms of 3-hydroxyl groups, and 2 oxygen atoms of 4-hydroxymethyl groups. The coordinate bond length is shown in Table 3, and the bond angle is shown in Table 4.
TABLE 314 dehydroxy-13 i dehydroandrographolide-12-sulfonate calcium acetone solvate coordinate bond length
TABLE 414 dehydroxy-13-dehydroandrographolide-12-sulfonate calcium acetone solvate coordinate bond angle
| Atom(s) | Atom(s) | Atom(s) | Key angle (°) |
| O1 | Ca1 | O1' | 156.96(17) |
| O1 | Ca1 | O2 | 72.83(13) |
| O1 | Ca1 | O2' | 128.81(14) |
| O1 | Ca1 | O8 | 96.70(18) |
| O1 | Ca1 | O9 | 78.86(16) |
| O1' | Ca1 | O2 | 127.50(15) |
| O1' | Ca1 | O2' | 72.13(12) |
| O1' | Ca1 | O8 | 78.61(15) |
| O1' | Ca1 | O9 | 78.11(16) |
| O2 | Ca1 | O2' | 74.98(13) |
| O8 | Ca1 | O2 | 80.42(18) |
| O8 | Ca1 | O2' | 115.9(2) |
| O8 | Ca1 | O9 | 80.4(2) |
| O9 | Ca1 | O2 | 143.45(15) |
| O9 | Ca1 | O2' | 141.56(14) |
| O10 | Ca1 | O1 | 80.80(14) |
| O10 | Ca1 | O1' | 96.18(15) |
| O10 | Ca1 | O2 | 116.45(15) |
| O10 | Ca1 | O2' | 79.24(14) |
| O10 | Ca1 | O8 | 160.8(2) |
| O10 | Ca1 | O9 | 80.38(15) |
The single crystal of 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate forms three-dimensional supramolecular structure by H bond, and the unit cell stacking pattern is shown in figure 9. Wherein, C3, C3', C3', C3A, C4, C4', C4', C4A, C9, C9', C9', C9A, C12, C12', C12', C12A are in R configuration, C5, C5', C5', C5A, C10, C10', C10', C10A are in S configuration.
As shown in fig. 3, in the X-ray powder diffraction (P-XRD) technique, which was used to verify that the acetone solvate of 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate has characteristic peaks expressed by 2 θ ° at 7.6 ± 0.1, 13.5 ± 0.1, 14.7 ± 0.1, 19.4 ± 0.1, 19.9 ± 0.1, and 23.7 ± 0.1, wherein the relative intensity of the characteristic peak at 13.5 ± 0.1 is 100%.
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-calcium sulfonate acetone solvate, and the TG-DSC spectrum of the solvate has characteristic endothermic peaks at 67 +/-5 ℃ and 263 +/-5 ℃.
In order to compare the solubility of the single crystal of the 14-dehydroxy-13-dehydroandrographolide-12-calcium-sulfonate acetone solvate, the invention adopts an acid-base neutralization method to prepare two new salt types of 14-dehydroxy-13-dehydroandrographolide-12-magnesium sulfonate and 14-dehydroxy-13-dehydroandrographolide-12-zinc sulfonate. On the basis of this, the obtained single crystal of 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate, the single crystal of 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate, the single crystal of 14-dehydroxy-13-dehydroandrographolide-12-magnesium sulfonate, and the single crystal of 14-dehydroxy-13-dehydroandrographolide-12-zinc sulfonate were subjected to measurement of solubility in water according to the method specified in chinese pharmacopoeia 2015 edition, and the obtained study results are shown in table 5.
TABLE 514 Dehydroxy-13-dehydroandrographolide-12-sulfonate calcium acetone solvate and solubility of sodium, magnesium, and zinc salts
| Compound (I) | Water (g/L) |
| 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate | 26.3 |
| 14-dehydroxy-13-dehydroandrographolide-12-zinc sulfonate | 51.0 |
| 14-dehydroxy-13-dehydroandrographolide-12-magnesium sulfonate | 85.3 |
| 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate | 544.9 |
As can be seen from Table 2, among the four salts tested, the solubility of the single crystal of 14-dehydroxy-13-dehydroandrographolide-12-sulfogaitone solvate was the smallest, and at room temperature, the solubility of the single crystal of 14-dehydroxy-13-dehydroandrographolide-12-sulfogaitone solvate in water was 26.3g/L, which is much less than the solubility of the single crystal of 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate in water. The single crystal of the 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate has the characteristic of low solubility in water, and is beneficial to crystallization and precipitation.
The obtained single crystal of 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate can be used for preparing high-purity 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate, and the operation experiment is as follows:
at room temperature, 36.9g of the 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate monocrystal prepared in the above process is added into 70mL of water, stirred to obtain a suspension, then heated to 50 ℃, 6mL of concentrated hydrochloric acid is slowly added, the solution is stirred to obtain a clear solution, the heating is stopped, the temperature is reduced to-10 ℃, crystallized and filtered to obtain refined 14-dehydroxy-13-dehydroandrographolide-12-sulfonic acid. Then, at room temperature, adding the obtained refined 14-dehydroxy-13-dehydroandrographolide-12-sulfonic acid into 40mL of water, stirring, slowly adding NaOH solution (3.56g of NaOH dissolved in 10mL of water), heating to 50 ℃, stirring for 10min to obtain a clear solution, stopping heating, cooling to 0 ℃, standing for crystallization, filtering, and drying to obtain 28.2g of 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate. Yield 72.6% and HPLC content 99.97% (fig. 8, table 6).
TABLE 614-Dehydroxy-13-dehydroandrographolide-12-sodium sulfonate HPLC test results
Peak Results
| Name | RT | Area | Height | USP Resolution | USP Plate Count | ％Area | |
| 1 | 7.653 | 1664 | 231 | 2.592535e+004 | 0.02 | ||
| 2 | 11.144 | 669 | 83 | 1.731860e+001 | 4.377538e+004 | 0.01 | |
| 3 | 16.585 | 8083186 | 260770 | 9.515956e+000 | 5.083366e+003 | 99.97 |
Experimental example 2:
adding 83.0g (0.2mol) of 14-dehydroxy-13-dehydroandrographolide-12-sulfonic acid (with the content of 97.1 percent) and 7.4g (0.1mol) of calcium hydroxide (analytically pure) into 900mL of water, heating at 60 ℃ for 12min to obtain a clear solution, then keeping the temperature at 60 ℃, adding 900mL of acetone, stopping heating, naturally cooling to 50 ℃, keeping the temperature at 50 ℃ for 2 hours, naturally cooling to 20 ℃, crystallizing for 36 hours, filtering, and carrying out vacuum drying on a filter cake at room temperature overnight to obtain 75.6g of a uniform and stable 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate single crystal. Yield 71.9% and content 99.95% (HPLC, fig. 7).
The single crystals of 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate prepared according to the method of experimental example 2 above have the crystal structures and characteristics shown in fig. 1, 3 and 5, and the content is shown in fig. 7.
Experimental example 3:
207.5g (0.5mol) of 14-dehydroxy-13-dehydroandrographolide-12-sulfonic acid (with the content of 97.1 percent) and 18.5g (0.25mol) of calcium hydroxide (analytically pure) are added into 2300mL of water, the mixture is heated for 18min at 60 ℃ to obtain a clear solution, then 2300mL of acetone is added while the temperature is kept at 60 ℃, the heating is stopped, the mixture is naturally cooled to 50 ℃, the mixture is kept at 50 ℃ for 2 hours, the temperature is naturally cooled to 20 ℃, the mixture is crystallized for 48 hours, the mixture is filtered, a filter cake is dried in vacuum at room temperature overnight, and 187.9g of a uniform and stable 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate single crystal is obtained. Yield 71.5% and content 99.95% (HPLC, fig. 7).
The single crystals of 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate prepared according to the method of experimental example 3 above had the crystal structure and characteristics shown in fig. 1, 3 and 5, and the content shown in fig. 7.
Experimental example 4:
207.5g (0.5mol) of 14-dehydroxy-13-dehydroandrographolide-12-sulfonic acid (with the content of 97.1 percent) and 18.5g (0.25mol) of calcium hydroxide (analytically pure) are added into 2450mL of water, the mixture is heated for 18min at 60 ℃ to obtain a clear solution, then, acetone with the volume of 2450mL is added while the temperature is kept at 60 ℃, the heating is stopped, the temperature is naturally reduced to 50 ℃, the mixture is kept at 50 ℃ for 2 hours, the temperature is naturally reduced to 20 ℃, crystallization is carried out for 45 hours, filtering is carried out, a filter cake is dried overnight under vacuum at room temperature, and 185.2g of a uniform and stable 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate single crystal is obtained. Yield 70.5% and content 99.95% (HPLC, fig. 7).
The single crystals of 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate prepared according to the method of experimental example 4 above have the crystal structures and characteristics shown in fig. 1, 3 and 5, and the content is shown in fig. 7.
The single crystal of 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate, the preparation method and the application thereof disclosed and proposed in the present invention can be realized by those skilled in the art by referring to the contents herein and 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 realized 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 (8)
1. A single crystal of 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate is characterized by having a chemical formula of C40H64CaO17S2.C3H6O.4(H2O), formula weight is 1051.3; the crystal structure is monoclinic system, space group is P1211,
α＝90°，β＝91.2637°，γ＝90°，
and Z is 4, and the chemical structure is as follows:
2. the single crystal of 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate according to claim 1, wherein the single crystal has characteristic peaks at 2 θ ° of 7.6 ± 0.1, 13.5 ± 0.1, 14.7 ± 0.1, 19.4 ± 0.1, 19.9 ± 0.1, and 23.7 ± 0.1 in terms of X-ray powder diffraction, wherein the relative intensity of the characteristic peaks at 13.5 ± 0.1 is 100%.
3. The single crystal of 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate according to claim 1, wherein the TG-DSC pattern of the single crystal shows characteristic endothermic peaks at 67 ± 5 ℃ and 263 ± 5 ℃.
4. The single crystal of 14-dehydroxy-13-dehydroandrographolide-12-calcium sulphonate acetone solvate according to any one of claims 1 to 3, having a single crystal content of > 99.9% by high pressure liquid phase analysis (HPLC).
5. A method for preparing a single crystal of 14-dehydroxy-13-dehydroandrographolide-12-calcium-sulfonate-acetone solvate according to claims 1 to 4, which is carried out by: mixing 14-dehydroxy-13-dehydroandrographolide-12-sulfonic acid and calcium hydroxide according to the weight ratio of 2: 1 substance, adding the mixture into water, heating the water to 60 ℃ to dissolve the mixture to obtain a clear solution, keeping the temperature at 60 ℃, adding acetone with the same volume as that of the water, after adding the acetone, performing gradient cooling, crystallization, filtration and vacuum drying at room temperature overnight to obtain the 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate monocrystal.
6. The method for preparing a single crystal of 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate according to claim 5, wherein the selection of gradient cooling is as follows: heating at 60 ℃ to react to obtain a clear solution, naturally cooling to 50 ℃, keeping at 50 ℃ 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-calcium sulfonate acetone solvate monocrystal.
7. Use of single crystals of 14-dehydroxy-13-dehydroandrographolide-12-calcium sulphonate acetone solvate according to any of claims 1 to 4 for the preparation of high purity sodium 14-dehydroxy-13-dehydroandrographolide-12-sulphonate.
8. The use of a single crystal of 14-dehydroxy-13-dehydroandrographolide-12-sulfonate calcium acetone solvate according to claim 7, wherein the sodium 14-dehydroxy-13-dehydroandrographolide-12-sulfonate is prepared by the following method: neutralizing the 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate with concentrated hydrochloric acid, crystallizing, separating to obtain 14-dehydroxy-13-dehydroandrographolide-12-sulfonic acid, and salifying with NaOH to obtain 14-dehydroxy-13-dehydroandrographolide-12-sodium sulfonate.
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